cochrane alendronate, risendronate systematic review

Alendronate for the primary and secondary prevention of

osteoporotic fractures in postmenopausal women (Review)

Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Welch V, Coyle D, Tugwell P

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2011, Issue 9

http://www.thecochranelibrary.com

Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

13RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Figure 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Figure 10. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Figure 11. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Figure 12. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Figure 13. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Figure 14. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Figure 15. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Figure 16. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Figure 17. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Figure 18. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Figure 19. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Figure 20. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Figure 21. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Figure 22. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

31DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 23. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

35AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

35ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

35REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

42CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

57DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

59ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

68FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

72WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

72HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

72CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

72DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

73SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

73INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iAlendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)


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[Intervention Review]

Alendronate for the primary and secondary prevention ofosteoporotic fractures in postmenopausal women

George A Wells1, Ann Cranney2, Joan Peterson3, Michel Boucher4, Beverley Shea5, Vivian Welch6, Doug Coyle7, Peter Tugwell8

1Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Canada. 2Division of Rheumatology, Ottawa

Hospital, Ottawa, Canada. 3Clinical Epidemiology Unit, Ottawa Civic Hospital / Loeb Research Institute, Ottawa, Canada. 4HTA

Development Canadian Agency for Drugs and Technologies in Health (CADTH), Ottawa, Canada. 5CIET, Institute of Population

Health, University of Ottawa, Ottawa, Canada. 6Centre for Global Health, Institute of Population Health, University of Ottawa,

Ottawa, Canada. 7Epidemiology and Community Medicine, Ottawa Health Research Institute, Ottawa, Canada. 8Department of

Medicine, University of Ottawa, Ottawa, Canada

Contact address: George A Wells, Department of Epidemiology and Community Medicine, University of Ottawa, Room H1-1, 40

Ruskin Street, Ottawa, Ontario, K1Y 4W7, Canada. [email protected].

Editorial group: Cochrane Musculoskeletal Group.

Publication status and date: Edited (no change to conclusions), comment added to review, published in Issue 9, 2011.

Review content assessed as up-to-date: 13 November 2007.

Citation: Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Welch V, Coyle D, Tugwell P. Alendronate for the primary and

secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database of Systematic Reviews 2008, Issue 1. Art.

No.: CD001155. DOI: 10.1002/14651858.CD001155.pub2.


A B S T R A C T

Background

Osteoporosis is an abnormal reduction in bone mass and bone deterioration leading to increased fracture risk. Alendronate belongs to

the bisphosphonate class of drugs, which act to inhibit bone resorption by interfering with the activity of osteoclasts.

Objectives

To assess the efficacy of alendronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women.

Search strategy

We searched CENTRAL, MEDLINE and EMBASE for relevant randomized controlled trials published between 1966 to 2007.

Selection criteria

Women receiving at least one year of alendronate, for postmenopausal osteoporosis, were compared to those receiving placebo and/or

concurrent calcium/vitamin D. The outcome was fracture incidence.

Data collection and analysis

We undertook study selection and data abstraction in duplicate. We performed meta-analysis of fracture outcomes using relative risks

and a > 15% relative change was considered clinically important. We assessed study quality through reporting of allocation concealment,

blinding and withdrawals.

1Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)


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mailto:[email protected]

Main results

Eleven trials representing 12,068 women were included in the review.

Relative (RRR) and absolute (ARR) risk reductions for the 10 mg dose were as follows. For vertebral fractures, a significant 45% RRR

was found (RR 0.55, 95% CI 0.45 to 0.67). This was significant for both primary prevention, with 45% RRR (RR 0.55, 95% CI 0.38

to 0.80) and 2% ARR, and secondary prevention with 45% RRR (RR 0.55, 95% CI 0.43 to 0.69) and 6% ARR. For non-vertebral

fractures, a significant 16% RRR was found (RR 0.84, 95% CI 0.74 to 0.94). This was significant for secondary prevention, with 23%

RRR (RR 0.77, 95% CI 0.64 to 0.92) and 2% ARR, but not for primary prevention (RR 0.89, 95% CI 0.76 to 1.04). There was a

significant 40% RRR in hip fractures (RR 0.60, 95% CI 0.40 to 0.92), but only secondary prevention was significant with 53% RRR

(RR 0.47, 95% CI 0.26 to 0.85) and 1% ARR. The only significance found for wrist was in secondary prevention, with a 50% RRR

(RR 0.50 95% CI 0.34 to 0.73) and 2% ARR.

For adverse events, we found no statistically significant differences in any included study. However, observational data raise concerns

regarding potential risk for upper gastrointestinal injury and, less commonly, osteonecrosis of the jaw.

Authors’ conclusions

At 10 mg per day, both clinically important and statistically significant reductions in vertebral, non-vertebral, hip and wrist fractures

were observed for secondary prevention (’gold’ level evidence, www.cochranemsk.org). We found no statistically significant results for

primary prevention, with the exception of vertebral fractures, for which the reduction was clinically important (’gold’ level evidence).

P L A I N L A N G U A G E S U M M A R Y

Alendronate for preventing fractures caused by osteoporosis in postmenopausal women

This summary of a Cochrane review presents what we know from research about the effect of alendronate for preventing fractures

(broken bones) caused by osteoporosis.

In women who have already been diagnosed with low bone density, putting them at risk for a fracture, or have already had a

fracture in the bones of their spine, alendronate:

- may prevent fractures in the spine, hip or wrist, or in bones other than the spine.

In women whose bone density is closer to normal, or who may not yet have had a fracture in the bones of their spine, alendronate:

- probably prevents fractures in the spine

- probably leads to no difference in fractures of the hip, wrist or bones other than the spine.

We often do not have precise information about side effects and complications. This is particularly true for rare but serious side effects.

Possible side effects may include digestive problems such as injury to the throat, esophagus and stomach and, less commonly, reduced

blood supply to the jaw bone, which causes the bone tissue to break down.

What is osteoporosis and what is alendronate?

Bone is a living, growing part of your body. Throughout your lifetime, new bone cells grow and old bone cells break down to make

room for the new, stronger bone. When you have osteoporosis, the old bone breaks down faster than the new bone can replace it. As

this happens, the bones lose minerals (such as calcium). This makes bones weaker and more likely to break even after a minor injury,

like a little bump or fall. Women are more likely to get osteoporosis after menopause.

Alendronate belongs to the class of drugs called bisphosphonates. It is a type of medication that slows down the cells that break down

the old bone.



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The best estimate of what happens to women that have already been diagnosed with low bone density or have already had a

fracture in the bones of their spine:

Fracture of the spine

- 12 out of 100 women had a fracture when taking a placebo

- 6 out of 100 women had a fracture when taking alendronate

Fracture in the hip or wrist



Fractures in bones other than the spine



The best estimate of what happens to women whose bone density is closer to normal or who may not yet have had a fracture

in the bones of their spine:




Fractures in bones other than the spine:

- 1 out of 100 women had a hip fracture when taking a placebo

- 1 out of 100 women had a hip fracture when taking alendronate

- 3 out of 100 women had a wrist fracture when taking a placebo

- 4 out of 100 women had a wrist fracture when taking alendronate

- 13 out of 100 women had a fracture somewhere other than the spine when taking a placebo

- 12 out of 100 women had a fracture somewhere other than the spine when taking alendronate

B A C K G R O U N D

Osteoporosis is in part a natural consequence of aging in post-

menopausal women (Hodsman 2002). It is a skeletal disorder char-

acterized by decreased bone mass, and deterioration in microar-

chitecture of bone resulting in an increased risk of fracture (NIH

Consensus 2001).

The most common consequences of osteoporosis are fractures of

the hip, wrist and vertebrae (Hodsman 2002). “Bone strength

reflects the integration of two main features: bone density and

bone quality” (Brown 2002). The clinical indicator of bone quality

is a patient’s history of a fragility fracture. A fragility fracture is a

fracture caused by an injury that would be insufficient to fracture

normal bone (e.g. a fall from a standing height or less)(Brown

2002). The preferred method of evaluating bone density is the

measurement of bone mineral density (BMD) of the spine and

hip by Dual Energy X-ray Absorptiometry (DXA), which can be

used to assess response to therapy (Hanley 2003).

The interpretation of BMD results is based on comparison of a



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patient’s BMD with the mean value for a young adult population.

The “T-score” is the number of standard deviations (SDs) above

or below the mean BMD for normal young adults (Brown 2002).

The World Health Organization (WHO) Study Group on Os-

teoporosis defined osteoporosis as “a hip BMD level of more than

2.5 SDs below the mean BMD for young, white, adult women”

(WHO 1994). Using the WHO definition, approximately 30%

of postmenopausal women have osteoporosis (Kanis 1994; WHO

1994). It should be noted that there are limitations associated with

the WHO definition. The predictive value of BMD measurement

for fracture varies depending on the site selected, database used

for comparison and the technology used. Furthermore, T-scores

do not provide a good basis to establish comparable diagnostic

thresholds between different regions of interest and different bone

mass measurement techniques (Black 2001). As a result, between-

site and technique variability introduces potential for misclassifi-

cation and inappropriate treatment of some individuals.

Osteoporosis can be detected by BMD measurement or diagnosed

by presence of osteoporosis-related fractures. The presence of pre-

existing osteoporotic fractures is an important risk factor for future

fractures (Hodsman 2002). It is reported that 25% of women

aged 80 have had at least one vertebral fracture (Melton 1989).

Cauley 2000 demonstrated excess mortality in women who have

experienced a clinical vertebral fracture. The cumulative lifetime

fracture risk for a 50-year-old woman with osteoporosis is stated to

be as high as 60% (Cummings 1989). As a result, effective fracture

prevention would have a major impact on morbidity and a smaller

but important impact on mortality in these women.

Osteoporosis-related morbidity is associated with significant med-

ical and social consequences (Brown 2002). The major source of

morbidity and mortality from osteoporosis is attributed to hip

fractures. Hip fractures are not only associated with an increased

mortality risk, but also influence long-term function and indepen-

dence. Fifty percent of women who sustain a hip fracture do not

return to their previous functional state and become dependent

on others for their daily activities (Brown 2002). The mortality

associated with hip fractures in older women may be as high as

20% in the first year (Cauley 2000). This excess mortality may

not be directly attributable to the hip fracture, but to comorbid

conditions (Browner 1996; Cooper 1993).

Prevention and treatment of osteoporosis can be complex, due to

the multifactorial etiology of the disorder. Anabolic therapies di-

rected at increasing bone formation, such as teriparatide (recombi-

nant human parathyroid hormone (1-34))(Shukla 2003) are avail-

able and very expensive; however, most currently available osteo-

porosis drugs are anti-resorptive agents that act to decrease bone

turnover. Anti-resorptive drugs include the bisphosphonates (e.g.

etidronate, alendronate and risedronate). They are recommended

as first-line preventive agents in postmenopausal women with low

BMD, and as first-line agents for the treatment of postmenopausal

women with osteoporosis (Brown 2002).

Bisphosphonates are stable analogues of naturally occurring py-

rophosphates. The mechanism of action of these drugs is to in-

hibit bone resorption through their effects on osteoclast function

(Brown 2002). Bisphosphonates are poorly absorbed and avidly

taken up by bone on active sites of resorption. Alendronate is a sec-

ond generation nitrogen containing bisphosphonate which is ad-

ministered daily or once weekly (depending on formulation) and

does not impair bone mineralization at doses that maximally in-

hibit bone resorption (Rodan 1993). The recommended doses for

the prevention and treatment of osteoporosis in postmenopausal

women are 5 mg/day (35 mg/week) or 10 mg/day (70 mg/week).

Alendronate at 10 mg/day or greater, relative to control, has been

shown to increase bone mineral density by 7.48% (95% CI, 6.12

to 8.85) after two to three years of treatment in the lumbar spine;

5.60% (95%CI, 4.80 to 6.39) after three to for years in the hip

and 2.08% (95% CI, 1.53 to 2.63) after two to four years in the

forearm (Cranney 2002). At 5 mg/day, bone mineral density was

increased by 5.81% (95% CI, 4.32 to 6.29) after two to three

years in the spine, 4.64% (95%CI, 4.27 to 5.01) after three to

four years in the hip and 1.83% (95% CI, 1.47 to 2.20) after three

to four years in the forearm. (Cranney 2002).

O B J E C T I V E S

The aim of this systematic review was to assess the clinical effi-

cacy of alendronate in the primary and secondary prevention of

osteoporotic fractures in postmenopausal women receiving these

agents, compared with untreated women over a follow-up period

of at least one year.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs) with a duration of at least

one year were included in this review.

Types of participants

We included only post-menopausal women, and accepted both

primary and secondary prevention trials. A hierarchy was used

to define primary versus secondary prevention according to the

information available. We selected a definition of primary and

secondary prevention that gave more weight to study inclusion

criteria, than baseline statistics. That is, if the inclusion criteria

restricted the population to women whose bone density was at least

2 SD values below the peak bone mass, or the inclusion criteria



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restricted the population to women who had experienced previous

vertebral compression fractures, then the trial was considered a

secondary prevention study. If such inclusion criteria were not

provided, then the baseline statistics were considered as follows: (a)

we considered the trial as primary prevention if the average T-score

(and SD) was such that it included women whose bone density

was within 2 SD of the mean, or if the prevalence of vertebral

fracture at baseline was less than 20%; and (b) when these data

were not available, we considered a trial as secondary prevention

if the average age was above 62 years.

Types of interventions

Treatment: Alendronate at any dose.

Comparators: No treatment (including placebo or calcium and/or

vitamin D). If the study used calcium and/or vitamin D controls,

these same treatments would have to be given concurrently in the

alendronate treatment groups.

Types of outcome measures

Incidence of fractures, including vertebral, non-vertebral, hip and

wrist fractures.

Search methods for identification of studies

The Cochrane Collaborative approach for identifying random-

ized controlled trials (RCTs) as described by Dickersin 1994, and

modified for the Cochrane Musculoskeletal Group, guided our

literature search. We searched the Cochrane Central Register of

Controlled Trials (CENTRAL), MEDLINE® (1966 to Novem-

ber 2004), Current Contents® and citations of relevant articles.

No language restrictions were applied to the search strategy. The

actual literature search was conducted in three stages. The first

stage was the basis for our systematic review published in 2002

(Cranney 2002) and the second and third stages involved updat-

ing the search. The first search, for the period 1966-99, included

CENTRAL, MEDLINE®, EMBASE® and Current Contents®.

This was followed by a MEDLINE® search for the time period

1999-November 2004. This MEDLINE search was confirmed by

a parallel literature search that was conducted for a companion

bisphosphonate economic report (CADTH 2006). For the final

update (2004 - February 2007), we searched CENTRAL, MED-

LINE and EMBASE.

Literature search for MEDLINE using OVID interface

1. osteoporosis, postmenopausal/

2. osteoporosis/

3. osteoporosis.tw.

4. exp bone density/

5. bone loss$.tw.

6. (bone adj2 densit$).tw.

7. or/2-6

8. menopause/

9. post-menopaus$.tw.

10. postmenopaus$.tw.

11. or/8-10

12. 7 and 11

13. 1 or 12

14. alendronate/

15. alendronate.tw,rn.

16. fosamax.tw.

17. aminohydroxybutane bisphosphonate.tw.

18. or/14-17

19. 13 and 18

20. meta-analysis.pt,sh.

21. (meta-anal: or metaanal:).tw.

22. (quantitativ: review: or quantitativ: overview:).tw.

23. (methodologic: review: or methodologic: overview:).tw.

24. (systematic: review: or systematic: overview).tw.

25. review.pt. and medline.tw.

26. or/20-25

27. 19 and 26

28. clinical trial.pt.

29. randomized controlled trial.pt.

30. tu.fs.

31. dt.fs.

32. random$.tw.

33. (double adj blind$).tw.

34. placebo$.tw.

35. or/28-34

36. 19 and 35


Selection of studies

Two reviewers examined each title generated from the search and

identified potentially eligible articles, for which we obtained the

abstracts. For abstracts consistent with study eligibility, the full

article text was obtained. Overall, we only considered for inclusion

studies for which findings were published, either as full article or

abstract.

Data abstraction strategy

Two independent reviewers abstracted all information and data

using standardized data abstraction forms, with a third reviewer

verifying the data. Abstraction included information on pertinent

methodological aspects of the study design, characteristics of the

participants, the specific dose of the study drug used and the out-

comes assessed (e.g. number of vertebral, non-vertebral, hip and

wrist fractures). For fracture data, we considered all reported frac-

tures (whether clinical or radiographic).

For the yearly data, our unit of analysis was number of patients

sustaining a fracture. If an article reported yearly data, we used

the time points available. For baseline denominators, we used the



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same baseline denominator for each time point. For follow-up

denominators, we used any yearly follow-up number of patients

reported in the article, if available. If these were not available,

we assumed a uniform drop-out rate for each year and calculated

the denominators by determining the proportion of subjects that

would have remained at the end of the year in question based

on the number of withdrawals over the course of the study. If

an article reported only end of study outcomes, these were used

for our analysis with the exception of outcomes for which the

numerator was zero for both treatment groups. In these instances,

we included the outcome (with any necessary adjustments for

follow-up denominators) for the earlier years in the duration of the

study. For example, if a trial reported zero hip fractures for both

treatment arms at the end of year three, we would also include in

our analysis zero hip fractures for that trial at years one and two.

For person year data, the unit of analysis, if available, was number

of fractures. When these data were not available (i.e. in the major-

ity of cases), we used the number of women sustaining a fracture.

For denominators, we multiplied the number of women followed

by the length of the study. For radiographic vertebral fractures, we

used the number of women with available radiographs, if the num-

ber was reported in the article. For clinical fractures, we estimated

the number of women followed over the duration of the study by

taking the mean of the baseline and follow-up denominators.

Strategy for quality assessment

Two reviewers assessed each eligible RCT for quality based on

allocation concealment. Research has shown that lack of adequate

allocation concealment is associated with bias (Higgins 2005), and

studies can be judged on the method of allocation concealment.

The method for assigning participants to interventions should be

robust against patient and clinician bias, and its description should

be clear. The reviewers were required to indicate whether allocation

concealment was adequate (A), unclear (B), or inadequate (C) as

per The Cochrane Collaboration criteria as follows.

Adequate: The following are some approaches that can be used to

ensure adequate concealment schemes: centralized or pharmacy-

controlled randomization, pre-numbered or coded identical con-

tainers which are administered serially to participants; on-site com-

puter system combined with allocations kept in a locked unread-

able computer file that can be accessed only after the characteris-

tics of an enrolled participant have been entered or sequentially

numbered; or sealed, opaque envelopes. Other approaches may

include those similar to ones listed previously, along with reassur-

ance that the person who generated the allocation scheme did not

administer it.

Inadequate: Approaches to allocation concealment that are con-

sidered inadequate include: alternation, use of case record num-

bers, dates of birth or day of the week and any procedure that is

entirely transparent before allocation, such as an open list of ran-

dom numbers.

Unclear: When studies do not report any concealment approach,

adequacy should be considered unclear. Examples include merely

stating that a list or table was used, only specifying that sealed en-

velopes were used and reporting an apparently adequate conceal-

ment scheme in combination with other information that leads

the reviewer to be suspicious.

In addition, blinding and loss to follow-up were assessed.

Data analysis

For the analysis of fractures (i.e. vertebral, non-vertebral, hip and

wrist), the relative risk (RR) of fracture was calculated. The meth-

ods we used for pooling the results are described elsewhere (Fleiss

1993). The pooled or weighted RRs, using the general inverse vari-

ance method for the weights were calculated. For the pooled re-

sults, site-specific 95% confidence intervals (CIs) were calculated

for vertebral, non-vertebral, hip and wrist fractures, and we tested

for association using a chi-square test procedure, taking P value

< 0.05 for presence of statistical association. Statistically signifi-

cant risk reductions were considered to be clinically important if

a 15% or greater relative benefit was shown. We also tested for

homogeneity using a chi-square test procedure, taking the specific

cut-off for presence of statistical heterogeneity as P value = 0.10 (

Fleiss 1993). In the event of significant heterogeneity, a random-

effects model was used.

If the relative risk reduction (RRR) was significant (P value <

0.05), then the absolute risk reduction (ARR) and number needed

to treat (NNT) were calculated. For these calculations, we based

the five-year risk of fracture in the untreated population on the

FRACTURE Index (FI)(Black 2001), and the lifetime and five-

year age-specific risks in the untreated population on the model by

Doherty et al. (Doherty 2001) for predicting osteoporotic fractures

in postmenopausal women (Figure 1; Figure 2; Figure 3; Figure

4).



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Figure 1. Models for fracture risk in postmenopausal women: FRACTURE Index



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Figure 2. Five year risk of fracture by Quintiles of the FRACTURE Index: Assessment with bone mineral

density

Figure 3. Five year risk of fracture by Quintiles of the FRACTURE Index: Assessment without bone mineral

density



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Figure 4. Estimated five year age-specific risks of first and subsequent osteoporotic fractures (from Doherty

et al 2001)

Trials varied as to the length of treatment (e.g. one to four years)

and the number of patients available for study at the start of treat-

ment (i.e. baseline denominator) compared to those available at

different time points during the trial (i.e. follow-up denomina-

tors). The base case taken for the review of fractures considered

the data available for the longest period of time for the treatment

in the trial (i.e. “all years”) and used the baseline denominators for

the number of patients in the trial.

Data was initially pooled broadly across primary and secondary

trials. The overall analysis was also considered using person-years

of observation. In addition, we conducted subgroup analysis for:

1) primary versus secondary, 2) treatment duration and 3) treat-

ment dose. Furthermore, we conducted sensitivity analysis for:

1) baseline denominators versus follow-up denominators, 2) fixed

versus random effects model and 3) baseline vertebral fracture rate.

For the last sensitivity analysis, recall that the vertebral fracture

criteria for a trial to be considered secondary was a prevalence of

vertebral fracture at baseline of greater than 20%. A sensitivity

analysis using different vertebral fracture rates (i.e. 100%, > 80%,

> 60%, > 40%, > 20%) without the BMD and age criteria was

conducted. Such sensitivity analysis allowed evaluating whether

the effect of bisphosphonates on the secondary prevention of os-

teoporotic fractures varied, depending on how strictly secondary

prevention was defined.

Grading of evidence

We graded results for the primary analyses using the system de-

scribed in Evidence-based Rheumatology (Tugwell 2004), as recom-

mended by the Musculoskeletal Group.

Platinum:

To achieve the platinum level of evidence, a published systematic

review that has at least two randomized controlled trials each sat-

isfying the following is required:

- sample sizes of at least 50 per group - if these do not find a

statistically significant difference, they are adequately powered for

a 20% relative difference in the relevant outcome;

- blinding of patients and assessors for outcomes;

- handling of withdrawals > 80% follow up (imputations based on

methods such as Last Observation Carried Forward (LOCF) are

acceptable);

- concealment of treatment allocation.

Gold:

The gold level of evidence requires at least one randomized clinical

trial meeting all of the following criteria for the major outcome(s)

as reported:

- sample sizes of at least 50 per group - if they do not find a

statistically significant difference, they are adequately powered for

a 20% relative difference in the relevant outcome;

- blinding of patients and assessors for outcomes;

- handling of withdrawals > 80% follow up (imputations based on

methods such as LOCF are acceptable);

- concealment of treatment allocation.

Silver:

The silver level of evidence requires a randomized trial that does



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not meet the above criteria for gold or platinum ranking, or ev-

idence from at least one study of non-randomized cohorts that

did and did not receive the therapy, or evidence from at least one

high-quality case-control study. A randomized trial with a ’head-

to-head’ comparison of agents would be considered silver level

ranking unless a reference were provided to a comparison of one

of the agents to placebo showing at least a 20% relative difference.

Bronze:

The bronze level of evidence requires at least one high-quality case

series without controls (including simple before/after studies in

which patients act as their own control) or a conclusion derived

from expert opinion based on clinical experience without reference

to any of the foregoing (for example, argument from physiology,

bench research or first principles).

Clinical relevance tables

Clinical relevance tables were compiled under “additional tables”

to improve the readability of the review. Results were presented

within the context of both the study population and moder-

ate-/high-risk women from the population at large. The num-

ber needed to treat (NNT) was calculated using the relative risk

(RR) in combination with either the risk of fracture in the control

group, or the five-year FRACTURE Index (Black 2001). To do

this, the Visual Rx NNT calculator (Cates 2004) was used. The

weighted absolute risk difference was calculated using the risk dif-

ference (RD) statistic in RevMan and RR-1 was used to calculate

the relative percent change (Table 1; Table 2).

In addition, for the outcomes of vertebral and hip fractures we

prepared Summary of Findings tables using the GRADE criteria

from the GRADE working group (GRADE 2004), (Figure 5;

Figure 6).



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Figure 5. Summary of Findings for Primary Prevention



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Figure 6. Summary of Findings for Secondary Prevention



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R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies.

Quantity of research available

The literature search revealed 1203 citations as depicted in Figure

7. Of these, 85 articles were retrieved for further review. A total of

74 articles were excluded for various reasons, including lack of ap-

propriate control group (19)(Black 2003; Body 2002; Chailurkit

2003; Davas 2003; Evio 2004; Iwamoto 2004; Kushida 2004;

Luckey 2004; Palomba 2002; Rittmaster 2000; Rizzoli 2002;

Rozkydal 2003; Sahota 2000; Sambrook 2004a; Schnitzer 2000;

Simon 2002; Sosa 2002; Tiras 2000; Vasikaran 1995); lack of

fracture outcome (25)(Aki 2003; Boivin 2000; Bouxsein 1999;

Chailurkit 2003; Chavassieux 1997; Cummings 2000; Dobnig

2006; Gonnelli 2002; Ho 2005; Johnell 2002; Kung 2000; Lau

2000; McClung 1998; Nenonen 2005; Ravn 1999a; Ravn 1999b;

Rhee 2006; Rossini 2000; Schneider 1999; Stepan 1999; Tutuncu

2005; Uusi-Rasi 2003; van der Poest 2000; Yen 2000; Yildirim

2005); lack of appropriate fracture data (i.e. reported as adverse

events or unspecified)(8), (Adami 1995; Bell 2002; Bone 2000;

Bonnick 1998; Downs 2000; Greenspan 2003; Hosking 2003;

Murphy 2001); lack of randomization (2), (Heijckmann 2002;

Sawka 2003); extension/discontinuation studies (6)(Bone 2004;

Greenspan 2002a; McClung 2004; Ravn 1999c; Ravn 2000;

Sambrook 2004b); duplicate report or earlier report of another

study (7)(Adami 1993; Bettembuk 1999; Black 2000; Devogelaer

1996; Hochberg 1999; Seeman 1999; Tucci 1996); duration

of therapy less than one year (7)(Cheng 2002; Chesnut 1993;

Greenspan 2002b; Harris 1993; Malavolta 1999; Payer 2000;

Rossini 1994). If we found duplicate reports of the same study in

preliminary abstracts and articles, we analyzed the data from the

most complete data set. In total, 11 trials met the selection criteria

for inclusion in this report (Ascott Evans 2003, Black 1996; Bone

1997; Chestnut 1995; Cummings 1998; Durson 2001; Greenspan

2002; Greenspan 1998; Hosking 1998; Liberman 1995; Pols

1999).



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Figure 7. Summary of literature search for alendronate



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Trial characteristics

The characteristics of the 11 selected trials are provided in the

’Characteristics of included studies’ table. A total of 12,068 women

were enrolled; of these, 5525 received placebo. Three trials were

in primary prevention (Ascott Evans 2003; Cummings 1998;

Hosking 1998), and the other eight involved women with low

BMD on densitometry and/or high prevalence of vertebral frac-

ture (Black 1996; Bone 1997; Chestnut 1995; Durson 2001;

Greenspan 2002; Greenspan 1998; Liberman 1995; Pols 1999).

Three trials (including the largest secondary prevention trial--the

Fracture Intervention Trial or FIT), used an initial dose of 5 mg and

then switched to 10 mg for the final years (Black 1996; Cummings

1998; Greenspan 1998). Two trials (Bone 1997; Hosking 1998)

evaluated only doses of 5 mg or less, four trials (Ascott Evans 2003;

Durson 2001; Greenspan 2002; Pols 1999) used only the 10 mg

dose and two trials (Chestnut 1995; Liberman 1995) evaluated 5,

10 and 20 mg doses. For some endpoints, studies which admin-

istered both 5 and 10 mg did not report the results separately by

dose (Black 1996; Cummings 1998; Greenspan 1998; Liberman

1995 ). To err on the conservative side, these endpoints were in-

cluded in the 10 mg analysis.

Length of follow up ranged from one to four years, and mean age

was 53 to 78 years. Eight trials excluded women with a history of

gastrointestinal disease (Black 1996; Bone 1997; Cummings 1998;

Durson 2001; Greenspan 2002; Hosking 1998; Liberman 1995;

Pols 1999) and three trials evaluated fractures as the stated primary

outcome (Black 1996; Cummings 1998; Durson 2001). All trials

administered at least 500 mg of calcium to all patients and vitamin

D, at daily doses ranging from 125-400 IU, was administered

in four trials (Black 1996; Cummings 1998; Greenspan 2002;

Greenspan 1998). We did not include data from the HRT arm of

the Hosking et al trial (Hosking 1998).

Risk of bias in included studies

Four trials concealed allocation (Black 1996; Bone 1997;

Cummings 1998; Hosking 1998) and for the remainder it was

unclear. Two trials achieved a loss to follow up of less than 5%

(Black 1996; Cummings 1998); five trials had losses to follow up

from 5% to 20% (Ascott Evans 2003; Chestnut 1995; Hosking

1998; Liberman 1995; Pols 1999); three trials had losses to follow

up over 20% (Bone 1997; Durson 2001; Greenspan 1998) and

one trial did not report losses to follow up (Greenspan 2002). All

studies but one were double blind (Durson 2001).

Effects of interventions

Effect on fractures

A summary of the overall review of fractures for the base case (i.e.

the longest treatment duration and use of the baseline denomina-

tors for the number of patients in the trial) for the standard 10

mg dose of alendronate is provided in Figure 8. In general, for

vertebral, non-vertebral, hip and wrist fractures, the pooled esti-

mate of the RR was significant for secondary prevention but not

for primary prevention (with the exception of vertebral fractures).

Figure 8. Weighted relative risk (RR) of fracture after alendronate (10 mg)



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Vertebral fractures

Vertebral fractures were reported in eight of 11 trials (Ascott Evans

2003; Black 1996; Bone 1997; Hosking 1998; Chestnut 1995;

Cummings 1998; Durson 2001; Liberman 1995). In two trials, no

fractures occurred in either treatment group (Ascott Evans 2003;

Chestnut 1995) and two trials (Bone 1997; Hosking 1998) eval-

uated only the 5 mg dose The pooled estimate of RR of verte-

bral fractures from the four trials (Black 1996; Cummings 1998;

Durson 2001; Liberman 1995) that could be analyzed for the 10

mg dose demonstrated a reduction (45%) in vertebral fractures

(RR 0.55, 95%, CI 0.45 to 0.67). For details, please refer to Figure

8 and Comparison 01.01. This supports a fracture risk reduction

with alendronate and results were consistent across the four trials

(P = 0.61). There was a significant reduction in vertebral fractures

for both primary and secondary prevention trials. Estimates for

the risk reduction were similar for the primary (RR 0.55, 95%

CI, 0.38 to 0.80) and secondary (RR 0.55, 95% CI 0.43 to 0.69)

prevention trials.

Corresponding to the significant RRR of 45% for the primary

or secondary prevention of vertebral fractures, the absolute mea-

sures ARR and NNT of the 5-year risk of vertebral fracture after

treatment with alendronate were calculated for different levels of

increasing risk as given by the FI. Results are provided in Figure

9, as well as for increasing age in Figure 10. For the illustrative

case of the patient with a FI of 6-7, the ARR in vertebral fracture

was 3.2% (i.e. a reduction in risk from 7.1% to 3.9%) and the

NNT was 31 (i.e. 31 patients would need to be treated to avoid

one vertebral fracture). Across the range of increasing FI risk, the

ARR for vertebral fracture ranged from 0.5% to 5.0%, and the

NNT to avoid one vertebral fracture ranged from 200 to 20. For

the illustrative patient in the age group 60-64 years, the ARR for

the first vertebral fracture was 0.5% (i.e. a reduction in risk from

1.0% to 0.55%) and the NNT was 222 patients treated to avoid

the first fracture. The ARR for a subsequent fracture was 4.4%

(i.e. a reduction in risk from 9.7% to 5.3%) and the NNT was

23 patients treated to avoid one subsequent fracture. For increas-

ing age, the 5-year age-specific ARR for the first vertebral fracture

increased from 0.1% for the youngest age group (50-54 years) to

2.1% in the highest age group (90+ years). Accordingly, the NNT

decreased from 1111 to 47. For the subsequent fracture, ARR in-

creased from 0.2% to 12.6% and the NNT decreased from 444

to 8.



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Figure 9. Five year FRACTURE Index specific risk of fracture after alendronate (10 mg)



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Figure 10. Five year age-specific fisk of first and subsequent fracture after alendronate (10 mg)

Non-vertebral fractures

Non-vertebral fractures were reported in nine trials (Ascott Evans

2003; Black 1996; Bone 1997; Chestnut 1995; Cummings 1998,

Hosking 1998; Greenspan 1998; Liberman 1995; Pols 1999).

One trial did not report fractures separately by treatment groups

(Chestnut 1995); one trial reported that no fractures occurred in

either treatment group (Ascott Evans 2003) and two trials evalu-

ated only the 2.5 and 5 mg doses. (Bone 1997; Hosking 1998).

The pooled estimate of the RR of non-vertebral fractures from

the five trials (Black 1996; Cummings 1998; Greenspan 1998;

Liberman 1995; Pols 1999) that could be analyzed for the 10 mg

dose demonstrated a significant reduction (16%) in non-vertebral

fractures (RR: 0.84, 95% CI 0.74 to 0.94). Details can be found

in (Figure 8 and Comparison 02.01) and results were consistent

across the five trials (p = 0.29). Although the primary and sec-

ondary prevention trials differed in significance of the reduction in

risk of non-vertebral fractures, the non-significant reduction (RR

0.89, 95% CI 0.76 to 1.04) in the one primary was not clearly

different from the significant reduction (RR 0.77, 95% CI 0.64

to 0.92) in the four secondary prevention trials.

Corresponding to the significant RRR of 23% for the secondary

prevention of non-vertebral fractures, the absolute measures ARR

and NNT of the five-year risk of non-vertebral fracture after treat-

ment with alendronate were calculated for different levels of in-

creasing risk as measured by the FI (Figure 9) and for increasing age

(Figure 10). For the illustrative case of the patient with a FI of 6-

7, the ARR in non-vertebral fracture was 4.6% (i.e. a reduction in

risk from 19.8% to 15.2%) and the NNT was 22 (i.e. 22 patients

need to be treated to avoid one non-vertebral fracture). Across the

range of increasing FI risk, ARR for non-vertebral fracture ranged

from 2.0% to 6.3% and NNT to avoid one non-vertebral frac-

ture ranged from 50 to 16. For the illustrative patient in the age

group 60-64 years, the ARR for the first non-vertebral fracture


NNT was 140 patients treated to avoid the first fracture. The ARR



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for a subsequent fracture was 1.4% (i.e. a reduction in risk from

6.2% to 4.8%) and the NNT was 70 patients treated to avoid one

subsequent fracture. For increasing age, the five-year age-specific

ARR for the first non-vertebral fracture increased from 0.4% for

the youngest age group (50-54 years) to 8.1% in the highest age

group (90+ years) and the NNT decreased from 272 to 12. The

ARR for subsequent fracture increased from 0.6% to 8.7% and

the NNT decreased from 167 to 12.

Hip fractures

Hip fractures were reported in seven trials (Ascott Evans 2003;

Black 1996; Cummings 1998; Greenspan 2002; Greenspan 1998;

Liberman 1995; Pols 1999), with one trial reporting that no frac-

tures occurred in either treatment group (Ascott Evans 2003). The

pooled estimate of the RR of hip fractures from the six trials re-

sulted in a significant reduction (39%) in hip fractures (RR 0.61,

95% CI 0.40 to 0.92) as presented in (Figure 8 and Compari-

son 03.01). The results were consistent across the six trials (p =

0.84). The reduction in the risk of hip fractures for the one pri-

mary prevention trial (Cummings 1998) was not significant (RR

0.79, 95% CI 0.44 to 1.44) compared to the significant reduction

demonstrated by the five secondary prevention trials (RR 0.47,

95% CI 0.26 to 0.85).


prevention of hip fractures, the absolute measures: ARR and NNT

of the five-year risk of hip fracture after treatment with alendronate

were calculated for different levels of increasing risk as measured

by the FI. Results are provided in Figure 9 in addition to those for

increasing age in Figure 10. For the illustrative case of the patient

with a FI of 6-7, the ARR in hip fracture was 2.1% (i.e. a reduction

in risk from 3.9% to 1.8%) and the NNT was 48 (i.e. 48 patients

need to be treated to avoid one hip fracture). Across the range of

increasing FI risk, the ARR for hip fracture ranged from 0.2% to

4.6% and the NNT to avoid one hip fracture ranged from 500

to 22. For the illustrative patient in the age group 60-64 years,

the ARR for the first hip fracture was 0.1% (i.e. a reduction in

risk from 0.2% to 0.1%) and the NNT was 943 patients treated

to avoid the first fracture. The ARR for a subsequent fracture


NNT was 943 patients treated to avoid one subsequent fracture.

For increasing age, the five-year age-specific ARR for the first hip

fracture increased from less than 0.05% for the youngest age group

(50-54 years) to 11.1% in the highest age group (90+ years) and

the NNT decreased from more than 272 to 9. For the subsequent

fracture, the ARR increased from less than 0.05% to 12.1% and

the NNT decreased from more than 472 to 8.

Wrist fractures

Wrist fractures were reported in five trials (Black 1996; Cummings

1998; Greenspan 1998; Liberman 1995; Pols 1999) and one trial

(Ascott Evans 2003) reported that no fractures occurred in either

treatment group. Results were not consistent across the five trials

which reported wrist fractures (p = 0.0007)(Figure 11). The pooled

estimate of the RR of wrist fracture from these five trials resulted in

a non-significant reduction in fractures, either using the random

effects (RR 0.68, 95% CI 0.34 to 1.37)(Figure 8) or fixed effect

(RR 0.83, 95%CI 0.65, 1.05) approach. We also could not identify

a statistically significant effect of alendronate when used for the

primary prevention of wrist fractures (RR 1.19, 95%CI 0.87 to

1.62)(Figure 8 and Comparison 04.01). In the case of the four

secondary prevention trials, a statistically significant effect was

observed (RR 0.50, 95%CI 0.34 to 0.73).

Figure 11. Weighted relative risk of fracture after alendronate (10 mg) by years of treatment



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Additional analysis

Person years

Results were similar for vertebral, non-vertebral, hip and wrist

fractures when person years were used, as illustrated in Figure 12.

Notably, the pooled estimates of the RR for the secondary pre-

vention trials all showed a significant risk reduction of fracture for

all fractures sites. Due to lack of consistency among the trials, a

random-effects estimate was used for the pooled estimate for ver-

tebral fractures; however, for wrist fractures, there was no incon-

sistency among the secondary prevention trials. The risk estimates

obtained from the one primary prevention trial for vertebral frac-

ture remained significant although results were non-significant for

the other fracture sites.

Figure 12. Weighted relative risk (RR) of fracture after alendronate (10 mg): Person years

Subgroup analysis

Treatment duration

There were no trends over years of treatments that deviated from

the overall RR estimates (Figure 11 and Comparisons 05.01;

06.01; 07.01; 08.01; 09.01), with the possible exception of hip

fracture risk reduction being greater in later years.

Treatment dose

For the 5 mg dose of alendronate, fracture data were available for



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vertebral and non-vertebral sites for secondary prevention trials,

as well as non-vertebral for primary prevention. (Figure 13; Figure

14; Figure 15; Comparison 12.01) For vertebral fractures, the

decrease in risk of fracture was statistically significant and there

was a further slight decrease in risk with the 5 mg dose (RR 0.40,

95%CI 0.29 to 0.55), compared to 10 mg (RR 0.55, 95%CI 0.43

to 0.69). For non-vertebral fractures, no significant difference was

found.

Figure 13. Weighted relative risk of fractrue after alendronate by dose



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Figure 14. Weighted relative risk of fracture after alendronate by dose: Person years



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Figure 15. Weighted relative risk of fracture after alendronate by years of treatment and dose

Sensitivity analysis

Baseline versus follow-up denominators

By using the data available for longest treatment duration, standard

dose of alendronate (10 mg) and follow-up denominators for the

number of patients in the trials, a summary of the overall review

of fractures was prepared (Figure 16). These data are also provided

by years of treatment. (Figure 17). The pooled estimates of the

RR of fracture after alendronate were essentially the same as those

obtained using the baseline denominators.



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Figure 16. Weighted relative risk of fracture after alendronate by dose: Follow-up denominators



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Figure 17. Weighted relative risk of fracture after alendronate by years of treatment and dose: Follow-up

denominators

Random versus fixed effects model

There were a few instances where heterogeneity of the trial results

was such that a random-effects model was required. In general,

results obtained using the random- and fixed-effects models were

similar.

Baseline vertebral fracture rate

Using different baseline vertebral fracture rates (i.e. 100%, > 80%,



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> 60%, > 40%, > 20%) for defining secondary trials, a summary

of the overall review of fractures was prepared (Figure 18). For

vertebral fractures, the pooled estimates of the RR of fracture after

alendronate were essentially the same as those obtained using the

definition of secondary trials with the > 20% baseline fracture rate.

Although the result for non-vertebral and hip fractures became

non-significant when the criteria increased from > 20% to > 40%

and > 40% to > 60% respectively, the relative risk of fracture was

exactly the same but the confidence intervals were now slightly

wider with the exclusion of the study by Liberman et al (Liberman

1995) for non-vertebral fractures and Greenspan et al (Greenspan

2002) for hip fractures. For wrist fractures, the non-significant

result was now significant when a > 20% baseline fracture rate

was used (without the BMD and age criteria) since a fixed-effects

model could now be used.



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Figure 18. Weighted relative risk (RR) of fracture after alendronate (10 mg): sensitivity analysis by baseline

prevalent vertebral fracture rate



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Adverse events

A summary of the adverse drug events reported in the 11 random-

ized placebo-controlled trials of alendronate is provided in Figure

19, Figure 20, Figure 21 and Figure 22. In general, the reported

events were similar between alendronate and placebo. In partic-

ular, there were seven studies (Ascott Evans 2003; Black 1996;

Cummings 1998; Greenspan 1998; Greenspan 2002; Hosking

1998; Pols 1999) reporting ’any upper gastrointestinal events’ re-

sulting in an overall RR 1.03 (95% CI 0.98 to 1.08) and two stud-

ies (Black 1996; Cummings 1998) reporting ’esophageal ulcer’,

resulting in an overall RR 1.16 (95% CI 0.39 to 3.45).

Figure 19. Summary of adverse drug events reported in randomized placebo-controlled trials of

alendronate (part 1)



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Toxicity and withdrawals

Discontinuations due to adverse events or dropouts overall were

available and analyzed for six (Ascott Evans 2003; Black 1996;

Bone 1997; Cummings 1998; Durson 2001; Pols 1999) and five

(Ascott Evans 2003; Durson 2001; Greenspan 1998; Hosking

1998; Pols 1999) of the alendronate trials respectively. The pooled

estimate demonstrated no statistical difference between alen-

dronate and placebo for the risk of discontinuing medication due

to adverse events (RR 0.95, 95% CI 0.83 to 1.09) or for dropouts

overall (RR 1.10, 95% CI 0.94 to 1.29)(Comparison 13.01 and

13.02). Results were consistent across the trials.

D I S C U S S I O N

Summary of results

Based on the longest treatment duration and use of baseline de-

nominators for the number of patients in the included trials, the

main benefit of alendronate was found to be in the secondary pre-

vention of osteoporotic fractures. At a dose of 10 mg per day, al-

endronate results in a statistically significant and clinically impor-

tant reduction in vertebral, non-vertebral, hip and wrist fractures

(gold level evidence). We also found that the use of alendronate 10

mg per day for the primary prevention of osteoporotic fractures is

not associated with statistically significant reductions in risk, with

the exception of vertebral fractures for which the reduction was

clinically important (gold level evidence).

Secondary analyses showed that a dose of 5 mg, for secondary pre-

vention resulted in a statistically significant and clinically impor-

tant reduction in vertebral fractures that is comparable to that of

the 10 mg dose (RR 0.40, 95% CI 0.27 to 0.52 versus RR 0.55,

95% CI 0.43 to 0.69). It is worth noting that these results were

driven primarily by the large Black trial (Black 1996). In Black,

the 5 mg data represented the first two years of follow up of the

treatment group which was switched to 10 mg for the third year.

No trials were available to assess the effectiveness of the 5 mg dose

for the primary prevention of vertebral fractures. For non-verte-

bral fractures, no statistically significant reductions were shown for

primary or secondary prevention. There were no trials available to

assess the efficacy of the 5 mg dose for hip and wrist fractures.

There were no substantive differences in the results whether base-

line, end of study or person year denominators were used. Sensi-

tivity analyses indicated that there were no major differences based

on the percentage of baseline vertebral fractures. Further, no trends

were found for years of treatment.

Adverse drug events were similar between alendronate and placebo.

There were also no statistically significant difference in either the

rate of treatment discontinuation due to adverse events (RR 0.95,

95% CI 0.83 to 1.09) or the overall withdrawal rate (RR 1.10, 95%

CI 0.94 to 1.29), compared to placebo. Thus, it was concluded

that study participants tolerated their alendronate treatment. Al-

though no increased incidence of adverse effects was detected with

alendronate, external to the randomized controlled trials, concerns

exist regarding the potential risk of upper gastrointestinal events

and osteonecrosis of the jaw.

Study limitations

The results of this systematic review are believed to be robust, as

a comprehensive literature search was performed, inclusion and

exclusion criteria were specified and a rigorous data analysis was

conducted. A potential limitation of our approach may be that

the update search (i.e. 2000 to 2004) did not include non-MED-

LINE® indexed journals. Recent empirical evidence indicates that

this approach may have introduced a slight risk of bias into our

meta-analysis. On average, such bias is estimated to result in a

6% variation in the pooled results (Egger 2003; Sampson 2003).

Accordingly, given that the initial literature search (i.e. 1966 to

2000) was very extensive, the impact of only using MEDLINE®

for the search update is expected to be minimal, if any. This

was confirmed by a parallel literature search update (i.e. 1999

to July 2004) that was conducted for an economic report pub-

lished by The Canadian Agency for Drugs and Technologies in

Health (CADTH 2006). The search update included etidronate,

alendronate and risedronate (daily dose regimen only) in addi-

tion to teriparatide. A number of databases were searched (i.e.

the Cochrane Library, MEDLINE®, EMBASE®, BIOSIS Pre-

views®, Toxfile and PubMed) and no additional articles meeting

the inclusion criteria were identified.

While our methodology was robust, the results of our meta-anal-

ysis, however, are only as strong as the primary studies included.

In keeping with this, the main limitations with regard to study

quality were fracture assessment and classification, the lack of clar-

ity of the concealment of allocation and large losses to follow up

(primarily in the smaller studies).

A potential source of heterogeneity is the lack of uniform defini-

tion of non-vertebral fracture. While some researchers may use a

rather liberal definition (any fracture other than vertebral fracture),

others may use a more conservative definition which includes only

fractures of the hip, clavicle, humerus, wrist, pelvis or leg (Mayo

Clin Proc 2005). Another consideration is the fact that fracture

data was not the primary outcome for many of the trials. In par-



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ticular, three of the 11 alendronate trials (Black 1996; Cummings

1998; Durson 2001) had fractures as the primary outcome. There

is another source of heterogeneity, and possible bias, related to

some of the secondary prevention studies. It concerns the inclu-

sion of participants with a low BMD but no proven fractures, and

the difficulty in discriminating between fracture types (traumatic

versus pathological).

Another methodological limitation concerns the approach used

for concealment of treatment allocation which was not reported

for most trials. Four of the 11 trials (Black 1996; Bone 1997;

Cummings 1998; Hosking 1998) concealed allocation, and for

the remainder it was unclear.

An additional limitation is the length of follow up in the studies.

It is difficult to extrapolate beyond the duration of the follow-up

trials in the review with respect to the long-term impact on frac-

tures. Ultimately, data from longer-term trials will help establish

if the effect on fractures is maintained, increased or diminished.

In regards to our own methodology, we acknowledge that the ap-

proach used to evaluate the effect of bisphosphonates over time

may result in some estimates that are not robust. In particular,

in order to determine the effect on the five-year risk of fracture,

we based our evaluation on the FRACTURE Index by Black et

al (Black 2001), and for lifetime and five-year age-specific risks,

we used an existing model from Doherty et al (Doherty 2001).

Although this latter approach allowed us to estimate the variation

in risks between younger and older postmenopausal women, these

estimates may be associated with a certain level of uncertainty.

Nonetheless, we believe such information may be useful to deci-

sion-makers.

Lastly, a limitation of evaluating data on adverse effects from sum-

mary meta-analyses is that participants in RCTs tend to be health-

ier, with fewer co-morbid diseases, and therefore the results may

not be generalizable to clinical practice. For alendronate, eight

trials (Black 1996; Bone 1997; Cummings 1998; Durson 2001;

Greenspan 2002; Hosking 1998; Liberman 1995; Pols 1999) ex-

cluded patients with pre-existing gastrointestinal (GI) disorders.

Furthermore, RCTs are underpowered for rare effects and meta-

analyses of these trials generally cannot provide conclusive infor-

mation pertaining to drug toxicity. In addition, the heterogeneity

of the adverse drug effects (ADEs) reported in the RCTs described

in this review, including their nature, low occurrence and way they

were assessed by investigators, made these improper for meta-anal-

ysis. Although a number of trials reported composite endpoints

such as “any GI event”, as well as a number of individual GI events,

only the two largest trials (Black 1996; Cummings 1998), for ex-

ample, specifically reported esophageal ulcers (an endpoint of par-

ticular interest, for which there were no statistically significant dif-

ferences between treatment and control). As well, the follow up

for the included trials, which ranged between one and four years,

does not allow for the assessment of long-term toxicity associated

with alendronate.

Recently, there have been concerns regarding the potential risk of

over suppressing bone turnover resulting in osteonecrosis of the

jaw (ONJ)(Khosla 2007; Woo 2006). Although the majority of

reported cases of ONJ have occurred in cancer patients receiv-

ing the intravenous bisphosphonates zolendrate or pamidronate

(at higher cumulative doses than used in the treatment of post-

menopausal osteoporosis), some osteoporosis patients receiving

oral bisphosphonates have developed the condition as well. In a

systematic review of cases reported in the medical literature, 13

of 368 bisphosphonate treated ONJ patients had received alen-

dronate and one risedronate (Woo 2006). Since that publication,

a review conducted by the American Society for Bone and Min-

eral Research (ASBMR) Task Force on Bisphosphonate-Associ-

ated ONJ has identified studies reporting a total of 67 cases (64

alendronate, two risedronate and one etidronate) among osteo-

porosis and Paget’s disease patients (Khosla 2007). Most notably,

an Australian study reported 30 of 114 ONJ cases related to al-

endronate (22 of whom were under treatment for osteoporosis)

and two related to risedronate. The median time to onset, for al-

endronate, was 24 months. The most common triggering factor

was dental extraction (Mavrokokki 2007). The ASBMR task force

has pointed out that the incidence of ONJ in the general popu-

lation not exposed to bisphosphonates is unknown, information

on the incidence of ONJ is rapidly evolving and that ,often, the

case ascertainment has been inadequate . They recommend that

a hierarchy of evidence quality, based on the completeness of in-

formation across seven categories related to diagnosis and history,

should be established for all future studies reporting cases of ONJ

(Khosla 2007).

No cases of ONJ were explicitly reported in any of the alendronate

trials in our review. As well, a recent 10-year follow up of patients

from the Black and Cummings trials (The Fracture Intervention

Trial Long-term Extension (FLEX) reported that no cases were

observed among the 662 women who were continued on alen-

dronate at 5 or 10 mg for a total of 10 years or the 437 women

who were switched to placebo following five years of alendronate

treatment (Black 2006). No difference between treatment groups

were found for any other adverse events in FLEX.

Finally, because RCTs are not designed to measure ADEs, partic-

ularly rare ones, it is common practice to include sources of infor-

mation other than RCTs. While some reviewers include ADEs re-

ported in observational studies, we elected to obtain information

from the Canadian Adverse Drug Reaction Monitoring Program

(CADRMP) (Health Canada 2005).

Generalizability of findings

Generalizability of our findings is limited by the controlled design

of the trials included in our review. Study participants were care-

fully selected in these trials, and so utilization of the drugs in real



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life may vary substantially from study conditions. Furthermore,

study participants were observed for periods of time varying from

one to four years. Consequently, while our results provide support

for efficacy (i.e. can the intervention have an effect on outcome?),

they may possibly only provide partial information on the long-

term effectiveness (i.e. does the intervention have an effect on out-

come?) of alendronate in preventing osteoporotic fractures.

From a safety perspective, we could not find any statistically signif-

icant difference in either the rates of adverse drug events or with-

drawal rates due to adverse drug events between patients receiv-

ing a bisphosphonate or patients receiving a placebo. However,

outside controlled trials, concerns exist regarding the safe use of

alendronate, for which esophageal ulcers and gastritis have been

reported (Kherani 2002). While such adverse events have mainly

been identified through case reports and endoscopic studies, simi-

lar concerns are also reflected in the proportions of gastrointestinal

adverse drug reactions associated with the use of bisphosphonates

reported to the CADRMP (Health Canada 2005). Indeed, GI ad-

verse drug reactions represented 38% of all reactions reported for

alendronate (Figure 23). These proportions should, however, be

interpreted with caution, as adverse drug reactions are reported

to CADRMP on a volunteer basis by health professionals, which

means that several reactions may be unreported. Indeed, it is es-

timated that less than 10% of adverse reactions are reported to

Health Canada (Health Canada 2005c). Also, a definite cause-

effect relationship has not been established for these adverse drug

reactions.



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Figure 23. Adverse drug reactions reported to CADRMP for etidronate, alendronate and risedronate



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A U T H O R S ’ C O N C L U S I O N SImplications for practice

Alendronate demonstrated a clinically important benefit in the

secondary prevention of all osteoporotic fractures. At a dose of 10

mg per day, statistically significant reductions in vertebral, non-

vertebral, hip and wrist were observed. The secondary prevention

population was defined as having a bone density of at least 2 SD

values below peak bone mass or one or more vertebral compres-

sion fractures, or both. There were no statistically significant re-

ductions found for the primary prevention of osteoporotic frac-

tures, with the exception of vertebral fractures, for which the re-

duction was clinically important. No increased incidence of ad-

verse effects were detected with alendronate, but clinicians should

be aware that outside of randomized controlled trials, concerns

exist regarding the potential risk of upper gastrointestinal events

and, less commonly, osteonecrosis of the jaw.

The prevention of osteoporotic fractures is an important public

health intervention. This is particularly true for hip and clinical

vertebral fractures (i.e. fractures of the spine that present for med-

ical attention). The RR of death following such fractures is six- to

nine-fold greater in postmenopausal women aged 55 to 81 years

with low BMD, which represents a typical postmenopausal pop-

ulation (Cauley 2000). In most cases, the mortality increase re-

flects poor underlying health status and comorbidity, in addition

to the fracture itself (Cauley 2000). Osteoporotic fractures are also

associated with increase in morbidity, as it is reported that 50%

of women who sustain a hip fracture do not return to their usual

daily activities (Brown 2002), while 33% will require long-term

care. Accordingly, reducing the incidence of such fractures can po-

tentially increase the quality of life of patients with osteoporosis.

Such interventions may also potentially decrease mortality.

Implications for research

It has been suggested from clinical trials with the bisphosphonates

(Black 2000b; Harris 1999; McClung 2001) that their effect in

reducing non-vertebral fractures may be greater in patients with

lower BMD who initiate treatment. The existing data have not

fully resolved the question of whether important differences in

risk reduction across groups of patients with varying degrees of

osteoporosis exist. The impact of the bisphosphonates on the RR

of non-vertebral fractures in populations without osteoporosis also

merits further investigation. Additional research is needed to clar-

ify the role of bisphosphonates in the primary prevention of os-

teoporotic fractures. There is also a need for further post-market-

ing safety. Finally, research into combination therapy with higher

doses of vitamin D or anabolic agents would be merited as would

research concerning adherence to bisphosphonate therapy.

Given the morbidity consequences associated with osteoporotic

fractures, preventing their recurrence can potentially lessen the

need for community-based health services (e.g. home care). It may

also reduce or delay the demand for long-term care beds. However,

very little comparative information is currently available to sup-

port this (Hodsman 2002). There is also a lack of studies which

evaluated the effect of bisphosphonates on hospital admissions

(Hodsman 2002).

A C K N O W L E D G E M E N T S

Thank you to Lara Maxwell and Marie Andree Nowlan from the

Cochrane Musculoskeletal Group for their editorial assistance, and

Tamara Rader for her assistance with the Consumer Summary.

R E F E R E N C E S

References to studies included in this review

Ascott Evans 2003 {published data only}

Ascott-Evans BH, Guanabens N, Kivinen S, Stuckey BG,

Magaril CH, Vandormael K, et al.Alendronate prevents

loss of bone density associated with discontinuation of

hormone replacement therapy: a randomized controlled

trial. Archives of Internal Medicine 2003;163(7):789–94.

Black 1996 {published data only}∗ Black DM, Cummings SR, Karpf DB, Cauley JA,

Thompson DE, Nevitt MC, et al.Randomised trial of effect

of alendronate on risk of fracture in women with existing

vertebral fractures. Fracture Intervention Trial Research

Group.[see comment]. Lancet 1996;348(9041):1535–41.

Bone 1997 {published data only}∗ Bone HG, Downs RW Jr, Tucci JR, Harris ST, Weinstein

RS, Licata AA, et al.Dose-response relationships for

alendronate treatment in osteoporotic elderly women.

Alendronate Elderly Osteoporosis Study Centers. Journal of

Clinical Endocrinology & Metabolism 1997;82(1):265–74.

Chestnut 1995 {published data only}∗ Chesnut CH III, McClung MR, Ensrud KE, Bell NH,

Genant HK, Harris ST, et al.Alendronate treatment of the

postmenopausal osteoporotic woman: effect of multiple

dosages on bone mass and bone remodeling. American

Journal of Medicine 1995;99(2):144–52.

Cummings 1998 {published data only}∗ Cummings SR, Black DM, Thompson DE, Applegate



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WB, Barrett-Connor E, Musliner TA, et al.Effect of

alendronate on risk of fracture in women with low bone

density but without vertebral fractures: results from the

Fracture Intervention Trial. [see comment]. JAMA 1998;

280(24):2077–82.

Durson 2001 {published data only}

Dursun N, Dursun E, Yalcin S. Comparison of alendronate,

calcitonin and calcium treatments in postmenopausal

osteoporosis. International Journal of Clinical Practice 2001;

55(8):505–9.

Greenspan 1998 {published data only}∗ Greenspan SL, Parker RA, Ferguson L, Rosen HN,

Maitland-Ramsey L, Karpf DB. Early changes in

biochemical markers of bone turnover predict the long-term

response to alendronate therapy in representative elderly

women: a randomized clinical trial. Journal of Bone and

Mineral Research 1998;13(9):1431–8.

Greenspan 2002 {published data only}

Greenspan S, Field-Munves E, Tonino R, Smith M,

Petruschke R, Wang L, et al.Tolerability of once-weekly

alendronate in patients with osteoporosis: a randomized,

double-blind, placebo-controlled study. [see comment].

Mayo Clinic Proceedings 2002;77(10):1044–52.

Hosking 1998 {published data only}∗ Hosking D, Chilvers CE, Christiansen C, Ravn P, Wasnich

R, Ross P, et al.Prevention of bone loss with alendronate

in postmenopausal women under 60 years of age. Early

Postmenopausal Intervention Cohort Study Group. New

England Journal of Medicine 1998;338(8):485–92.

Liberman 1995 {published data only}

Liberman UA, Weiss SR, Broll J, Minne HW, Quan H,

Bell NH, et al.Effect of oral alendronate on bone mineral

density and the incidence of fractures in postmenopausal

osteoporosis. The Alendronate Phase III Osteoporosis

Treatment Study Group. [see comment]. New England


Pols 1999 {published data only}∗ Pols HA, Felsenberg D, Hanley DA, Stepan J, Munoz-

Torres M, Wilkin TJ, et al.Multinational, placebo-

controlled, randomized trial of the effects of alendronate on

bone density and fracture risk in postmenopausal women

with low bone mass: results of the FOSIT study. Fosamax

International Trial Study Group. Osteoporosis International

1999;9(5):461–8.

References to studies excluded from this review

Adami 1993 {published data only}

Adami S, Baroni MC, Broggini M, Carratelli L, Caruso I,

Gnessi L, et al.Treatment of postmenopausal osteoporosis

with continuous daily oral alendronate in comparison with

either placebo or intranasal salmon calcitonin. Osteoporosis

International 1993;3 Suppl 3:S21–S27.

Adami 1995 {published data only}

Adami S, Passeri M, Ortolani S, Broggini M, Carratelli L,

Caruso I, et al.Effects of oral alendronate and intranasal

salmon calcitonin on bone mass and biochemical markers of

bone turnover in postmenopausal women with osteoporosis.

Bone 1995;17(4):383–90.

Aki 2003 {published data only}

Aki S, Gulbaba RG, Eskiyurt N. Effect of alendronate

on bone density and bone markers in postmenopausal

osteoporosis. Journal of Back & Musculoskeletal

Rehabilitation 2003;17(1):27–31. [MEDLINE: 669]

Bell 2002 {published data only}

Bell NH, Bilezikian JP, Bone HG III, Kaur A, Maragoto

A, Santora AC, Study Group. Alendronate increases bone

mass and reduces bone markers in postmenopausal African-

American women. Journal of Clinical Endocrinology &

Metabolism 2002;87(6):2792–7.

Bettembuk 1999 {published data only}

Bettembuk P, Balogh A. [The effect of a one-year

alendronate therapy on postmenopausal osteoporosis.

(Results in Hungarian of an international multicenter

clinical study)]. Orvosi Hetilap 1999;140(50):2799–803.

Black 2000 {published data only}

Black DM, Thompson DE, Bauer DC, Ensrud K, Musliner

T, Hochberg MC, et al.Fracture risk reduction with

alendronate in women with osteoporosis: the Fracture

Intervention Trial. FIT Research Group. [erratum appears

in J Clin Endocrinol Metab 2001 Feb;86(2):938]. Journal of


Black 2003 {published data only}

Black DM, Greenspan SL, Ensrud KE, Palermo L,

McGowan JA, Lang TF, et al.The effects of parathyroid

hormone and alendronate alone or in combination in

postmenopausal osteoporosis. [see comment]. New England


Body 2002 {published data only}

Body JJ, Gaich GA, Scheele WH, Kulkarni PM, Miller PD,

Peretz A, et al.A randomized double-blind trial to compare

the efficacy of teriparatide (recombinant human parathyroid

hormone (1-34)) with alendronate in postmenopausal

women with osteoporosis. [see comment]. Journal of


Boivin 2000 {published data only}

Boivin GY, Chavassieux PM, Santora AC, Yates J, Meunier

PJ. Alendronate increases bone strength by increasing the

mean degree of mineralization of bone tissue in osteoporotic

women. Bone 2000;27(5):687–94.

Bone 2000 {published data only}

Bone HG, Greenspan SL, McKeever C, Bell N, Davidson

M, Downs RW, et al.Alendronate and estrogen effects in

postmenopausal women with low bone mineral density.

Alendronate/Estrogen Study Group. Journal of Clinical

Endocrinology & Metabolism 2000;85(2):720–6.

Bone 2004 {published data only}

Bone HG, Hosking D, Devogelaer JP, Tucci JR, Emkey

RD, Tonino RP, et al.Ten years’ experience with alendronate

for osteoporosis in postmenopausal women. [see comment].

New England Journal of Medicine 2004;350(12):1189–99.



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Bonnick 1998 {published data only}

Bonnick S, Rosen C, Mako B, DeLucca P, Byrned C, Melton

M. Alendronate vs calcium for treatment of osteoporosis in

postmenopausal women.. Bone 1998;350(5S):S476.

Bouxsein 1999 {published data only}

Bouxsein ML, Parker RA, Greenspan SL. Forearm bone

mineral densitometry cannot be used to monitor response

to alendronate therapy in postmenopausal women.

Osteoporosis International 1999;10(6):505–9.

Chailurkit 2003 {published data only}

Chailurkit LO, Jongjaroenprasert W, Rungbunnapun S,

Ongphiphadhanakul B, Sae-tung S, Rajatanavin R. Effect

of alendronate on bone mineral density and bone turnover

in Thai postmenopausal osteoporosis. Journal of Bone &

Mineral Metabolism 2003;21(6):421–7.

Chailurkit 2004 {published data only}

Chailurkit LO, Aunphongpuwanart S, Ongphiphadhanakul

B, Jongjaroenprasert W, Sae-tung S, Rajatanavin R.

Efficacy of intermittent low dose alendronate in Thai

postmenopausal osteoporosis. Endocrine Research 2004;30

(1):29–36.

Chavassieux 1997 {published data only}

Chavassieux PM, Arlot ME, Reda C, Wei L, Yates

AJ, Meunier PJ. Histomorphometric assessment of the

long-term effects of alendronate on bone quality and

remodeling in patients with osteoporosis. Journal of Clinical

Investigation 1997;100(6):1475–80.

Cheng 2002 {published data only}

Cheng ZQ, Yin W, Fan JY, Ma TJ. [The efficacy

of alendronate in the prevention and treatment of

postmenopausal osteoporosis]. [Chinese]. Chung-Kuo i

Hsueh Ko Hsueh Yuan Hsueh Pao Acta Academiae Medicinae

Sinicae 2002;24(3):306–9.

Chesnut 1993 {published data only}

Chesnut CH, Harris ST. Short term effect of alendronate on

bone mass and bone remodeling in postmenopausal women.

Osteoporosis International 1993;3(Suppl 3):S17–S19.

Cummings 2000 {published data only}

Cummings SR, Palermo L, Browner W, Marcus R, Wallace

R, Pearson J, et al.Monitoring osteoporosis therapy with

bone densitometry: misleading changes and regression to

the mean. Fracture Intervention Trial Research Group.

JAMA 2000;283(10):1318–21.

Davas 2003 {published data only}

Davas I, Altintas A, Yoldemir T, Varolan A, Yazgan A, Baksu

B. Effect of daily hormone therapy and alendronate use on

bone mineral density in postmenopausal women. Fertility

& Sterility 2003;80(3):536–40.

Devogelaer 1996 {published data only}

Devogelaer JP, Broll H, Correa-Rotter R, Cumming DC,

De Deuxchaisnes CN, Geusens P, et al.Oral alendronate

induces progressive increases in bone mass of the spine, hip,

and total body over 3 years in postmenopausal women with

osteoporosis. [erratum appears in Bone 1996 Jul;19(1):78].

Bone 1996;18(2):141–50.

Dobnig 2006 {published data only}

Dobnig H, Hofbauer LC, Viereck V, Obermayer-Pietsch

B, Fahrleitner-Pammer A, Dobnig H, et al.Changes in the

RANK ligand/osteoprotegerin system are correlated to

changes in bone mineral density in bisphosphonate-treated

osteoporotic patients. Osteoporosis International 2006;17(5):

693–703. [MEDLINE: 13]

Downs 2000 {published data only}

Downs RW Jr, Bell NH, Ettinger MP, Walsh BW, Favus MJ,

Mako B, et al.Comparison of alendronate and intranasal

calcitonin for treatment of osteoporosis in postmenopausal

women. Journal of Clinical Endocrinology & Metabolism

2000;85(5):1783–8.

Evio 2004 {published data only}

Evio S, Tiitinen A, Laitinen K, Ylikorkala O, Valimaki MJ.

Effects of alendronate and hormone replacement therapy,

alone and in combination, on bone mass and markers of

bone turnover in elderly women with osteoporosis. Journal

of Clinical Endocrinology & Metabolism 2004;89(2):626–31.

Gonnelli 2002 {published data only}

Gonnelli S, Cepollaro C, Montagnani A, Martini S,

Gennari L, Mangeri M, et al.Heel ultrasonography in

monitoring alendronate therapy: a four-year longitudinal

study. Osteoporosis International 2002;13(5):415–21.

Greenspan 2002a {published data only}

Greenspan SL, Emkey RD, Bone HG, Weiss SR, Bell

NH, Downs RW, et al.Significant differential effects of

alendronate, estrogen or combination therapy on the

rate of bone loss after discontinuation of treatment of

postmenopausal osteoporosis. A randomized, double-blind,

placebo-controlled trial. [summary for patients in Ann

Intern Med. 2002 Dec 3;137(11):I31; PMID: 12459003].

Annals of Internal Medicine 2002;137(11):875–83.

Greenspan 2002b {published data only}

Greenspan SL, Schneider DL, McClung MR, Miller

PD, Schnitzer TJ, Bonin R, et al.Alendronate improves

bone mineral density in elderly women with osteoporosis

residing in long-term care facilities. A randomized, double-

blind, placebo-controlled trial. [summary for patients in

Ann Intern Med. 2002 May 21;136(10):I54; PMID:

12020160]. Annals of Internal Medicine 2002;136(10):

742–6.

Greenspan 2003 {published data only}

Greenspan SL, Resnick NM, Parker RA. Combination

therapy with hormone replacement and alendronate for

prevention of bone loss in elderly women: a randomized

controlled trial. JAMA 2003;289(19):2525–33.

Harris 1993 {published data only}

Harris ST, Gertz BJ, Genant HK, Eyre DR, Survill TT,

Ventura JN, et al.The effect of short term treatment with

alendronate on vertebral density and biochemical markers

of bone remodeling in early postmenopausal women.

Journal of Clinical Endocrinology & Metabolism 1993;76(6):

1399–1406.



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Heijckmann 2002 {published data only}

Heijckmann AC, Juttmann JR, Wolffenbuttel BH.

Intravenous pamidronate compared with oral alendronate

for the treatment of postmenopausal osteoporosis. [see

comment]. Netherlands Journal of Medicine 2002;60(8):

315–9.

Ho 2005 {published data only}

Ho AY, Kung AW, Ho AYY, Kung AWC. Efficacy

and tolerability of alendronate once weekly in Asian

postmenopausal osteoporotic women. Annals of

Pharmacotherapy 2005;39(9):1428–33. [MEDLINE: 109]

Hochberg 1999 {published data only}

Hochberg MC, Ross PD, Black D, Cummings SR, Genant

HK, Nevitt MC, et al.Larger increases in bone mineral

density during alendronate therapy are associated with

a lower risk of new vertebral fractures in women with

postmenopausal osteoporosis. Fracture Intervention Trial

Research Group. Arthritis & Rheumatism 1999;42(6):

1246–54.

Hosking 2003 {published data only}

Hosking D, Adami S, Felsenberg D, Andia JC, Valimaki

M, Benhamou L, et al.Comparison of change in bone

resorption and bone mineral density with once-weekly

alendronate and daily risedronate: a randomised, placebo-

controlled study. Current Medical Research & Opinion 2003;

19(5):383–94.

Iwamoto 2004 {published data only}

Iwamoto J, Takeda T, Sato Y, Uzawa M. Determinants

of one-year response of lumbar bone mineral density to

alendronate treatment in elderly Japanese women with

osteoporosis. Yonsei Medical Journal 2004;45(4):676–82.

Johnell 2002 {published data only}

Johnell O, Scheele WH, Lu Y, Reginster JY, Need AG,

Seeman E. Additive effects of raloxifene and alendronate on

bone density and biochemical markers of bone remodeling

in postmenopausal women with osteoporosis. [see

comment]. Journal of Clinical Endocrinology & Metabolism

2002;87(3):985–92.

Kung 2000 {published data only}

Kung AW, Yeung SS, Chu LW. The efficacy and tolerability

of alendronate in postmenopausal osteoporotic Chinese

women: a randomized placebo-controlled study. Calcified

Tissue International 2000;67(4):286–90.

Kushida 2004 {published data only}

Kushida K, Shiraki M, Nakamura T, Kishimoto H, Morii

H, Yamamoto K, et al.Alendronate reduced vertebral

fracture risk in postmenopausal Japanese women with

osteoporosis: a 3-year follow-up study. Journal of Bone &

Mineral Metabolism 2004;22(5):462–8.

Lau 2000 {published data only}

Lau EM, Woo J, Chan YH, Griffith J. Alendronate prevents

bone loss in Chinese women with osteoporosis. Bone 2000;

27(5):677–80.

Luckey 2004 {published data only}

Luckey M, Kagan R, Greenspan S, Bone H, Kiel RD, Simon

J, et al.Once-weekly alendronate 70 mg and raloxifene 60

mg daily in the treatment of postmenopausal osteoporosis.

Menopause 2004;11(4):405–15.

Malavolta 1999 {published data only}

Malavolta N, Zanardi M, Veronesi M, Ripamonti C, Gnudi

S. Calcitriol and alendronate combination treatment in

menopausal women with low bone mass. International

Journal of Tissue Reactions 1999;21(2):51–9.

McClung 1998 {published data only}

McClung M, Clemmesen B, Daifotis A, Gilchrist NL,

Eisman J, Weinstein RS, et al.Alendronate prevents

postmenopausal bone loss in women without osteoporosis.

A double-blind, randomized, controlled trial. Alendronate

Osteoporosis Prevention Study Group. [see comment].


McClung 2004 {published data only}

McClung MR, Wasnich RD, Hosking DJ, Christiansen

C, Ravn P, Wu M, et al.Prevention of postmenopausal

bone loss: six-year results from the Early Postmenopausal

Intervention Cohort Study. Journal of Clinical Endocrinology

& Metabolism 2004;89(10):4879–85. [MEDLINE: 190]

Murphy 2001 {published data only}

Murphy MG, Weiss S, McClung M, Schnitzer T, Cerchio K,

Connor J, et al.Effect of alendronate and MK-677 (a growth

hormone secretagogue), individually and in combination,

on markers of bone turnover and bone mineral density in

postmenopausal osteoporotic women. Journal of Clinical


Nenonen 2005 {published data only}

Nenonen A, Cheng S, Ivaska KK, Alatalo SL, Lehtimaki T,

Schmidt-Gayk H, et al.Serum TRACP 5b is a useful marker

for monitoring alendronate treatment: Comparison with

other markers of bone turnover. Journal of Bone & Mineral

Research 2005;20(8):1804–12. [MEDLINE: 576]

Palomba 2002 {published data only}

Palomba S, Orio F Jr, Colao A, di Carlo C, Sena T,

Lombardi G, et al.Effect of estrogen replacement plus low-

dose alendronate treatment on bone density in surgically

postmenopausal women with osteoporosis. Journal of


Payer 2000 {published data only}

Payer J Jr, Killinger Z, Masaryk P, Tomkova S, Kmecova Z,

Ondrejkova J, et al.[Effect of alendronate therapy on bone

turnover--results of a multicenter study]. [Slovak]. Vnitrni

Lekarstvi 2000;46(10):689–92.

Ravn 1999a {published data only}

Ravn P, Clemmesen B, Christiansen C. Biochemical markers

can predict the response in bone mass during alendronate

treatment in early postmenopausal women. Alendronate

Osteoporosis Prevention Study Group. Bone 1999;24(3):

237–44.

Ravn 1999b {published data only}

Ravn P, Hosking D, Thompson D, Cizza G, Wasnich RD,

McClung M, et al.Monitoring of alendronate treatment and

prediction of effect on bone mass by biochemical markers in

the early postmenopausal intervention cohort study. Journal

of Clinical Endocrinology & Metabolism 1999;84(7):2363–8.



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Ravn 1999c {published data only}

Ravn P, Bidstrup M, Wasnich RD, Davis JW, McClung

MR, Balske A, et al.Alendronate and estrogen-progestin in

the long-term prevention of bone loss: four-year results

from the early postmenopausal intervention cohort study.

A randomized, controlled trial. [see comment]. Annals of

Internal Medicine 1999;131(12):935–42.

Ravn 2000 {published data only}

Ravn P, Weiss SR, Rodriguez-Portales JA, McClung MR,

Wasnich RD, Gilchrist NL, et al.Alendronate in early

postmenopausal women: effects on bone mass during

long-term treatment and after withdrawal. Alendronate

Osteoporosis Prevention Study Group. Journal of Clinical


Rhee 2006 {published data only}

Rhee Y, Kang M, Min Y, Byun D, Chung Y, Ahn C,

et al.Effects of a combined alendronate and calcitriol

agent (Maxmarvil) on bone metabolism in Korean

postmenopausal women: a multicenter, double-blind,

randomized, placebo-controlled study. Osteoporosis

International 2006;17(12):1801–7. [MEDLINE: 7]

Rittmaster 2000 {published data only}

Rittmaster RS, Bolognese M, Ettinger MP, Hanley DA,

Hodsman AB, Kendler DL, et al.Enhancement of bone

mass in osteoporotic women with parathyroid hormone

followed by alendronate. [see comment]. Journal of Clinical


Rizzoli 2002 {published data only}

Rizzoli R, Greenspan SL, Bone G III, Schnitzer TJ, Watts

NB, Adami S, et al.Two-year results of once-weekly

administration of alendronate 70 mg for the treatment of

postmenopausal osteoporosis. Journal of Bone & Mineral

Research 2002;17(11):1988–96.

Rossini 1994 {published data only}

Rossini M, Gatti D, Zamberlan N, Braga V, Dorizzi R,

Adami S. Long-term effects of a treatment course with oral

alendronate of postmenopausal osteoporosis. Journal of

Bone & Mineral Research 1994;9(11):1833–7.

Rossini 2000 {published data only}

Rossini M, Gatti D, Girardello S, Braga V, James G, Adami

S. Effects of two intermittent alendronate regimens in the

prevention or treatment of postmenopausal osteoporosis.

Bone 2000;27(1):119–22.

Rozkydal 2003 {published data only}

Rozkydal Z, Janicek P. The effect of alendronate in the

treatment of postmenopausal osteoporosis. Bratislavske

Lekarske Listy 2003;104(10):309–13.

Sahota 2000 {published data only}

Sahota O, Fowler I, Blackwell PJ, Lawson N, Cawte SA,

San P, et al.A comparison of continuous alendronate,

cyclical alendronate and cyclical etidronate with calcitriol

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a randomized controlled trial. Osteoporosis International

2000;11(11):959–66.

Sambrook 2004a {published data only}

Sambrook PN, Geusens P, Ribot C, Solimano JA, Ferrer-

Barriendos J, Gaines K, et al.Alendronate produces greater

effects than raloxifene on bone density and bone turnover

in postmenopausal women with low bone density: results

of EFFECT (Efficacy of FOSAMAX versus EVISTA

Comparison Trial) International. Journal of Internal

Medicine 2004;255(4):503–11.

Sambrook 2004b {published data only}

Sambrook PN, Rodriguez JP, Wasnich RD, Luckey MM,

Kaur A, Meng L, et al.Alendronate in the prevention of

osteoporosis: 7-year follow-up. Osteoporosis International

2004;15(6):483–8.

Sawka 2003 {published data only}

Sawka AM, Adachi JD, Ioannidis G, Olszynski WP, Brown

JP, Hanley DA, et al.What predicts early fracture or bone

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Densitometry 2003;6(4):315–22.

Schneider 1999 {published data only}

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U, Semler J, et al.Alendronate increases bone density and

bone strength at the distal radius in postmenopausal women.

Journal of Bone & Mineral Research 1999;14(8):1387–93.

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Schnitzer T, Bone HG, Crepaldi G, Adami S, McClung M,

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101:40–5.

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Simon JA, Lewiecki EM, Smith ME, Petruschke RA,

Wang L, Palmisano JJ. Patient preference for once-weekly

alendronate 70 mg versus once-daily alendronate 10 mg:

a multicenter, randomized, open-label, crossover study.

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Sosa 2002 {published data only}

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PE, Betancor P. Effect of two forms of alendronate

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Stepan 1999 {published data only}

Stepan JJ, Vokrouhlicka J. Comparison of biochemical

markers of bone remodelling in the assessment of the effects

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of alendronate and hormone replacement therapy, alone or

in combination, on bone mass in postmenopausal women

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Tucci JR, Tonino RP, Emkey RD, Peverly CA, Kher U,

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a randomized controlled trial. Bone 2003;33(1):132–43.

van der Poest 2000 {published data only}

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Lips P. The effect of alendronate on bone mass after distal

forearm fracture. Journal of Bone & Mineral Research 2000;

15(3):586–93.

Vasikaran 1995 {published data only}

Vasikaran SD, Khan S, McCloskey EV, Kanis JA. Sustained

response to intravenous alendronate in postmenopausal

osteoporosis. Bone 1995;17(6):517–20.

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Yen ML, Yen BL, Jang MH, Hsu SH, Cheng WC, Tsai

KS. Effects of alendronate on osteopenic postmenopausal

Chinese women. Bone 2000;27(5):681–5.

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Yildirim K, Gureser G, Karatay S, Melikoglu MA, Ugur M,

Erdal A, et al.Comparison of the effects of alendronate,

risedronate and calcitonin treatment in postmenopausal


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Melton LJ III, Kan SH, Frye MA, Wahner HW, O’Fallon

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References to other published versions of this review

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Wells GA, Cranney A, Bouchere M, Peterson J, Shea

B, Robinson V, et al.Bisphosphonates for the primary



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and secondary prevention of osteoporotic fractures in

postmenopausal women: a meta-analysis [Technology

report no 69]. Ottawa: Canadian Agency for Drugs and

Technologies in Health 2006.∗ Indicates the major publication for the study



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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Ascott Evans 2003

Methods Randomized controlled trial

Primary prevention

Duration: 1 year

Blinding: double blind matching placebo, all study personnel blinded

Withdrawals:

Alendronate: 12/95 (12.6%)

Placebo: 13/49 (26.5%)

Total: 25/144 (17.4%)

Participants Source: 18 centres in 9 countries.

Inclusion Criteria: Women under 80 yrs old who had been postmenopausal for at least 3

years. Previous HRT for at least 1 yr which had been discontinued at least 3 months prior

to study. Low bone density between -3.5 and -1.5 of young normal

Exclusion Criteria: History of osteoporotic fracture or metabolic bone disease. Recent

bisphosphonate or other treatment known to affect bone metabolism

Treatment N = 95

Control N = 49

Age: 67.3 (6.6); YSM: 11.5 (7.3)

Calcium: not reported

BMD: not reported

T-score: -2.27 (0.65)

Vertebral Fractures: 0%

Interventions Alendronate 10 mg x 1 year vs placebo

(Calcium 500mg/day)

Outcomes Vertebral, Non Vertebral, Hip and Wrist Fractures: Adverse experiences were recorded

by blinded study personnel at each visit using non leading questions. No fractures were

reported

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear



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Black 1996


Secondary prevention

Blinding: double blind identical placebo, blinded radiologist

Duration: 3 years

Withdrawals:

Alendronate (available radiographs): 44 (4.2%)

Placebo (available radiographs): 37/1005 (3.7%)

Total (available radiographs): 81/2027 (4.0%)

Total (lost to follow up at close out): 78/2027 (3.8%)

Participants Source: Population-based listings in 11 metropolitan areas of the USA. Fracture Interven-

tion Trial

Inclusion Criteria: Age 55-81, postmenopausal for at least 2 years, femoral neck BMD 0.68

g/cm² Hologic

(2.1 SD below peak bone mass) or less.

Exclusion Criteria: Peptic ulcer disease (single hospital admission for upper GI bleeding

or 2 or more documented ulcers in previous 5 years), dyspepsia requiring daily treatment,

abnormal renal function, major medical problems, severe malabsorption, uncontrolled hy-

pertension, MI in previous 6 months, unstable angina, thyroid or parathyroid dysfunction,

estrogen or calcitonin in previous 6 months, bisphosphonates or fluorides at any time

Treatment N = 1022

Control N = 1005

Age: 71.0 (5.6); YSM: not reported

Calcium: 636 (407) mg/day

BMD (hip): 0.57 g/cm 2 (0.07)

T-score (hip): -3.3

Vertebral Fractures : 100%

Interventions Alendronate 5 mg x 2 years then 10 mg x 1 year vs placebo

(If intake < 1000 mg then received 500 mg Ca and 250 IU Vitamin D)

Outcomes Morphometric Vertebral Fractures:

Lateral radiographs were taken at baseline 24 and 36 months intervals. Morphometry was

performed with a translucent digitizer and cursor marking anterior, posterior and middle

heights for each vertebra. Baseline fractures were defined a height of > 3 SD below the mean

population level for that vertebrae. Incident fractures were defined as a decrease of 20%

and at least 4 mm from baseline. Any questionable fractures were reviewed by the study

radiologist. Technicians and radiologist were all blinded

Clinical Vertebral Fractures: Fractures that came to medical attention and were reported

by participants. Copy of radiograph was obtained and compared with baseline study ra-

diograph. Incident clinical fracture was defined by a semiquantitative reading by the study

radiologist

Non Vertebral, Hip and Wrist Fractures: Clinical fractures were initially reported by par-

ticipants and confirmed by a written radiological report. Excluded pathological fractures

e.g. malignancies, excessive trauma, face and skull

Notes

Risk of bias



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Black 1996 (Continued)


Allocation concealment (selection bias) Low risk A - Adequate

Bone 1997



Blinding: double blind

Duration: 2 years

Withdrawals:

Total (for BMD analysis):

131/359 (36.5%)

Participants Source: 15 clinical sites in USA. Subjects stratified so that 2/3 would be age 70-85

Inclusion Criteria: Women age 60-85 in good health apart from osteoporosis. Lumbar

spine < -2.00 SD of peak bone mass (BMD 0.824g/cm² or less by Hologic DXA or 9.44

g/cm² or less by Lunar DXA)

Exclusion Criteria: More than 1 spinal crush fracture or spinal anatomy otherwise unsuitable

for DXA, history of recent major GI disease - peptic ulcer, esophageal ulcer, malabsorption,

use of drug to inhibit gastric acid secretion for > 2 wks, chronic NSAID therapy, agents

known to affect bone metabolism, unstable dose thyroid hormone replacement, uncorrected

vitamin D deficiency.

Treatment N = 86, 89, 93

Control N = 91

Age: 70.4 (5.6); YSM: 24.2 (9.9)

Calcium: 891(629) mg/day

BMD: 0.71 g/cm 2 (0.08)

T-score: -3.1

Vertebral Fractures: 37.4%

Interventions Alendronate 1, 2.5, or 5 mg placebo.

(500 mg calcium/day)

Outcomes Vertebral Fractures: Lateral thoracic and lumbar radiographs obtained at baseline and an-

nual visits were sent to a central evaluation facility where they were evaluated by a single

radiologist. Prevalent and incident fractures were scored using a semiquantitative scale as

being intact (unfractured or questionably fractured), or fractured (mild - 20 to 25% height

loss; moderate - 25-40% or severe - >40%)

Non-vertebral Fractures: Reported at each centre based on clinical presentation and con-

firmatory radiographs

Notes

Risk of bias




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Bone 1997 (Continued)


Chestnut 1995



Blinding: double blind unspecified

Duration: 2 years

Withdrawals:

Total: 34/188 (18%)

Loss to follow up: 34/188 (18.09%)

Participants Source: Recruited by advertisements and medical announcements through seven centres in

the USA

Inclusion Criteria: Healthy women age 42 to 75 who were at least 5 years postmenopausal.

BMD = 2 SD below young normal (0.88g/cm²)

Exclusion Criteria: Presence of spine or hip fractures attributable to osteoporosis. Any

disease or drug therapy potentially affecting bone metabolism

Treatment N = 32, 30, 32, 32

Control N = 31

Age: 63.04 (6.27); YSM: 15.6 (7.3)


BMD: 0.75 g/cm 2 (0.09)

T-score: -2.7


Interventions Alendronate 5mg/day, or 10 mg/day, for 2 years 20 mg/day or 40 mg/day for 1 year followed

by 1 year of placebo or 40 mg for 3 months followed by 2.5 mg for 21 months vs placebo

for 2 years


Outcomes Vertebral Fractures: Lateral thoracic and lumbar radiographs were evaluated at each centre

for presence of prevalent and incident fractures at baseline and completion of treatment

Non-vertebral Fractures: Ascertainment not specified but patients were questioned about

intercurrent health problems at each visit. This outcome was not included in the meta-

analysis as non vertebral fractures weren’t broken down by study group

Notes

Risk of bias





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Cummings 1998


Primary prevention

Blinding: double blind, collection and review of data was blinded

Study duration: 4 years

Withdrawals:

Total (lost to follow at close out)

160/4432 (3.6 %)

Participants Source: Recruited principally though mass mailings from 11 community-based clinical

research centres in the USA. Fracture Intervention Trial

Inclusion Criteria: Age 55-80, postmenopausal for at least 2 years, femoral neck BMD 0.68

g/cm² or less Hologic. At the time of study this was thought to correspond to -2 SD below

peak mass but subsequently found to correspond to a t-score of -1.6 based on the Third

National Health and Nutritional Examination Survey. Consequently 1/3 of participants

had higher BMD than expected

Exclusion Criteria: Vertebral fractures, Peptic ulcer disease (single hospital admission for

upper GI bleeding or 2 or more documented ulcers in previous 5 years), dyspepsia requiring

daily treatment, abnormal renal function, major medical problems, severe malabsorption,

uncontrolled hypertension, MI in previous 6 mos, unstable angina, thyroid or parathyroid

dysfunction, estrogen or calcitonin in previous 6 mos, bisphosphonates or fluorides at any

time

Treatment N = 2214

Control N = 2218

Age : 67.6 (6.1); YSM: not reported


BMD: 0.84 g/cm2 (0.13)

T-score: -1.9


Interventions Alendronate 5 mg for 2 yrs then increased to 10 mg for 2 years vs placebo

(If intake < 1000 mg then received 500 mg Ca and 250 IU Vitamin D)

Outcomes Vertebral Morphometric Fractures: Lateral spine radiographs were obtained at baseline and

4 years. An incident fracture was defined as a decrease of 20% and 4 mm or more in any

vertebral height which was confirmed by repeat measurement. All assessments were blinded

Clinical Fractures: Defined as a fractured diagnosed by a physician. Self reports were con-

firmed by written reports of radiographs or other tests. Excluded pathologic fractures,

trauma sufficient to fracture a young adult bone, facial and skull fractures

Notes

Risk of bias





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Durson 2001



Blinding: no blinding reported

Duration: 1 year

Withdrawals:


Control: 15/50 (30.0%)

Total: 28/101 (28%)

Participants Source: Postmenopausal women applying to one centre’s department of physical medicine

and rehabilitation in Turkey

Inclusion Criteria: BMD of 2 SD or more below young adult mean at either lumbar spine

or femoral neck

Exclusion Criteria: Drug or alcohol abuse, bone metabolism disorder, active GI or liver

disease, renal failure or calculi, treatment with specific therapy for osteoporosis, corticos-

teroids, malignancy, disorder of calcium metabolism, lumbar vertebrae abnormalities pre-

venting evaluation of BMD.

Treatment N = 51

Control N = 50

Age: 61 (7.8); YSM: 15.59 (8.04)


BMD: 0.84 g/cm (0.08)

T-score: -1.9

Vertebral Fractures: not reported

Interventions Alendronate 10 mg/day plus calcium 1000 mg/day x 1 yr vs calcium 1000 mg

Outcomes Vertebral Fractures: Lateral and anteroposterior X-rays of thoracic and lumbar vertebrae

were performed at baseline, 6 months and 12 months. A new vertebral fracture was defined

as a decrease of 20% and at least 4 mm of height in any vertebrae

Notes

Risk of bias





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Greenspan 1998



Blinding: double blind, matching placebo

Study duration: 2.5 years

Loss to follow up: Alendronate:14/60 (23.3%)

Placebo:15/60 (25.0%)

Total: 29/120 (24.2%)

Participants Source: Unselected women from one city (Boston) in the USA were recruited by advertise-

ment

Inclusion Criteria: Healthy ambulatory community dwelling age 65 or older. Criteria not

based on BMD

Exclusion Criteria: History of any illness affecting bone and mineral metabolism - (renal,

malignancy, hyperthyroidism, hyperparathyroidism, malabsorption), medications affecting

bone metabolism, treatment for osteoporosis (bisphosphonates, HRT, calcitonin) within 1

year.

Treatment N = 60

Control N = 60

Age: 70 (4.6); YSM: not reported


BMD: 0.57 g/cm2 (0.11)

T-score: -4.3


Interventions Alendronate 5 mg for year 1, 10 mg for year 2 vs placebo,

(if Ca intake < 1000 mg - 250 mg Ca and/or 125 IU vitamin D/day)

Outcomes Non-vertebral Hip and Wrist: Ascertainment not described.

Notes

Risk of bias



Greenspan 2002



Blinding: double blind matching placebo

Duration: 2 years

Withdrawals:

Not reported

Participants Source: Female residents in long term care facilities in 25 centre in USA

Inclusion Criteria: Ambulatory, age 65 or older with BMD T-score of -2 or less at lumbar



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Greenspan 2002 (Continued)

spine or hip.

Exclusion Criteria: Disorders of bone mineralization, 25-hydroxycholecalciferol < 25 nmol/

L, untreated hyperthyroidism, recent major upper GI mucosal erosive disease, or use of

bone active agents

Treatment N = 163

Control N = 164

Age: 78.5 (range 65-91); YSM: not reported


BMD: not reported

T-score: (mean range hip and spine) -3.5 to-2.4

Fractures: (history of any) 55%

Interventions Alendronate 10 mg/day x 2yrs vs placebo

(Vitamin D 400 IU/day and if dietary calcium was < 1500 mg/day they received calcium

500mg/day.)

Outcomes Hip Fractures: Ascertainment not reported.

Notes

Risk of bias



Hosking 1998


Primary prevention

Blinding: double blind, blinded BMD measurement and analysis

Duration: 2 years

Withdrawals: Alendronate:2.5mg 92/499 (18.4%)

Alendronate 5mg: 102/498 (20.5%)

Placebo: 93/502 (18.5%)

Total: 287/1499 (19.1%)

Withdrawals

Participants Source: Recruited by direct mailing, advertisements or telephone. Multicentre - USA, UK

and Denmark

Inclusion Criteria: Postmenopausal at least 6 months (confirmed by FSH) and in good

health. Only 10% of women at each centre were allowed to have a lumbar-spine BMD

below 0.8 g/square metre

(DEXA).

Exclusion Criteria: Abnormal renal function, cancer, peptic ulcer or esophageal disease

requiring prescription medication within the previous five years, previous treatment with

bisphosphonate or fluoride, therapy with phosphate-binding antacid, HRT within previous

3 months, therapy with any drug which affects the skeleton.



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Hosking 1998 (Continued)

Treatment N = 499, 498

Control N = 502

Age: 53 (4); YSM: 6 (5)


BMD: 0.94 g/cm 2 (0.12)

T-score: -1.0

Vertebral Fractures: NR

Interventions Alendronate 2.5 or 5mg vs placebo

(< 500mg calcium intake encouraged to increase)

Outcomes Vertebral and Non-Vertebral Fractures:

Women were questioned about any symptoms at clinic visits every 3 months. All un-

favourable clinical effects including fractures were evaluated with respect to severity, dura-

tion, seriousness, relation to study drug and outcome

Notes

Risk of bias



Liberman 1995



Blinding: double blind, blinded radiologists

Withdrawals:


Placebo: 65/397 (16.5%)

Total: 162/994 (16.3 %)

Duration: 3 years

Participants Source: Two multicentre studies, one in the US, and the other in Australia, Canada, Europe,

Israel, Mexico, New Zealand, South America

Inclusion Criteria: Postmenopausal (= 5 yrs) women age 45-80 with lumbar BMD at least

2.5 SD below premenopausal mean

Exclusion Criteria: Other causes for osteoporosis (glucocorticoids, vitamin D deficiency,

Pagets, hyperparathyroidism), active peptic ulcer disease, abnormal renal or hepatic func-

tion, abnormalities of spine precluding assessment of BMD for 3 lumbar vertebrae, history

or hip fracture, prior bisphosphonates, HRT, calcitonin, fluoride, or anabolic steroid in

previous 12 months.

Treatment N = 597

Control N = 397

Age:64 (7); YSM: 16.5




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Liberman 1995 (Continued)

BMD: 0.71

T-score: -3.1

Vertebral Fractures: 21%

Interventions Alendronate 5, 10 or 20/5 mg vs placebo


Outcomes Vertebral fractures, vertebral deformities and height loss. (Deformities and height loss not

included in this review.)

Vertebral Fractures: Lateral thoracic and lumbar spine films were obtained at baseline, one,

two, and three years. Standard values for target-to-film distance and centering were used at

each centre. Vertebral heights were determined at a radiology centre by observers blinded

to both treatment and sequence. All films from each woman were digitized at the same time

and anterior, middle and posterior vertebral heights were calculated with using computer

software. Prevalent fractures were determined by comparing baseline vertebral height ratios

to a reference group. A ratio of > -3 SD was considered a fracture. Incident fractures were

defined as a reduction of at least 20% and 4 mm between baseline and follow up

Non-Vertebral Fractures, Hip and Wrist: All reported symptomatic fractures were recorded

with no attempt to exclude fractures on the basis of degree of trauma

Notes

Risk of bias



Pols 1999



Blinding: double blind matching placebo

Duration: 1 year

Withdrawals:

Alendronate: 118/950 (12.4%)

Control: 93/958 (9.7%)

Total: 211/1908 (11.1 %)

Participants Source: 153 centres in 34 countries in Europe, Latin America, Australia, Canada, South

Africa and China.

.

Inclusion Criteria: Postmenopausal for at least 3 years, not older than age 85, lumbar BMD

(L2-4) at least 2 SD below the premenopausal mean (=0.86 g/cm² (DXA) or =0.98 g/cm²

(Hologic)). At lease 3 vertebrae from L1-L4 had to be evaluable by DXA to determine

BMD. In good health and between 20% below and 50% above ideal body weight

Exclusion Criteria: Other metabolic bone disease, disturbed parathyroid or thyroid, major

GI disease (peptic ulcer or malabsorption, drug to inhibit gastric > 2 week within past 3



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Pols 1999 (Continued)

mos), MI within 1 year, uncontrolled hypertension or angina, impaired renal function,

bisphosphonates or fluoride within 6 months, estrogen ipriflavone or calcitonin within

4 months, anabolic steroids, glucocorticoid or progestin within 6 months, medication

influencing bone metabolism - vitamin A > 10,000 IU/day, vitamin D > 1000 IU/day,

anticonvulsants, phosphate-binding antacids,

Treatment N = 950

Control N = 958

Age: 62.8 (7.4); YSM: 15.9 (1.5)

Calcium: Not available

BMD: 0.72 g/cm2 (0.08)

T-score: -2.97


Interventions Alendronate 10 mg, vs placebo

(500mg calcium/day)

Outcomes Non- Vertebral, Hip, Wrist: Clinical fractures were assessed through adverse event reporting.

Supporting documentation for each fracture i.e. radiographs and/or radiology reports,

hospital discharge reports with clinical diagnosis or confirmation by investigator/treating

physician

Notes

Risk of bias



t-score calculated using the lumbar spine BMD [(LS BMD -1.047)/0.110];

YSM=Years Since Menopause;

BMD=Bone Mineral Density;

Txt=Treatment;

HRT=Hormone Replacement Therapy

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Adami 1993 Duplicate or earlier report of another study.

Adami 1995 Lack of appropriate fracture data (i.e. reported as adverse events or unspecified)

Aki 2003 Lack of fracture outcome.



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(Continued)

Bell 2002 Lack of appropriate fracture data (i.e. reported as adverse events or unspecified)

Bettembuk 1999 Duplicate or earlier report of another study.

Black 2000 Duplicate or earlier report of another study.

Black 2003 Lack of an appropriate control group.

Body 2002 Lack of an appropriate control group.

Boivin 2000 Lack of fracture outcome.

Bone 2000 Lack of appropriate fracture data (i.e. reported as adverse events or unspecified)

Bone 2004 Extension/discontinuation study.

Bonnick 1998 Lack of appropriate fracture data (i.e. reported as adverse events or unspecified)

Bouxsein 1999 Lack of fracture outcome.

Chailurkit 2003 Lack of fracture outcome.

Chailurkit 2004 Lack of an appropriate control group.

Chavassieux 1997 Lack of fracture outcome.

Cheng 2002 Duration of therapy < 1 year.

Chesnut 1993 Duration of therapy < 1 year.

Cummings 2000 Lack of fracture outcome.

Davas 2003 Lack of an appropriate control group.

Devogelaer 1996 Duplicate or earlier report of another study.

Dobnig 2006 Lack of fracture outcome.

Downs 2000 Lack of appropriate fracture data (i.e. reported as adverse events or unspecified)

Evio 2004 Lack of an appropriate control group.

Gonnelli 2002 Lack of fracture outcome.

Greenspan 2002a Extension/discontinuation study.

Greenspan 2002b Duration of therapy < 1 year.



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(Continued)

Greenspan 2003 Lack of appropriate fracture data (i.e. reported as adverse events or unspecified)

Harris 1993 Duration of therapy < 1 year.

Heijckmann 2002 Non randomized.

Ho 2005 Lack of fracture outcome.

Hochberg 1999 Duplicate or earlier report of another study.

Hosking 2003 Lack of appropriate fracture data (i.e. reported as adverse events or unspecified)

Iwamoto 2004 Lack of an appropriate control group.

Johnell 2002 Lack of fracture outcome.

Kung 2000 Lack of fracture outcome.

Kushida 2004 Lack of an appropriate control group.

Lau 2000 Lack of fracture outcome.

Luckey 2004 Lack of an appropriate control group.

Malavolta 1999 Duration of therapy < 1 year.

McClung 1998 Lack of fracture outcome.

McClung 2004 Extension study.

Murphy 2001 Lack of appropriate fracture data (i.e. reported as adverse events or unspecified)

Nenonen 2005 Lack of fracture outcome.

Palomba 2002 Lack of an appropriate control group.

Payer 2000 Duration of therapy < 1 year.

Ravn 1999a Lack of fracture outcome.

Ravn 1999b Lack of fracture outcome.

Ravn 1999c Extension/discontinuation study.

Ravn 2000 Extension/discontinuation study.

Rhee 2006 Lack of fracture outcome.



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(Continued)

Rittmaster 2000 Lack of an appropriate control group.

Rizzoli 2002 Lack of an appropriate control group.

Rossini 1994 Duration of therapy < 1 year.

Rossini 2000 Lack of fracture outcome.

Rozkydal 2003 Lack of an appropriate control group.

Sahota 2000 Lack of an appropriate control group.

Sambrook 2004a Lack of an appropriate control group.

Sambrook 2004b Extension/discontinuation study.

Sawka 2003 Non-randomized.

Schneider 1999 Lack of fracture outcome.

Schnitzer 2000 Lack of an appropriate control group.

Seeman 1999 Duplicate or earlier report of another study.

Simon 2002 Lack of an appropriate control group.

Sosa 2002 Lack of an appropriate control group.

Stepan 1999 Lack of fracture outcome.

Tiras 2000 Lack of an appropriate control group.

Tucci 1996 Duplicate or earlier report of another study.

Tutuncu 2005 Lack of fracture outcome.

Uusi-Rasi 2003 Lack of fracture outcome.

van der Poest 2000 Lack of fracture outcome.

Vasikaran 1995 Lack of an appropriate control group.

Yen 2000 Lack of fracture outcome.

Yildirim 2005 Lack of fracture outcome.



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D A T A A N D A N A L Y S E S

Comparison 1. Alendronate 10 mg vs Control - all years baseline denominators

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Vertebral Fractures 6 7361 Risk Ratio (M-H, Fixed, 95% CI) 0.55 [0.45, 0.67]

1.1 Vertebral primary 2 4576 Risk Ratio (M-H, Fixed, 95% CI) 0.55 [0.38, 0.80]

1.2 Vertebral secondary 4 2785 Risk Ratio (M-H, Fixed, 95% CI) 0.55 [0.43, 0.69]



studies

No. of


1 Non Vertebral Fractures 6 9625 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.74, 0.94]

1.1 Non-vertebral primary 2 4576 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.76, 1.04]

1.2 Non vertebral secondary 4 5049 Risk Ratio (M-H, Fixed, 95% CI) 0.77 [0.64, 0.92]



studies

No. of


1 Hip Fractures 7 9952 Risk Ratio (M-H, Fixed, 95% CI) 0.61 [0.40, 0.92]

1.1 Hip primary 2 4576 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.44, 1.44]

1.2 Hip secondary 5 5376 Risk Ratio (M-H, Fixed, 95% CI) 0.47 [0.26, 0.85]



studies

No. of


1 Wrist Fractures 6 9729 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.66, 1.06]

1.1 Wrist primary 2 4576 Risk Ratio (M-H, Fixed, 95% CI) 1.19 [0.87, 1.62]

1.2 Wrist secondary 4 5153 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.36, 0.75]



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Comparison 5. Alendronate 10 mg vs Control - 1 year baseline denominators


studies

No. of


1 Fractures 4 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

1.1 Vertebral 3 306 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.43, 1.63]

1.2 Nonvertebral fractures 2 2052 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.30, 0.89]

1.3 Hip fractures 2 2052 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.11, 4.01]

1.4 Wrist fractures 2 2052 Risk Ratio (M-H, Fixed, 95% CI) 0.40 [0.16, 1.04]

Comparison 6. Alendronate 10 mg vs Control - 1 year baseline denominators


studies

No. of





1.3 Nonvertebral primary 1 144 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]






Comparison 7. Alendronate 10 mg vs Control - 2 years baseline denominators


studies

No. of







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studies

No. of




1.2 Nonvertebral secondary 3 3141 Risk Ratio (M-H, Fixed, 95% CI) 0.82 [0.67, 0.99]





studies

No. of




1.2 Nonvertebral primary 1 4432 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.76, 1.04]





studies

No. of




1.2 Non vertebral primary 1 999 Risk Ratio (M-H, Fixed, 95% CI) 1.58 [0.82, 3.05]




studies

No. of


1 Withdrawals due to side effects 6 8796 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.83, 1.09]

2 Withdrawals overall 5 3273 Risk Ratio (M-H, Fixed, 95% CI) 1.10 [0.94, 1.29]



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A D D I T I O N A L T A B L E S

Table 1. Clinical Relevance Table for Fracture - Primary Prevention Trials

Outcome # Patients #

Trials

Control

Event Rate

Wt Absolute

RD

Wt Rel %

Change

NNT B Statistical Sig Quality of

Evidence

Verte-

bral Fractures

(Trial Popula-

tions)

- Primary Pre-

vention (alen-

dronate

10 mg/day for

1-4 yrs)

4,576 (2) 3.4% (3 out of

100)

-2% 2 fewer

patients out of

100

-45% (I) 66 Statistically

significant

Gold

95% confi-

dence interval

(-2, -1) (-62, -20) (48, 148)

Verte-

bral Fractures

(Low

Risk Woman)

- Primary Pre-

vention (alen-

dronate

10 mg/day for

1-4 yrs)

4,576 (2) 1.2 % (1 out of

100)

Not applicable -45% (I) 186 Statistically

significant

Gold

95% confi-

dence interval

(-62, -20) (135, 417)

Verte-

bral Fractures

(Moderate

Risk Woman)

- Primary Pre-

vention (alen-

dronate

10 mg/day for

1-4 yrs)

4,576 (2) 5.3 % (5 out of

100)


significant

Gold

95% confi-

dence interval

(-62, -20) (31, 95)

Non Vertebral

Fractures

(Trial Popula-

tions)

- Primary Pre-

vention (alen-

4,576 (2) 13.0%

(13 out of 100

patients)

-1% 1 fewer

patient out of

100

-11% (I) Not applicable Not statis-

tically signifi-

cant

Gold



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Table 1. Clinical Relevance Table for Fracture - Primary Prevention Trials (Continued)

dronate

10mg/day for

1-4 years)

95% confi-

dence interval

(-3, 0) (-24, 4)

Non Vertebral

Fractures

(Low

Risk Woman)

- Primary Pre-

vention (alen-

dronate

10mg/day for

1-4 years)

4,576 (2) 8.6% (9 out of

100)

Not applicable -11% (I) Not applicable Not statis-

tically signifi-

cant

Gold

95% confi-

dence interval

(-24, 4)

Non Vertebral

Fractures

(Moderate

Risk Woman)

- Primary Pre-

vention (alen-

dronate

10mg/day for

1-4 years)

4,576 (2) 16.5% (17 out

of 100)


tically signifi-

cant

Gold

95% confi-

dence interval

(-24, 4)

Hip Fractures

(Trial Popula-

tions)

- Primary Pre-

vention (alen-

dronate

10mg/day for

1-4 yrs

4,576 (2) 1.1% (1 out of

100)

0% fewer pa-

tients out of

100


tically signifi-

cant

Gold

95% confi-

dence interval

(-1, 0) (-56, 44)

Hip Fractures

(Low

Risk Woman)

- Primary Pre-

vention (alen-

4,576 (2) 0.4% (0 out of

100)


tically signifi-

cant

Gold



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dronate

10mg/day for

1-4 yrs

95% confi-

dence interval

(-56, 44)

Hip Fractures

(Moderate

Risk Woman)

- Primary Pre-

vention (alen-

dronate

10mg/day for

1-4 yrs

4,576 (2) 1.9% (2 out of

100)


tically signifi-

cant

Gold

95% confi-

dence interval

(-56, 44)

Wrist Frac-

tures (Trial

Populations)

- Primary Pre-

vention (alen-

dronate

10 mg/day for

1-4 yrs)

4,576 (2) 3.1% (3 out of

100)

1 1 more pa-

tient out of

100

19% (W) Not applicable Not statis-

tically signifi-

cant

Gold

95% confi-

dence interval

(0, 2) (-13, 38)

Wrist Frac-

tures (Low

Risk Woman)

- Primary Pre-

vention (alen-

dronate

10 mg/day for

1-4 yrs)

4,576 (2) Not available Not applicable 19% (W) Not applicable Not statis-

tically signifi-

cant

Gold

95% confi-

dence interval

(-13, 38)

Wrist Frac-

tures (Moder-

ate

Risk Woman)

- Primary Pre-

vention (alen-

dronate

4,576 (2) Not available Not applicable 19% (W) Not applicable Not statis-

tically signifi-

cant

Gold



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10 mg/day for

1-4 yrs)

95% confi-

dence interval

(-13, 38)

Legend Pri-

mary preven-

tion = bone

density < 2

SD values be-

low peak bone

mass

and/or no his-

tory of verte-

bral compres-

sion fractures

For Trial Pop-

ulation rates

are based on

the event rate

in the control

group. Low

and Mod-

erate Risk, are

5 year com-

munity popu-

lation risks de-

rived from the

following vari-

ables from the

FRACTURE

Index: age,

fracture after

50 yrs., mater-

nal hip frac-

ture after 50

yrs., weight <

125 lbs, smok-

ing, using

arms to assist

standing and

BMD. Low =

FRACTURE

Index score 1-

2, Moderate =

FRAC-

TURE Index

score 5 (Black

2001) see Fig-

ure 1

Wt =

weighted, RD

= risk differ-

ence

Wt Rel

= weighted rel-

ative percent

change, I = im-

provement

NNT

B = number

needed to ben-

efit

Gold level: At

least one ran-

domised clini-

cal trial meets

all of the fol-

lowing criteria

for the major

outcome

(s) as reported:

Sample sizes of

at least 50 per

group. If a sta-

tistically

significant dif-

ference is not

found they

must be pow-

ered for 20%

relative differ-

ence in the rel-

evant out-

come. Blind-

ing of patients

and as-

sessors for out-

comes. Han-

dling of with-

drawals > 80%

follow up (im-

puta-

tions based on

methods such

as Last Obser-

vation Carried

For-

ward (LOCF)

acceptable).

Concealment

of treatment



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allocation. Sil-

ver level: Ran-

domised trial

does not meet

the above cri-

teria

Table 2. Clinical Relevance Table for Fracture - Secondary Prevention Trials


Trials

Control

Event Rate

Wt Absolute

RD

Wt Rel %

Change

NNT B Statistical Sig Quality of

Evidence

Verte-

bral Fractures

(Trial popula-

tions) - Sec-

ondary Pre-

vention (alen-

dronate 10 mg

for 1-3 yrs)

2,785 (4) 12.2% (12 out

of 100)

-6% 6 fewer

patients out of

100


significant

Gold

95% confi-

dence interval

(-8, -4) (-57, -31) (15, 25)

Verte-

bral Fractures

(Moderate

Risk Woman)

- Secondary

Pre-

vention (alen-

dronate 10 mg

for 1-3 yrs)

2,785 (4) 5.3% (5 out of

100)

NA -45% (I) 42 Statistically

significant

Gold

95% confi-

dence interval

(-57, -31) (34, 61)

Verte-

bral Fractures

(High

Risk Woman)

- Secondary

Pre-

vention (alen-

dronate 10 mg

for 1-3 yrs)

2,785 (4) 11.2% (11 out

of 100)


significant

Gold



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Table 2. Clinical Relevance Table for Fracture - Secondary Prevention Trials (Continued)

95% confi-

dence interval

(-57, -31) (16, 29)

Non Vertebral

Fractures

(Trial Popula-

tion)- Sec-

ondary Pre-

vention (alen-

dronate

10mg/day for

1 - 3 yrs)

5049 (4) 9.3% (9 out of

100)

-2% 2 fewer

patients out of

100


significant

Gold

95% confi-

dence interval

(-4, -1) (-36, -8) (30, 135)

Non Vertebral

Fractures

(Moderate

Risk Woman)

- Secondary

Prevention

(alendronate

10mg/day for

1 - 3 yrs)

5049 (4) 16.5% (17 out

of 100)


significant

Gold

95% confi-

dence interval

(-36, -8) (17, 76)

Non Vertebral

Fractures

(High

Risk Woman)

- Secondary

Prevention

(alendronate

10mg/day for

1 - 3 yrs)

5049 (4) 27.5% (28 out

of 100)

NA -23% 16 Statistically

significant

Gold

95% confi-

dence interval

(-36, -8) (I) (11, 46)

Hip Fractures

(Trial Popula-

tion) - Sec-

ondary Pre-

vention (alen-

dronate

10mg/day for

5,376 (5) 1.3% ( out of

100)

-1% 1 fewer

patients out of

100

-53% ( -74, -

15) (I)

146 Statistically

significant

Gold



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1-3 yrs)

95% confi-

dence interval

(-1, 0) (104, 513)

Hip Fractures

(Moderate

Risk Woman)

- Secondary

Prevention

(alendronate

10mg/day for

1-3 yrs)

5,376 (5) 1.9% (2 out of

100)

NA -53% ( -74, -

15) (I)

100 Statistically

significant

Gold

95% confi-

dence interval

(72, 351)

Hip Fractures

(High

Risk Woman)

- Secondary

Prevention

(alendronate

10mg/day for

1-3 yrs)

5,376 (5) 8.9% (9 out of

100)

NA -53% ( -74, -

15) (I)

22 Statistically

significant

Gold

95% confi-

dence interval

(16, 75)

Wrist

Fractures

(Trial Popula-

tion) - Sec-

ondary Pre-

vention (alen-

dronate

10mg/day for

1-3 yrs)

5,153 (4) 2.9% (3 out of

100)

-1% 1 fewer

patients out of

100

-50% (-66, -

27) (I)

69 Statistically

significant

Gold

95% confi-

dence interval

(-2, -1) (53, 128)

Wrist Frac-

tures - Sec-

ondary Pre-

vention (alen-

dronate

10mg/day for

1-3 yrs)

5,153 (4) NA NA -50% (-66, -

27) (I)

NA Statistically

significant

Gold



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95% confi-

dence interval

Wrist Frac-

tures - Sec-

ondary Pre-

vention (alen-

dronate

10mg/day for

1-3 yrs)

5,153 (4) NA NA -50% (-66, -

27) (I)

NA Statistically

significant

Gold

Legend Secondary

prevention =

bone density

of at least 2

SD values be-

low peak bone

mass and/

or one or more

vertebral com-

pression frac-

tures

For Trial Pop-

ulation

rates are based

on the event

rate in the

control group.

Moderate and

High Risk, are

5 year com-

munity popu-

lation risks de-

rived from the

following vari-

ables

in the FRAC-

TURE Index:

age,

fracture after

50 yrs., mater-

nal hip frac-

ture after 50

yrs., weight <

125 lbs, smok-

ing, using

arms to assist

standing and

BMD. Mod-

erate = FRAC-

TURE Index

score 5, High

= FRAC-

TURE In-

dex score 8-13

(Black 2001)

see Figure 1

Wt =

weighted, RD

= risk differ-

ence

Wt Rel

= weighted rel-

ative percent

change, I = im-

provement

NNT

B = number

needed to ben-

efit

Gold level:

At

least one ran-

domised clini-

cal trial meets

all of the fol-

lowing criteria

for the major

outcome(s) as

reported:

Sample

sizes of at least

50 per group.

If a statistically

significant dif-

ference is not

found they

must be pow-

ered

for 20% rela-

tive difference

in the relevant

outcome.

Blind-

ing of patients

and assessors

for outcomes.

Han-

dling of with-

drawals > 80%

follow up (im-

puta-

tions based on

methods such



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as Last Obser-

vation Carried

For-

ward (LOCF)

acceptable).

Concealment

of treatment

allocation.

Silver level:

Ran-

domised trial

does not meet

the above cri-

teria.

F E E D B A C K

Feedback from Maryann Napoli, 2 June 2008

Summary

Date of Submission: 02-Jun-2008

Name: Maryann Napoli

Email Address: [email protected]

Personal Description: Occupation a consumer advocate

Feedback: I like the new format of the plain language summary, particularly the way you have expressed “best estimates.” But there is

a glaring omission: You should also provide an estimate of the number of hip fractures, vertebral fractures, etc out of 100 women who

do NOT take alendronate. If this and future PLS do not include numerical information about the no-treatment options, then it will

not be clear to readers what their chances of having a hip fracture, vertebral fracture, etc. are to begin with. People will want to know

“one fewer than what?”

Submitter agrees with default conflict of interest statement: I certify that I have no affiliations with or involvement in any organization

or entity with a financial interest in the subject matter of my feedback.

Reply

Thank you for your feedback about the Plain language summary. The CSMG has been and continues to be actively involved in research

to summarise our reviews in a format that is useful and comprehensible to consumers.

Your feedback addresses the issues around providing absolute event rates and absolute differences to consumers, in particular for

dichotomous outcomes. In summaries that we have published in earlier reviews, review authors presented primarily absolute event

rates without differences. In this review, differences were provided, but event rates were not. Unfortunately we do not have high quality

evidence to determine the best presentation, but we continue to investigate and explore the options. User testing of a variety of Plain

language summary formats, which is funded by the Cochrane Collaboration Opportunity Fund, is pending and we look forward to

the results.

As you have suggested, we have edited this Plain language summary to present absolute event rates.



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http://mailto:[email protected]

Contributors

George A. Wells, Nancy Santesso, Tamara Rader.

Feedback from Mark Porcheret, 22 December 2010

Summary

Date of Submission: 22-Dec-2010

Name: Mark Porcheret


Personal Description: Occupation GP Research fellow

Feedback: In figure 6 on page 20 the “corresponding risk” for the outcome “hip fractures” for the moderate risk population is stated to

be 19 per 1000 (CI 5 to 16). Could you confimr this is a typo and should be 9 per 1000.

Also, I am trying to interpret this data for an EBP group I facilitate and have a question: the risks in figure 6 are 5yr risks comparing

people on alendronate to those not taking it. But the heading states it is for alendronate for 1-3yrs. So, I am not sure how to phrase the

evidence for use in the consultation. Does that data mean, for example for vertebral factures in the moderate risk populations, that:

“If you take a 1000 people like you, those at moderate risk, in 5yrs time 63 will have had a vertebral fracture, but if all 1000 took

alendronate for the 5 years only 29 will have had a vertebral fracture.” This is how such a comparison would normally be comminicated

with the period of risk / benefit being the same as the period of treatment, but the figure presents 5yr risks for 1-3yrs of treatment,

which complicates the message. Your views on this would be welcome before the meeting we have to discuss this on 12th January 2011.

Many thanks Mark Porcheret

Submitter agrees with default conflict of interest statement:

I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of

my feedback.

Reply

Many thanks for your feedback on this review. Please find below our response to your comment after consultation with the lead author,

George Wells.

Regarding your first point, yes, we can confirm that there is a typo here and it should state 9 per 1000. We will fix this for the next

issue of the Library.

For your second point, yes, the risks in the table are for 5 year risks and your interpretation is correct (though the ’63’ in your email

should be ’53’ as from the table). The ’1-3’ years in the heading simply indicates that the relative risk came from studies of 1 to 3 years

duration (since this is the best evidence that we have) but were modeled on a 5-year time horizon. We agree this heading is confusing

so we will take the ’1-3’ out of the heading and explain this in a footnote in the table for the next issue. We also noticed that the high-

risk population should state 62/1000 instead of 62/100.

Thanks again for bringing this to our attention.

Contributors

George A Wells, Lara Maxwell.



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Feedback from Aaron M Tejani, 17 December 2010

Summary

Date of Submission: 17-Dec-2010

Name: Aaron M Tejani

Email Address: [email protected] Personal Description: Occupation a pharmacist

Feedback: In the review, alendronate was found to have a statistically significant benefit for primary vertebral fracture prevention (45%

RRR, 95% CI of 0.38 to 0.80). The results were compiled from two studies that were conducted by Ascott-Evans et al. (2) (2003) and

Cummings et al. (3) (1998) (as shown by Analysis 1.1 figure). Based on closer inspection of these two studies we have some specific

concerns.

The review (1) cited that vertebral fractures did not occur in neither the treatment nor control group in the study by Ascott-Evans et

al. (2) as shown in the Analysis 1.1 figure. However, the study did not report the incidence of vertebral fractures. It is incorrect to

assume that no vertebral fractures occurred simply because they were not reported in the trial publication. The authors of the review

need to clarify if unpublished vertebral fracture information was received from Ascott-Evans et al.

The other study that contributed to the vertebral fracture meta-analysis for alendronate was Cummings et al. 2003 (3). In this trial

vertebral fractures were solely radiographically determined and not clinical fractures. The review authors should emphasize that the

data used in the meta-analysis of alendronate in primary prevention from Cummings et al. 2003 was only for non-clinical vertebral

fractures.

If this review is revised, we urge the authors to also clarify whether alendronate reduces the risk of clinical vertebral fractures in

secondary prevention. It would be very useful if these authors also clarify the non-clinical versus clinical fracture issue for all the oral

bisphosphonate reviews.(4,5)

1. Wells GA, Crannery A, Peterson J, Boucher M, Shea B, Welch V, Coyle D, Tugwell P. Alendronate for the primary and secondary

prevention of osteoporotic fractures in postmenopausal women. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.:

CD001155. DOI: 10.1002/14651858.CD001155.pub2.

2. Ascott-Evans BH, Guanabens N, Kivinen S, Stuckey BG, Magaril CH, Vandormael K, et al. Alendronate prevents loss of bone

density associated with discontinuation of homrone replacement therapy: a randomized controlled trial. Archives of Internal Medicine

2003; 163(7): 789-94.

3. Cummings SR, Black DM, Thompson DE, Appleggate WB, Barrett-Connor E, Musliner TA, et al. Effect of alendronate on risk

of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998;

280(24):2077-82.

4. Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Welch V, Coyle D, Tugwell P. Etidronate for the primary and secondary


CD003376. DOI: 10.1002/14651858.CD003376.pub3.

5. Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Welch V, Coyle D, Tugwell P. Risedronate for the primary and secondary


CD004523. DOI: 10.1002/14651858.CD004523.pub3.

Submitter agrees with default conflict of interest statement:


my feedback.



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Reply

Dear Dr Tejani,

Thank you for your feedback regarding our review.

With respect to the Ascott-Evans study, we determined the absence of vertebral fractures from the information provided in the

publication. (We did not request additional data from any study authors as the selective response often elicited to such a request may

introduce a source of bias.) Fractures, in this paper, were assessed as adverse events. Adverse events were recorded by study personnel at

each visit using non-leading questions. In reporting these events, in the results section of the paper, the authors stated that “no fractures

were reported during the study”. We agree that it may have been presumptuous of us to assume the absence of vertebral fractures from

this report and we would not be adverse to removing this study from the analysis. Doing so, however, would not substantially alter our

results or conclusions.

Your concern regarding the Cummings paper is a point well taken. This was the only primary prevention study which reported both

radiographic and clinical fractures as separate outcomes. Since the other papers (with the exception of Ascott-Evans having 0 events)

reported only radiographic vertebral fractures we decided, for the sake of consistency, to use the radiographic outcome for Cummings

in the meta-analysis. (As well, all of the alendronate studies in the secondary prevention analysis reported only radiographic fractures.)

Your suggestion that we clarify the issue surrounding clinical and non clinical fractures for future bisphosphonate updates is a good

one and will be included in the next update of the review.

We hope that these responses are helpful. Please do not hesitate to contact us should you have any further questions or concerns.

Contributors

Geroge A. Wells, Elizabeth Ghogomu.

Feedback from George Hannah, 5 November 2010

Summary

Name: George hannah


Personal Description: Occupation GP

Feedback: I am uncertain what length of treatment of alendronate is being referred to in the review, to produce the NNT. When you

may be treating women in their 60s to prevent fractures in their 80s? Does treatment have to be ongoing to produce the benefit? Is 5

years a standard length. How does this affect NNT? ie is the NNT in year one, less than year 2, year 3 etc of treatment.

Submitter has modified conflict of interest statement:


my feedback.

Reply

Dear Dr Hannah,

The NNTs reported in our review are derived from the pooling of trials varying in length between 1 and 4 years. (The majority of

subjects stemmed from trials which had follow ups of 3 or 4 years). These studies were designed to evaluate the current use of alendronate

and did not provide for an off drug follow up period. The estimates reported in our review cannot be extrapolated to a future date at

which the patient is no longer taking the medication.

You had also asked if 5 years was a standard treatment length. We did not make any recommendations in the review regarding length

of treatment. We used 5 year risk estimates in our Summary of Findings tables and in Figure 9 as the FRACTURE Index (Black 2001)

used to classify women according to baseline risk factors was based on 5 year community population risks.

With respect to the effect of length of treatment on the NNTs, we did provide a breakdown of treatment effects by year of follow up

in Figure 11,which could, theoretically, be translated into NNTs. These estimates, however, should be viewed with caution as in some

cases they are comprised of interim time point data.



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Contributors

George A. Wells, Elizabeth Ghogomu.

W H A T ’ S N E W

Last assessed as up-to-date: 13 November 2007.

Date Event Description

8 July 2011 Feedback has been incorporated Responses to queries about:

1. clincal and non-clinical fractures

2. NNT calculation.

H I S T O R Y

Protocol first published: Issue 3, 2005

Review first published: Issue 1, 2008


13 January 2011 Feedback has been incorporated Amendments in Figure 6: Summary of Findings for Secondary Prevention

12 August 2008 Feedback has been incorporated Absolute event rates included in the Plain language summary.

28 May 2008 Amended Converted to new review format.CMSG ID C004-R

C O N T R I B U T I O N S O F A U T H O R S

George Wells was involved in the conception, design and implementation of the project and contributed significantly to the writing of

the report.

Ann Cranney was involved with the conception of the review, data abstraction, analysis, interpretation and revision of the final report.

Joan Peterson screened the literature, was involved in the data abstraction, quality assessment and analysis of the primary trials and

contributed significantly to the writing of the report.

Michel Boucher assisted in the design of the analysis, reporting and interpretation of the findings and was involved in the writing of

the report.

Beverley Shea was involved in developing the protocol and conducting the systematic review.

Vivian Robinson was involved in developing the protocol and conducting the systematic review.

Douglas Coyle assisted with the design of the review and reviewed the analysis.

Peter Tugwell provided clinical rheumatology expertise and methodological guidance.



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D E C L A R A T I O N S O F I N T E R E S T

None.

S O U R C E S O F S U P P O R T

Internal sources

• Ottawa Hospital Research Institute, Canada.

External sources

• Canadian Agency for Drugs and Technologies in Health, Canada.

I N D E X T E R M S

Medical Subject Headings (MeSH)

Alendronate [∗therapeutic use]; Bone Density Conservation Agents [∗therapeutic use]; Fractures, Bone [∗prevention & control];

Fractures, Spontaneous [prevention & control]; Hip Fractures [prevention & control]; Osteoporosis, Postmenopausal [∗drug therapy];

Randomized Controlled Trials as Topic; Spinal Fractures [prevention & control]

MeSH check words

Female; Humans



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Risedronate for the primary and secondary prevention of

osteoporotic fractures in postmenopausal women (Review)

Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Welch V, Coyle D, Tugwell P



Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)


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1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


3BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

13RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Figure 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Figure 10. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Figure 11. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Figure 12. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Figure 13. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Figure 14. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Figure 15. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Figure 16. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Figure 17. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Figure 18. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Figure 19. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Figure 20. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Figure 21. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Figure 22. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

31DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 23. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34



35REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

39CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

49DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


60WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

60HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

60CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

61DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


61NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

62INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iRisedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)


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[Intervention Review]

Risedronate for the primary and secondary prevention ofosteoporotic fractures in postmenopausal women

George A Wells1, Ann Cranney2, Joan Peterson3, Michel Boucher4, Beverley Shea5, Vivian Welch6, Doug Coyle7, Peter Tugwell8

1Cardiovascular Research Reference Centre, University of Ottawa Heart Institute, Ottawa, Canada. 2 Division of Rheumatology, Ottawa

Hospital, Ottawa, Canada. 3Clinical Epidemiology Unit, Ottawa Civic Hospital / Loeb Research Institute, Ottawa, Canada. 4HTA

Development Canadian Agency for Drugs and Technologies in Health (CADTH), Ottawa, Canada. 5Institute of Population Health,

University of Ottawa, Ottawa, Canada. 6Centre for Global Health, Institute of Population Health, University of Ottawa, Ottawa,

Canada. 7Epidemiology and Community Medicine, Ottawa Health Research Institute, Ottawa, Canada. 8Centre for Global Health,

Institute of Population Health, Department of Medicine, Ottawa Hospital, Ottawa, Canada

Contact address: George A Wells, Cardiovascular Research Reference Centre, University of Ottawa Heart Institute, Room H1-1, 40

Ruskin Street, Ottawa, Ontario, K1Y 4W7, Canada. [email protected].

Editorial group: Cochrane Musculoskeletal Group.

Publication status and date: Edited (no change to conclusions), published in Issue 7, 2010.

Review content assessed as up-to-date: 13 November 2007.

Citation: Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Welch V, Coyle D, Tugwell P. Risedronate for the primary and

secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database of Systematic Reviews 2008, Issue 1. Art.

No.: CD004523. DOI: 10.1002/14651858.CD004523.pub3.


A B S T R A C T

Background

Osteoporosis is an abnormal reduction in bone mass and bone deterioration leading to increased fracture risk. Risedronate belongs to

the bisphosphonate class of drugs which act to inhibit bone resorption by interfering with the activity of osteoclasts.

Objectives

To assess the efficacy of residronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women.

Search strategy

We searched CENTRAL, MEDLINE and EMBASE. Relevant randomized controlled trials published between 1966 to 2007 were

identified.

Selection criteria

Women receiving at least one year of risedronate for postmenopausal osteoporosis were compared to those receiving placebo or

concurrent calcium/vitamin D or both. The outcome was fracture incidence.


We carried out study selection and data abstraction in duplicate. Study quality was assessed through the reporting of allocation

concealment, blinding and withdrawals. Meta-analysis was preformed using relative risks and a >15% relative change was considered

clinically important.

1Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)


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mailto:[email protected]

Main results

Seven trials were included in the review representing 14,049 women.

Relative (RRR) and absolute (ARR) risk reductions for the 5 mg dose were as follows. Risk estimates for primary prevention were

available only for vertebral and non vertebral fractures and showed no statistically significant effect of risedronate on fractures. For

secondary prevention, a significant 39% RRR in vertebral fractures (RR 0.61, 95% CI 0.50 to 0.76) with 5% ARR was found. For non-

vertebral fractures, a significant 20% RRR (RR 0.80, 95% CI 0.72 to 0.90) with 2% ARR and for hip fractures there was a significant

26% RRR (RR: 0.74, 95% CI 0.59 to 0.94) with a 1% ARR. When primary and secondary prevention studies were combined, the

reduction in fractures remained statistically significant for both vertebral (RR 0.63, 0.51 to 0.77) and non vertebral fractures (RR 0.80,

0.72 to 0.90)

For adverse events, no statistically significant differences were found in any of the included studies. However, observational data has

led to concerns regarding the potential risk for upper gastrointestinal injury and, less commonly, osteonecrosis of the jaw.


At 5 mg/day a statistically significant and clinically important benefit in the secondary prevention of vertebral, non-vertebral and hip

fractures was observed, but not for wrist. The level of evidence for secondary prevention is Gold (www.cochranemsk.org) for vertebral

and non-vertebral and Silver for hip and wrist. There were no statistically significant reductions in the primary prevention of vertebral

and non-vertebral fractures. The level of evidence is Silver.


Risedronate for preventing fractures caused by osteoporosis in postmenopausal women

This summary of a Cochrane review, presents what we know from research about the effect of Risedronate for preventing fractures

(broken bones) caused by osteoporosis.

In women who have already been diagnosed with low bone density putting them at risk for fracture or have already had a

fracture in the bones of their spine, risedronate:

- probably prevents fractures in the bones of the spine and in bones other than in the spine;

- may prevent hip fractures;

- may not lead to any difference in wrist fractures.

In women whose bone density is closer to normal or who may not yet have had a fracture in the bones of their spine, risedronate:

may not lead to any difference in fractures in the bones of the spine, hip fractures or wrist fractures;

there is not enough information to tell if Risedronate prevents fractures in bones other than in the spine.

We do not have precise information about side effects and complications. This is particularly true for rare but serious side effects.

Possible side effects may include digestive problems such as damage to the throat, esophagus and stomach and, less commonly, reduced

blood supply to the jaw bone, which causes the bone tissue to breakdown .

What is osteoporosis and what is risedronate?

Bone is a living, growing part of your body. Throughout your lifetime, new bone cells grow and old bone cells break down to make

room for the new, stronger bone. When you have osteoporosis, the old bone breaks down faster than the new bone can replace it. As

this happens, the bones lose minerals (such as calcium). This makes bones weaker and more likely to break even after a minor injury,

like a little bump or fall. Women who have gone through menopause are more likely to get osteoporosis than other people.



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Risedronate belongs to the class of drugs called bisphosphonates. It is a type of medication that slows down the cells that break down

the old bone.

Best estimate of what happens to women that have already been diagnosed with low bone density putting them at risk for

fracture or have already had a fracture in the bones of their spine, who take Risedronate:



- 9 out of 100 women had a fracture when taking Risedronate

Fracture in the hip



Fracture in the wrist


- 3 out of 100 women had a fracture when taking Risedronate.

Fractures in bones other than the spine



Best estimate of what happens to women whose bone density is closer to normal or who may not yet have had a fracture in the

bones of their spine who take risedronate:

- there is no difference in the number of women out of 100 who will have a spine fracture. This may be the result of chance.

- for hip and wrist fractures, it is not possible to calculate the effect because no one had fractures of the hip or wrist in the

studies.

- there is not enough information to tell if Risedronate prevents fractures in bones other than in the spine.

B A C K G R O U N D

Osteoporosis is in part a natural consequence of aging in post-

menopausal women (Hodsman 2002). It is a skeletal disorder char-

acterized by decreased bone mass and deterioration of microar-

chitecture of bone resulting in an increased risk of fracture (NIH

Consensus 2001).

The most common consequences of osteoporosis are fractures of



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the hip, wrist and vertebrae (Hodsman 2002). “Bone strength re-

flects the integration of two main features: bone density and bone

quality” (Brown 2002b). The clinical indicator of bone quality is a

patient’s history of a fragility fracture. A fragility fracture is a frac-

ture caused by an injury that would be insufficient to fracture nor-

mal bone (for example, a fall from a standing height or less)(Brown

2002b). The preferred method of evaluating bone density is the

measurement of bone mineral density (BMD) of the lumbar spine

and hip by Dual Energy X-ray Absorptiometry (DXA), which can

be used to assess response to therapy (Hanley 2003).

The interpretation of BMD results is based on comparison of a

patient’s BMD with the mean value for a young adult population.

The “T-score” is the number of standard deviations (SDs) above

or below the mean BMD for normal young adults (Brown 2002b).

The World Health Organization (WHO) Study Group on Os-

teoporosis defined osteoporosis as “a hip BMD level of more than

2.5 SDs below the mean BMD for young, white, adult women”

(WHO 1994). Using the WHO definition, approximately 30%

of postmenopausal women have osteoporosis (Kanis 1994; WHO

1994). It should be noted that there are limitations associated with

the WHO definition. The predictive value of BMD measurement

for fracture varies depending on the site selected, database used

for comparison and the technology used. Furthermore, T-scores

do not provide a good basis to establish comparable diagnostic

thresholds between different regions of interest and different bone

mass measurement techniques (Black 2001). As a result, between-

site and technique variability introduces potential for misclassifi-

cation and inappropriate treatment of some individuals.

Osteoporosis can be detected by BMD measurement or diagnosed

by presence of osteoporosis-related fractures. The presence of pre-

existing osteoporotic fractures is an important risk factor for future

fractures (Hodsman 2002). It is reported that 25% of women

aged 80 have had at least one vertebral fracture (Melton 1989)

and Cauley et al., (Cauley 2000) demonstrated excess mortality

in women who have experienced a clinical vertebral fracture. The

cumulative lifetime fracture risk for a 50-year-old woman with

osteoporosis is stated to be as high as 60% (Cummings 1989). As

a result, effective fracture prevention would have a major impact

on morbidity and a smaller but important impact on mortality in

these women.

Osteoporosis-related morbidity is associated with significant med-

ical and social consequences (Brown 2002b). The major source

of morbidity and mortality from osteoporosis is attributed to hip

fractures. Hip fractures are not only associated with an increase

mortality risk but also influence long-term function and indepen-

dence. Fifty per cent of women who sustain a hip fracture do not

return to their previous functional state and become dependent

on others for their daily activities (Brown 2002b). The mortality

associated with hip fractures in older women may be as high as

20% in the first year (Cauley 2000). This excess mortality may

not be directly attributable to the hip fracture, but to comorbid

conditions (Browner 1996; Cooper 1993).

Prevention and treatment of osteoporosis can be complex, due to

the multifactorial etiology of the disorder. New anabolic therapies

directed at increasing bone formation, such as teriparatide (recom-

binant human parathyroid hormone (1-34)), (Shukla 2003) are

available, however most currently available osteoporosis drugs are

anti-resorptive agents that act to decrease bone turnover. One class

of anti resorptive drugs includes the bisphosphonates: etidronate,

alendronate and risedronate. They are recommended as first-line

preventive agents in postmenopausal women with low BMD and

as first-line agents for the treatment of postmenopausal women

with osteoporosis (Brown 2002b).

Bisphosphonates are stable analogues of naturally occurring py-

rophosphates. The mechanism of action of these drugs is to in-

hibit bone resorption through their effects on osteoclasts (Brown

2002b). Bisphosphonates are poorly absorbed and avidly taken

up by bone on active sites of resorption. Risedronate is a nitro-

gen containing pyridinyl third generation bisphosphonate which

is administered daily or once weekly (depending on formulation).

The recommended dose for the prevention and treatment of os-

teoporosis in postmenopausal women is 5 mg/day (35 mg / week)

. Risedronate at 5 mg, relative to control, has been shown to in-

crease bone mineral density after 1.5 to three years of treatment

by 4.54% (95% CI 4.12 to 4.97) in the lumbar spine, and 2.75%

(95% CI 2.32 to 3.17) in the femoral neck (Cranney 2002). At

a dose of 2.5 mg increases at the lumbar spine and femoral neck

were 2.94% (95% CI 1.55 to 4.34) and 1.71%, (95% CI 1.17 to

2.25) (Cranney 2002).

O B J E C T I V E S

The aim of this systematic review was to assess the clinical effi-

cacy of risedronate in the primary and secondary prevention of

osteoporotic fractures in postmenopausal women receiving these

agents compared with untreated women over a follow-up period

of at least one year.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs) with a duration of at least

one year were included in this review.



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The population group of interest was post menopausal women.

Both primary and secondary prevention trials were accepted. A

hierarchy was used to define primary versus secondary prevention

according to the information available. We selected a definition of

primary and secondary prevention that gave more weight to study

inclusion criteria than baseline statistics. That is, if the inclusion

criteria restricted the population to women whose bone density

was at least 2 SD values below the peak bone mass or the inclu-

sion criteria restricted the population to women that had experi-

enced previous vertebral compression fractures, then the trial was

considered a secondary prevention study. If such inclusion criteria

were not provided then the baseline statistics were considered as

follows: (a) we considered the trial as primary prevention if the

average T-score (and SD) was such that it included women whose

bone density was within 2 SD of the mean or if the prevalence

of vertebral fracture at baseline was less than 20%; and (b) when

these data were not available, we considered a trial as secondary

prevention if the average age was above 62 years.

Types of interventions

Treatment: Risedronate at any dose.

Comparators: No treatment (including placebo or calcium or vita-

min D or both). If the study used calcium or vitamin D controls or

both, these same treatments would have to be given concurrently

in the risedronate treatment group.


Incidence of fractures, including vertebral, non-vertebral, hip and

wrist fractures.

Search methods for identification of studies

The Cochrane Collaborative approach for identifying randomized

controlled trials (RCTs) as described by Dickersin et al., (Dickersin

1994) and modified for the Cochrane Musculoskeletal Group,

guided our literature search. We searched the Cochrane Cen-

tral Register of Controlled Trials (CENTRAL), MEDLINE from

1966 to November 2004, Current Contents, and citations of rel-

evant articles. No language restrictions were applied to the search

strategy. The actual literature search was conducted in three stages.

The first stage was the basis for our systematic review published

in 2002 (Cranney 2002) and the second and third stages involved

updating the search. The first search, for the time period 1966

to December 2000, included Cochrane Controlled Trials Regis-

ter, MEDLINE, EMBASE, Current Contents, and handsearching

of conference abstracts and FDA proceedings. This was followed

by a MEDLINE search for the time period 2000 to November

2004. This MEDLINE search was confirmed by a parallel litera-

ture search that was conducted for a companion bisphosphonate

economic report CADTH 2006. For the final update (2004 to

February 2007), we searched the Cochrane Central Register of

Controlled Trials (CENTRAL), MEDLINE and EMBASE.

Search Strategy MEDLINE Using OVID Interface

1. osteoporosis, postmenopausal/

2. osteoporosis/

3. osteoporosis.tw.

4. exp bone density/

5. bone loss$.tw.

6. (bone adj2 densit$).tw.

7. or/2-6

8. menopause/

9. post-menopaus$.tw.

10. postmenopaus$.tw.

11. or/8-10

12. 7 and 11

13. 1 or 12

14. risedronate.tw.

15. 13 and 14

16. meta-analysis.pt,sh.

17. (meta-anal: or metaanal:).tw.

18. (quantitativ: review: or quantitativ: overview:).tw.

19. (methodologic: review: or methodologic: overview:).tw.

20. (systematic: review: or systematic: overview).tw.

21. review.pt. and medline.tw.

22. or/16-21

23. 15 and 22

24. clinical trial.pt.

25. randomized controlled trial.pt.

26. tu.fs.

27. dt.fs.

28. random$.tw.

29. (double adj blind$).tw.

30. placebo$.tw.

31. or/24-30

32. 15 and 31


Selection of studies

Two review authors examined each title generated from the search

and identified potentially eligible articles, for which we obtained

the abstracts. We obtained the full article text for abstracts consis-

tent with study eligibility. Overall, we only considered published

studies for inclusion, either as the full article or abstract.

Data abstraction strategy

Two independent review authors abstracted all information and

data using standardized data abstraction forms with a third review

author verifying the data. Abstraction included information on

pertinent methodological aspects of the study design, character-

istics of the participants, the specific dose of the study drug used

and the outcomes assessed (e.g. number of vertebral, non-verte-



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bral, hip and wrist fractures). For fracture data, we considered all

reported fractures (whether clinical or radiographic).

For the yearly data, our unit of analysis was number of patients

sustaining a fracture. If an article reported yearly data, we used

the time points available. For baseline denominators we used the

same baseline denominator for each time point. For follow-up

denominators we used any yearly follow-up number of patients

reported in the article, if available. If these were not available, we

assumed a uniform drop-out rate for each year and calculated the

denominators by determining the proportion of participants that

would have remained at the end of the year in question based

on the number of withdrawals over the course of the study. If

an article reported only end of study outcomes, these were used

for our analysis with the exception of outcomes for which the

numerator was zero for both treatment groups. In these instances,

we included the outcome (with any necessary adjustments for

follow-up denominators) for the earlier years in the duration of the

study. For example, if a trial reported zero hip fractures for both

treatment arms at the end of year three, we would also include in

our analysis zero hip fractures for that trial at years one and two.

For person year data, the unit of analysis, if available, was number

of fractures. When these data were not available (that is, in the

majority of cases), we used the number of women sustaining a

fracture. For denominators, we multiplied the number of women

followed by the length of the study. For radiographic vertebral frac-

tures we used the number of women with available radiographs,

if the number was reported in the article. For clinical fractures,

we estimated the number of women followed over the duration

of the study by taking the mean of the baseline and follow-up

denominators.

Strategy for quality assessment

Two review authors assessed each eligible RCT for quality based on

allocation concealment. Research has shown that lack of adequate

allocation concealment is associated with bias, (Higgins 2005) and

studies can be judged on the method of allocation concealment.

The method for assigning participants to interventions should be

robust against patient and clinician bias and its description should

be clear. The review authors were required to indicate whether

allocation concealment was adequate (A), unclear (B), or inade-

quate (C) as per the Cochrane Collaboration criteria as follows:

Adequate: The following are some approaches that can be used to

ensure adequate concealment schemes: centralized or pharmacy-

controlled randomization, pre-numbered or coded identical con-

tainers which are administered serially to participants, on-site com-

puter system combined with allocations kept in a locked unread-

able computer file that can be accessed only after the characteristics

of an enrolled participant have been entered or sequentially num-

bered or sealed, opaque envelopes. Other approaches may include

those similar to ones listed previously, along with reassurance that

the person who generated the allocation scheme did not adminis-

ter it.

Inadequate: Approaches to allocation concealment that are con-

sidered inadequate include: alternation, use of case record num-

bers, dates of birth or day of the week and any procedure that is

entirely transparent before allocation, such as an open list of ran-

dom numbers.

Unclear: When studies do not report any concealment approach,

adequacy should be considered unclear. Examples include merely

stating that a list or table were used, only specifying that sealed en-

velopes were used and reporting an apparently adequate conceal-

ment scheme in combination with other information that leads

the review author to be suspicious.

In addition, blinding and loss to follow up were assessed.

Data analysis

For the analysis of fractures (i.e. vertebral, non-vertebral, hip and

wrist), we calculated the relative risk (RR) of fracture using a fixed-

effect model. The methods we used for pooling the results are de-

scribed elsewhere by Fleiss, (Fleiss 1993). We calculated the pooled

or weighted RRs using the general inverse variance method for

the weights. For the pooled results, we calculated site-specific 95%

confidence intervals (CIs) for vertebral, non-vertebral, hip and

wrist fractures and we tested for association using a chi-squared

test procedure taking P value < 0.05 for presence of statistical as-

sociation. Statistically significant risk reductions were considered

to be clinically important if a 15% or greater relative benefit was

shown. We also tested for homogeneity using a chi-squared test

procedure taking the specific cut-off for presence of statistical het-

erogeneity as P = 0.10 ( Fleiss 1993). In the event of significant

heterogeneity, a random-effects model was used.

If the relative risk reduction (RRR) was significant (P < 0.05),

then the absolute risk reduction (ARR) and number needed to

treat to benefit (NNTB) were calculated. For these calculations,

the five year risk of fracture in the untreated population was based

on the FRACTURE Index (FI) of Black et al., (Black 2001) and

the lifetime and five year age-specific risks in the untreated popu-

lation were based on the model by Doherty et al., (Doherty 2001)

for predicting osteoporotic fractures in postmenopausal women

(Figure 1; Figure 2; Figure 3; Figure 4.)



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Figure 1. Models for fracture risk in postmenopausal women: FRACTURE Index



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Figure 2. Five year risk of fracture by Quintiles of the FRACTURE Index: Assessment with bone mineral

density

Figure 3. Five year risk of fracture by Quintiles of the FRACTURE Index: Assessment without bone mineral

density



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Figure 4. Estimated five year age-specific risks of first and subsequent osteoporotic fractures (from Doherty

et al 2001)

Trials varied as to the length of treatment (for example, one to four

years) and the number of patients available for study at the start

of treatment (that is, baseline denominator) compared to those

available at different time points during the trial (that is, follow-

up denominators). The base case taken for the review of fractures

considered the data available for the longest period of time for the

treatment in the trial (that is, “all years”) and used the baseline

denominators for the number of patients in the trial.

Data was initially pooled broadly across primary and secondary

trials. The overall analysis was also considered using person years of

observation. In addition, we conducted subgroup analysis for: 1)

primary versus secondary, 2) treatment duration and 3) treatment

dose. Furthermore, we conducted sensitivity analysis for: 1) base-

line denominators versus follow-up denominators, 2) fixed versus

random-effects model, and 3) baseline vertebral fracture rate. For

the last sensitivity analysis, recall that the vertebral fracture criteria

for a trial to be considered secondary was a prevalence of vertebral

fracture at baseline of greater than 20%. A sensitivity analysis us-

ing different vertebral fracture rates (i.e. 100%, > 80%, > 60%, >

40%, > 20%) without the BMD and age criteria was conducted.

Such sensitivity analysis allowed evaluating whether the effect of

bisphosphonates on the secondary prevention of osteoporotic frac-

tures varied, depending on how strictly secondary prevention was

defined.

Grading of evidence

Results from the primary analyses were graded according to the

system described in the 2004 book Evidence-based Rheumatol-

ogy (Tugwell 2004) and recommended by the Cochrane Muscu-

loskeletal Group:

Platinum

To achieve the platinum level of evidence, a published systematic

review that has at least two randomized controlled trials each sat-

isfying the following is required.

• Sample sizes of at least 50 per group - if these do not find a

statistically significant difference, they are adequately powered

for a 20% relative difference in the relevant outcome.

• Blinding of patients and assessors for outcomes.

• Handling of withdrawals > 80% follow up (imputations

based on methods such as Last Observation Carried Forward

(LOCF) are acceptable).

• Concealment of treatment allocation.

Gold

The gold level of evidence requires at least one randomized clinical

trial meeting all of the following criteria for the major outcome(s)

as reported:

• Sample sizes of at least 50 per group - if these do not find a

statistically significant difference, they are adequately powered

for a 20% relative difference in the relevant outcome.

• Blinding of patients and assessors for outcomes.

• Handling of withdrawals > 80% follow up (imputations

based on methods such as LOCF are acceptable).

• Concealment of treatment allocation.



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Silver

The silver level of evidence requires a randomized trial that does

not meet the above criteria for gold or platinum ranking or ev-

idence from at least one study of non-randomized cohorts that

did and did not receive the therapy, or evidence from at least one

high quality case-control study. A randomized trial with a ’head-

to-head’ comparison of agents would be considered silver level

ranking unless a reference were provided to a comparison of one

of the agents to placebo showing at least a 20% relative difference.

Bronze

The bronze level of evidence requires at least one high quality case

series without controls (including simple before/after studies in

which patients act as their own control) or a conclusion derived

from expert opinion based on clinical experience without reference

Clinical relevance tables

Clinical relevance tables were compiled under “Additional tables”

to improve the readability of the review. Results were presented

within the context of both the study population and moderate/

high risk women from the population at large. The number needed

to treat to benefit (NNTB) was calculated using the relative risk

(RR) in combination with either the risk of fracture in the control

group, or the five year FRACTURE Index (Black 2001). To do

this, the Visual Rx NNT calculator (Cates 2004) was used. The

weighted absolute risk difference was calculated using the risk

difference (RD) statistic in RevMan and RR-1 was used to calculate

the relative per cent change (Table 1; Table 2).

In addition, for the outcomes of vertebral and hip fractures we

prepared ’Summary of Findings tables using the GRADE criteria

from the GRADE working group (GRADE 2004), (Figure 5;

Figure 6).



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Figure 5. Summary of Findings for Primary Prevention



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Figure 6. Summary of Findings for Secondary Prevention



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R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies.

Quantity of research available

The literature search revealed 419 citations as depicted in Figure 7.

Of these, 36 articles were retrieved for further scrutiny. A total of

29 articles were excluded for various reasons including lack of ap-

propriate control group (4), (Brown 2002b; Harris 2001b; Harris

1999b; Kushida 2004) lack of fracture outcome (8), (Delmas

1997; Dobnig 2006; Eriksen 2002; Hooper 1999; Hu 2005;

Leung 2005; Li 2005; Yildirim 2005) lack of appropriate frac-

ture data (that is, reported as adverse events and unspecified) (1),

(Hosking 2003) lack of randomization (5), (Goa 1998; Licata

1997; Reszka 1999; Singer 1995; Watts 1998) extension/discon-

tinuation study (2), (Sorensen 2003; Ste-Marie 2004) duplicate

report or earlier report of another study (7), (Eastell 2003; Miller

1999; Reginster 2001; Ribot 1999; Roux 2004; Watts 1999; Watts

2003) duration of therapy less than one year (1) (Zegels 2001) and

no extractable data (1). (McClung 1998 1) If duplicate reports of

the same study were found in preliminary abstracts and articles,

the data from the most complete data set was analyzed. In the end,

seven trials met the selection criteria (Clemmesen 1997; Fogelman

2000; Harris 1999; Hooper 2005; McClung 2001; Mortensen

1998; Reginster 2000). (See Figure 7.)



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Figure 7. Summary of literature search for risedronate



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Trial characteristics

The characteristics of the seven selected trials are provided in

the ’Characteristics of included studies’ table. In total, there were

14,049 women enrolled in these trials, and of these, 4746 re-

ceived placebo. Two trials were primary prevention (Hooper 2005;

Mortensen 1998) and the other five studied women with low

BMD on densitometry or who had experienced previous frac-

tures or both. (Clemmesen 1997; Fogelman 2000; Harris 1999;

McClung 2001; Reginster 2000) All trials had three treatment

arms that included two arms involving risedronate at different

doses (i.e. 2.5 mg or 5 mg) or different schedules or both and a

placebo arm. In our analysis, we did not include data from the

two risedronate arms in any single meta-analysis in order to avoid

duplication of data in the pooled estimates. In the case of the Mc-

Clung study, results were not reported separately in the form of

raw data for the 2.5 mg and 5 mg doses. We therefore used the

combined dose data in our primary 5 mg analysis. Length of fol-

low up ranged from two to three years and mean age was 51 to 78.

No trial excluded women with a history of gastrointestinal disease

and in three trials fractures were evaluated as the stated primary

outcome (Harris 1999; McClung 2001; Reginster 2000). All trials

with the exception of one (Mortensen 1998) administered 1000

mg of calcium to all patients. Three trials administered up to 500

IU of vitamin D (Harris 1999; McClung 2001; Reginster 2000).

Risk of bias in included studies

Treatment allocation was concealed in two trials (Harris 1999;

Hooper 2005) and was unclear for the other five . All seven trials

had losses to follow up that exceeded 20%. Two trials (Clemmesen

1997; Hooper 2005) had losses to follow up between 20 and 30%,

three trials between 30 and 40% (Fogelman 2000; Harris 1999;

McClung 2001) and two trials exceeded 40% (Mortensen 1998;

Reginster 2000). All trials were double blind.

Effects of interventions

Effect on fractures

A summary of the overall review of fractures with the standard dose

of risedronate (5 mg) for the base case (i.e. the longest treatment

duration in the trial and using the baseline denominators for the

number of patients) is provided in (Figure 8). Primary prevention

estimates were available only for vertebral and non- vertebral frac-

tures, neither of which were statistically significant. For each of

vertebral, non-vertebral, and hip fracture, the pooled estimate of

the RR of fracture was significant for secondary prevention. The

exception was wrist fracture, which was not significant.

Figure 8. Weighted relative risk of fracture after risedronate (5mg)



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Vertebral fractures

For primary prevention, Mortensen (Mortensen 1998) reported

no fractures leaving Hooper (Hooper 2005) as the only primary

prevention study reporting vertebral fractures. The estimate of the

RR was not statistically significant (RR 0.97, 95% CI 0.42 to

2.25).

Vertebral fractures were reported in four secondary prevention

trials (Clemmesen 1997; Fogelman 2000; Harris 1999; Reginster

2000). One study was not included in analysis due to the apparent

inclusion of an off-drug treatment period in the data (Clemmesen

1997). The pooled estimate of the RR of vertebral fractures from

the three trials (Fogelman 2000; Harris 1999; Reginster 2000) that

could be analyzed demonstrated a significant reduction (39%) in

vertebral fractures (RR 0.61, 95% CI 0.50 to 0.76) as detailed in

’Comparison 01, 01’. This demonstrates a fracture risk reduction

with risedronate 5 mg daily and results are consistent across studies

(P = 0.75).

For both primary and secondary prevention trials combined the

pooled estimate (RR 0.63, 95% CI 0.51 to 0.77) was similar to

that for that for secondary prevention alone


prevention of vertebral fractures, the absolute measures ARR and

NNT of the five year risk of vertebral fracture after treatment with

risedronate were calculated for different levels of increasing risk

as given by the FI. Results are provided in (Figure 9) as well as

for increasing age in (Figure 10). For the illustrative case of the

patient with a FI of 6 to 7, the ARR in vertebral fracture was

2.8% (that is, a reduction in risk from 7.1% to 4.3%) and the

NNTB was 36 (that is, 36 patients need to be treated to avoid one

vertebral fracture). Across the range of increasing FI risk, the ARR

for vertebral fracture ranged from 0.5% to 4.4% and the NNT

to avoid one vertebral fracture ranged from 214 to 23. For the

illustrative patient in the age group 60 to 64 years, the ARR for the

first vertebral fracture was 0.4% (that is, a reduction in risk from

1.0% to 0.6%) and the NNT was 256 patients treated to avoid the

first fracture. The ARR for a subsequent fracture was 3.8% (that

is, a reduction in risk from 9.7% to 5.9%) and the NNT was 26

patients treated to avoid one subsequent fracture. For increasing

age, the five-year age-specific ARR for the first vertebral fracture

increased from 0.1% for the youngest age group (50 to 54 years) to

1.8% in the highest age group (90+ years) and the NNT decreased

from 1282 to 55. For the subsequent fracture, ARR increased from

0.2% to 10.9% and the NNT decreased from 513 to 9.



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Figure 9. Five year FRACTURE Index specific risk of fracture after risedronate (5mg)



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Figure 10. Five year age-specific risk of first and subsequent fracture after risedronate (5 mg)

Non-vertebral fractures

One primary prevention trial (Hooper 2005) reported non-verte-

bral fractures. The risk estimate (RR 0.81, 95% CI 0.25 to 2.58)

was not statistically significant.

Non-vertebral fractures were reported in five secondary prevention

trials (Clemmesen 1997; Fogelman 2000; Harris 1999; McClung

2001; Reginster 2000). After excluding the study with a possible

off drug treatment period, the pooled estimate of the RR of non-

vertebral fractures from four trials (Fogelman 2000; Harris 1999;

McClung 2001; Reginster 2000) that could be analyzed demon-

strated a significant 20% reduction in non-vertebral fractures (RR

0.80, 95% CI 0.72 to 0.90). Results are provided in Comparison

02, 01 and they were consistent across studies (P = 0.43).

For both primary and secondary prevention trials combined the

pooled estimate (RR 0.80, 95% CI 0.72 to 0.90) was the same

that for that for secondary prevention alone as the Hooper trial

comprised only 1.04% of the total weight.


prevention of non-vertebral fractures, the absolute measure: ARR

and NNT of the five year risk of non-vertebral fracture after treat-

ment with risedronate were calculated for different levels of in-

creasing risk as given by the FI (Figure 9) and for increasing age

(Figure 10). For the illustrative case of the patient with a FI of 6 to

7, the ARR in non-vertebral fracture was 4.0% (that is, a reduction

in risk from 19.8% to 15.8%) and the NNT was 25 (that is, 25

patients need to be treated to avoid one non-vertebral fracture).

Across the range of increasing FI risk, the ARR for non-vertebral

fracture ranged from 1.7% to 5.5% and the NNT to avoid one

non-vertebral fracture ranged from 58 to 18. For the illustrative

patient in the age group 60 to 64 years, the ARR for the first non-

vertebral fracture was 0.6% (i.e. a reduction in risk from 3.1% to

2.5%) and the NNT was 161 patients treated to avoid the first

fracture. The ARR for a subsequent fracture was 1.2% (that is,

a reduction in risk from 6.2% to 5.0%) and the NNT was 81

patients treated to avoid one subsequent fracture. For increasing

age, the five year age-specific ARR for the first non-vertebral frac-

ture increased from 0.3% for the youngest age group (50 to 54

years) to 7.0% in the highest age group (90+ years). Accordingly,

the NNT decreased from 313 to 14. For the subsequent fracture,

ARR increased from 0.5% to 7.5% and NNT decreased from 192

to 13.

Hip fractures

Hip fractures were reported in three of the secondary prevention

trials (Harris 1999; McClung 2001; Reginster 2000). The pooled

estimate of the RR of hip fractures from the three trials showed

a significant 26% reduction in hip fractures (RR 0.74, 95% CI

0.59 to 0.94). Results are provided in Comparison 03, 01 and they

were consistent across trials (P = 0.95).


prevention of hip fractures, the absolute measures ARR and NNT

of the five year risk of hip fracture after treatment with risedronate

were calculated for different levels of increasing risk as given by the

FI (Figure 9) and for increasing age (Figure 10). For the illustrative

case of the patient with a FI of 6 to 7, the ARR for hip fracture

was 1.0% (that is, a reduction in risk from 3.9% to 2.9%) and the



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NNT was 99 (that is, 99 patients need to be treated to avoid one

hip fracture). Across the range of increasing FI risk, the ARR for

hip fracture ranged from 0.1% to 2.3% and the NNT to avoid one

hip fracture ranged from 962 to 44. For the illustrative patient in

the age group 60 to 64 years, the ARR for the first hip fracture was

0.05% (i.e. a reduction in risk from 0.2% to 0.15%) and the NNT

was 1923 patients treated to avoid the first fracture. The ARR and

NNT for a subsequent fracture were the same. For increasing age,

the five year age-specific ARR for the first hip fracture increased

from less than 0.05% for the youngest age group (50 to 54 years) to

5.4% in the highest age group (90+ years) and the NNT decreased

from more than 1923 to 18. For the subsequent fracture, ARR

increased from less than 0.05% to 5.9% and the NNT decreased

from more than 962 to 17.

Wrist fractures

Wrist fractures were reported in two of the secondary trials (Harris

1999; Reginster 2000). The pooled estimate of the RR of wrist

fractures from the two trials showed a 33% reduction which was

not significant (RR 0.67, 95% CI 0.42 to 1.07). Results are given

in Comparison 04, 01 and they were consistent across trials (P =

0.81).

Additional analysis

Person years

Results were similar for vertebral, non-vertebral, hip and wrist

fractures when using person years as depicted in (Figure 11). Of

note, the pooled estimates of the RR for the secondary prevention

trials all showed a significant risk reduction of fracture, with the

exception of wrist fractures.

Subgroup analysis

Treatment duration

No trends over years of treatments were found that deviated from

the overall RR estimates. For details, please refer to Figure 12 and

’Comparisons 05, 01; 06, 01; 07, 01; 08, 01; 09, 01; 10, 01; 11,

01’.

Figure 11. Weighted relative risk (RR) of fracture after risedronate (5 mg): Person years



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Figure 12. Weighted relative risk of fracture after risedronate (5 mg) by years of treatment

Treatment dose

For risedronate 2.5 mg, fracture data were only available for ver-

tebral and non-vertebral sites. There was no protective effect ob-

served for the primary prevention of vertebral fractures. For the

secondary prevention trials, the decrease in risk of vertebral frac-

ture was significant and there was a further, albeit slight, decrease

in risk with the 2.5 mg dose, compared with 5 mg (Figure 13;

Figure 14; Figure 15; Comparison 12, 01; Comparison 12, 02).

For non-vertebral fractures, the decrease in risk was not statisti-

cally significant for either primary or secondary prevention but

was more pronounced with the 2.5 mg dose compared with 5 mg.



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Figure 13. Weighted relative risk of fracture after risedronate by dose



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Figure 14. Weighted relative risk of fracture after risedronate by dose: Person years



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Figure 15. Weighted relative risk of fracture after risedronate by years of treatment and dose



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Sensitivity analysis

Baseline versus follow-up denominators

By using the data available for the longest treatment duration,

standard dose of risedronate (5 mg) and follow-up denominators

for the number of patients in the trials, a summary of the overall

review of fractures was prepared (Figure 16). These data are also

provided by years of treatment (Figure 17). The pooled estimates

of the RR of fracture after risedronate were essentially the same as

those obtained using the baseline denominators, with the excep-

tion that the pooled estimate of the RR of wrist fractures from two

secondary prevention trials (Harris 1999; Reginster 2000) demon-

strated a significant reduction (39%) in wrist fractures (RR 0.61,

95% CI 0.38 to 0.96) for risedronate 5 mg.



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Figure 16. Weighted relative risk of fracture after risedronate by dose: Follow-up denominators



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Figure 17. Weighted relative risk of fracture after risedronate by years of treatment and dose: Follow-up

denominators



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Random versus fixed-effect model

There were a few instances where heterogeneity of the trial results

was such that a random-effects model was needed (that is, only

involving the person years analysis). In general, results obtained

using the random and fixed-effect models were similar.

Baseline vertebral fracture rate

Using different baseline vertebral fracture rates (i.e. 100%, > 80%,

> 60%, > 40%, > 20%) for defining secondary trials, a summary

of the overall review of fractures was prepared (Figure 18). For

vertebral, non-vertebral and wrist fractures, the pooled estimates

of the RR of fracture after risedronate were essentially the same as

those obtained using the definition of secondary trials with the >

20% baseline fracture rate. Although the result for hip fractures

became non-significant when the criteria increased from > 40%

to > 60%, the relative risk of fracture was about the same (0.74

compared to 0.81) but the confidence interval was now wider since

the large 2001 trial by McClung et al (McClung 2001) with over

6000 participants was excluded from the analysis.

Figure 18. Weighted relative risk (RR) of fracture after risedronate (5 mg): sensitivity analysis by baseline

prevalent vertebral fracture rate



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Adverse events

A summary of the adverse drug reactions reported in the six ran-

domized placebo-controlled trials of risedronate is provided in

Figure 19; Figure 20; Figure 21 and Figure 22. In general, the

reported events were similar between risedronate and placebo. In

particular, there were five studies reporting ’any upper gastroin-

testinal events’ resulting in an overall RR 1.01 (95% CI 0.94 to

1.09) and four studies reporting ’esophageal ulcer’ resulting in an

overall RR 0.75 (95% CI 0.39 to 1.47).


risedronate (part 1)



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risedronate (part 3





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Toxicity and withdrawals

Discontinuations due to adverse events or dropouts overall

were available and analyzed for five (Fogelman 2000; Harris

1999; Hooper 2005; McClung 2001; Reginster 2000) and six

(Clemmesen 1997; Fogelman 2000; Harris 1999; Hooper 2005;

McClung 2001; Reginster 2000) of the risedronate trials respec-

tively. The pooled estimate demonstrated no statistical difference

between risedronate and placebo for the risk of discontinuing med-

ication due to adverse events (RR 0.96, 95% CI 0.88 to 1.05) or

for dropouts overall (RR 0.96, 95% CI 0.91 to 1.00) (Comparison

13.01, 13.02). Results were consistent across the trials.

D I S C U S S I O N

Based on longest treatment duration and use of baseline denom-

inators for the number of patients in each of the included trials,

risedronate at 5 mg per day was associated with a statistically sig-

nificant and clinically important reduction in the secondary pre-

vention of vertebral, non-vertebral and hip fractures but not wrist.

The level of evidence was Gold for vertebral and non-vertebral

fractures and Silver for hip and wrist. For primary prevention, one

trial reported vertebral and non-vertebral fractures but no statisti-

cally significant reductions were found (Silver level evidence).

Secondary analyses showed that a dose of 2.5 mg, for secondary

prevention resulted in a statistically significant and clinically im-

portant reduction in vertebral fractures that is comparable to that

of the 5 mg dose (Gold level evidence). Only one primary pre-

vention trial reported vertebral fractures for the 2.5 mg dose and

no reduction was found (Silver level evidence). For non-vertebral

fractures, no statistically significant reductions were shown for ei-

ther primary or secondary prevention (Silver level evidence). In the

case of hip fractures, McClung et al (2001), randomized women

to receive placebo, 2.5 mg risedronate or 5.0 mg risedronate. This

was done separately for younger (70 to 79 years) and older (80 +

years) women. Although the results were not generally reported

separately by dose and age groups, the authors did note that the

effects of dose (2.5 mg versus 5.0 mg) for the younger age group

were similar (for 2.5 mg RR 0.5 (95% CI 0.3 to 0.9); for 5 mg RR

0.7 (95% CI 0.4 to 1.1). There were no trials available to assess

the efficacy of the 2.5 mg dose for wrist fractures.

There were no substantive differences in the results whether base-

line, end of study, or person year denominators were used. Sensi-

tivity analyses indicated that there were no major differences based

on the percentage of baseline vertebral fractures. Further, no trends

were found for years of treatment.

Adverse drug events observed with risedronate were similar to the

ones observed with placebo. The use of risedronate was not asso-

ciated with any statistically significant difference in withdrawals

due to adverse events (RR 0.96; 95% CI 0.88 to 1.05) or overall

withdrawals (RR 0.96; 95% CI 0.91 to 1.00), when compared to

placebo. In keeping with this, it was concluded that study partici-

pants tolerated their risedronate treatment. Although no increased

incidence of adverse effects were detected with risedronate, exter-

nal to the randomized controlled trials, concerns exist regarding

the potential risk of upper gastrointestinal events and osteonecro-

sis of the jaw.

Study limitations

The results of this systematic review are believed to be robust, as

we performed a comprehensive literature search, inclusion and ex-

clusion criteria were specified and we conducted a rigorous data

analysis. A potential limitation of our approach may be that the

update search (that is, 2000 to 2004) did not include non-MED-

LINE indexed journals. Recent empirical evidence indicates that

this approach may have introduced a slight risk of bias into our

meta-analysis. On average, such bias is estimated to result in a 6%

variation in the pooled results (Egger 2003; Sampson 2003). Ac-

cordingly, given that the initial literature search (that is, 1966 to

2000) was very extensive, the impact of only using MEDLINE for

the search update is expected to be minimal, if any. This was con-

firmed by a parallel literature search update (that is, 1999 to July

2004) that was conducted for an economic report for the Canadian

Agency for Drugs and Technologies in Health. The search update

included etidronate, alendronate and risedronate (daily dose reg-

imen only) in addition to teriparatide. We searched a number of

databases (i.e. The Cochrane Library, MEDLINE, EMBASE, BIO-

SIS Previews, Toxfile, PubMed) and no additional articles meeting

the inclusion criteria were identified (CADTH 2006).

While our methodology was robust, the results of our meta-analy-

sis, however, are only as strong as the primary studies included. In

keeping with this, the main limitations with regard to study qual-

ity were fracture assessment and classification, the lack of clarity of

the concealment of allocation and large numbers of withdrawals.

A potential source of heterogeneity is the lack of uniform defini-

tion of non-vertebral fracture. While some researchers may use a

rather liberal definition (any fracture other than vertebral fracture),

others may use a more conservative definition which includes only

fractures of the hip, clavicle, humerus, wrist, pelvis or leg (Mayo

Clin Proc 2005). Also, the statistical power to detect heterogeneity

was extremely limited for some tests due to the low number of

fractures in some categories. Another consideration is the fact that

fracture data was not the primary outcome for some of the trials. In

particular, four of the seven risedronate trials had fractures as the

primary outcome. There is another source of heterogeneity, and

possible bias, related to some of the secondary prevention stud-

ies. It concerns the inclusion of participants with a low BMD but

no proven fractures and the difficulty in discriminating between

fracture types (traumatic versus pathological). Also, at times, our

criteria for categorizing a study as a secondary prevention trial dif-

fered from those used by study investigators. An example is the

study by McClung et al (McClung 2001) which included two



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age subgroups. In our review, we considered that both subgroups

evaluated the effect of risedronate in secondary prevention of os-

teoporotic fractures, although we acknowledge study investigators

may not have intended the same. However both subgroups sat-

isfied two of our secondary prevention criteria, that is, baseline

fracture rate and age. Indeed, both age subgroups had a baseline

fracture rate > 20% (primary prevention studies were required to

have a baseline fracture rate of < 20%). In addition, study partic-

ipants in both subgroups were over 62 years of age (we consid-

ered a trial as secondary prevention if the average age was above

62 years). Finally, the exploration of differences in effect between

primary and secondary prevention trials was a particular concern

in our review.

Another methodological limitation concerns the approach used

for concealment of treatment allocation which was not reported

for most trials (that is, classified as ’unclear’). Treatment allocation

was concealed in two trials (Harris 1999; Hooper 2005) and was

unclear for the other five trials.

The length of follow up in the studies (two to three years) is

an additional limitation. It is difficult to extrapolate beyond the

duration of the follow-up trials in the review with respect to the

long-term impact on fractures. Ultimately, data from longer-term

trials will help establish if the effect on fractures is maintained,

increased or diminished.

In regards to our own methodology, we acknowledge that the ap-

proach used to evaluate the effect of bisphosphonates over time

may result in some estimates that are not robust. In particular,

in order to determine the effect on the five year risk of fracture

we based our evaluation on the FRACTURE Index by Black et

al. (Black 2001) and for lifetime and five year age-specific risks

we used an existing model from Doherty et al. (Doherty 2001).

Although this latter approach allowed us to estimate the variation

in risks between younger and older postmenopausal women, these

estimates may be associated with a certain level of uncertainty.

Nonetheless, we believe such information may be useful to deci-

sion-makers.

Lastly, a limitation of evaluating data on adverse effects from sum-

mary meta-analyses is that participants in RCTs tend to be health-

ier with fewer co-morbid diseases and therefore the results may not

be generalizable to clinical practice. None of the six risedronate

trials, however, explicitly excluded patients with pre existing GI

disorders. Furthermore, RCTs are underpowered for rare effects

and meta-analyses of these trials generally cannot provide con-

clusive information pertaining to drug toxicity. In addition, the

heterogeneity of the adverse drug events (ADEs) reported in the

RCTs described in this review, including their nature, low occur-

rence, and way they were assessed by investigators, were obstacles

for meta-analysis. As well, the follow up for the included trials,

which ranged between one and three years, does not allow for the

assessment of long term toxicity associated with risedronate.

Recently, there have been concerns regarding the potential risk of

over suppressing bone turnover resulting in osteonecrosis of the

jaw (ONJ), (Khosla 2007; Woo 2006). Although the majority of

reported cases of ONJ have occurred in cancer patients receiv-

ing the intravenous bisphosphonates zolendrate or pamidronate

(at higher cumulative doses than used in the treatment of post-

menopausal osteoporosis), some osteoporosis patients receiving

oral alendronate or risedronate have developed the condition as

well. In a systematic review of cases reported in the medical litera-

ture, 13 of 368 bisphosphonate treated ONJ patients had received

alendronate and one risedronate (Woo 2006). Since that publica-

tion, a review conducted by the American Society for Bone and

Mineral Research (ASBMR) Task Force on Bisphosphonate-Asso-

ciated ONJ has identified studies reporting a total of 67 cases (64

alendronate, 2 risedronate and 1 etidronate) among osteoporosis

and Paget’s disease patients (Khosla 2007). Most notably, an Aus-

tralian study reported 30 of 114 ONJ cases related to alendronate

(22 of whom were under treatment for osteoporosis) and 2 related

to risedronate. The median time to onset, for alendronate, was 24

months. The most common triggering factor was dental extrac-

tion (Mavrokokki 2007). The ASBMR task force has pointed out

that the incidence of ONJ in the general population not exposed

to bisphosphonates is unknown, information on the incidence of

ONJ is rapidly evolving and that, often, the case ascertainment

has bee inadequate. They recommend that a hierarchy of evidence

quality, based on the completeness of information across seven

categories related to diagnosis and history, should be established

for all future studies reporting cases of ONJ (Khosla 2007). No

cases of ONJ were reported in any of the risedronate trials in our

review.

Finally, because RCTs are not designed to measure ADEs, partic-

ularly rare ones, it is common practice to include sources of infor-

mation other than RCTs. While some reviewers include ADEs re-

ported in observational studies, we elected to obtain information

from the Canadian Adverse Drug Reaction Monitoring Program

(CADRMP, see below) (Health Canada 2005).

Generalizability of findings

Generalizability of our findings is limited by the controlled de-

sign of the trials included in our review. Study participants were

carefully selected in these trials and so utilization of the drugs in

real life may vary substantially from study conditions. Further-

more, study participants were observed for periods of time varying

from one to three years. Consequently, while our results provide

support for efficacy (that is, can the intervention have an effect

on outcome?) they may possibly only provide partial information

on the long-term effectiveness (that is, does the intervention have

an effect on outcome?) of bisphosphonates in preventing osteo-

porotic fractures.



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From a safety perspective, we could not find any statistically sig-

nificant difference in either the rates of adverse drug events or

withdrawal rates due to adverse drug events between patients re-

ceiving a bisphosphonate or patients receiving a placebo. How-

ever, outside controlled trials, concerns exist regarding the safe

use of these drugs, especially alendronate and, to a lesser extent,

risedronate, for which esophageal ulcers and gastritis have been

reported (Kherani 2002). While such adverse events have mainly

been identified through case reports and endoscopic studies, sim-

ilar concerns are also reflected in the proportions of gastrointesti-

nal adverse drug reactions associated with the use of risedronate

reported to the CADRMP (Health Canada 2005). Indeed, GI

adverse drug reactions represented 35% of reports for risedronate

(Figure 23). These proportions should however be interpreted with

caution as adverse drug reactions are reported to CADRMP on a

volunteer basis by health professionals, which means that several

reactions may be unreported. Indeed, it is estimated that less than

10% of adverse reactions are reported to Health Canada (Health

Canada 2005c). Also, a definite cause-effect relationship has not

been established for these adverse drug reactions.



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Figure 23. Adverse drug reactions reported to CADRMP for etidronate, alendronate and risedronate

A U T H O R S ’ C O N C L U S I O N SImplications for practice

Risedronate demonstrated a clinically important benefit in the sec-

ondary prevention of the majority of osteoporotic fractures. At a

dose of 5 mg per day, statistically significant reductions in verte-

bral, non-vertebral and hip fractures were observed (but not wrist).

No statistically significant reduction in the primary prevention of

vertebral and non-vertebral fractures and no evidence was available

for the primary prevention of hip or wrist fractures. No increased

incidence of adverse effects were detected with risedronate, but



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clinicians should be aware that outside of randomized controlled

trials, concerns exist regarding the potential risk of upper gastroin-

testinal events and, less commonly, osteonecrosis of the jaw.

The prevention of osteoporotic fractures is an important public

health intervention. This is particularly true for hip and clinical

vertebral fractures (i.e. fractures of the spine that present for med-

ical attention). The RR of death following such fractures is six- to

nine-fold greater in postmenopausal women aged 55 to 81 years

with low BMD, which represents a typical postmenopausal pop-

ulation (Cauley 2000). In most cases, the mortality increase re-

flects poor underlying health status and comorbidity in addition

to the fracture itself (Cauley 2000). Osteoporotic fractures are also

associated with increase in morbidity, as it is reported that 50%

of women who sustain a hip fracture do not return to their usual

daily activities (Brown 2002b) while 33% will require long-term

care. Accordingly, reducing the incidence of such fractures can po-

tentially increase the quality of life of patients with osteoporosis.

Such interventions may also potentially decrease mortality.


It has been suggested from clinical trials with the bisphosphonates

(Black 2000; Harris 1999; McClung 2001) that their effect in

reducing non-vertebral fractures may be greater in patients with

lower BMD who initiate treatment. The existing data have not

fully resolved the question of whether important differences in

risk reduction across groups of patients with varying degrees of

osteoporosis exist. The impact of risedronate on the RR of non-

vertebral fractures in populations without osteoporosis also merits

further investigation. Additional research is also needed to clarify

the role of risedronate in the primary prevention of osteoporotic

fractures. There is also a need for additional post marketing sa-

fety data. Finally, research into combination therapy with higher

doses of vitamin D or anabolic agents would be merited as would

research concerning adherence to bisphosphonate therapy.

Given the morbidity consequences associated with osteoporotic

fractures, preventing their recurrence can potentially lessen the

need for community-based health services (for example, home

care). It may also reduce or delay the demand for long-term care

beds. However, very little comparative information is currently

available to support this (Hodsman 2002). There is also a lack of

studies which evaluated the effect of bisphosphonates on hospital

admissions (Hodsman 2002).


Thank you to Lara Maxwell and Marie Andree Nowlan from the

Musculoskeletal Group for their editorial assistance and Tamara

Rader for her assistance with the Consumer Summaries.

R E F E R E N C E S


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Hanley 2003

Hanley DA. Osteoporosis. In: Gray J editor(s). Therapeutic

Choices. 4th Edition. Ottawa: Canadian Pharmaceutical

Association, 2003:637–46.

Harris 2001b

Harris, S.T, Eriksen, E.F, Davidson, M, Ettinger, M.P,

Moffett, A. H, Baylink, D.J. Effect of combined risedronate

and hormone replacement therapies on bone mineral

density in postmenopausal women. Journal of Clinical

Endocrinology and Metabolism 2001;86(5):1890–7.

Health Canada 2005

Canadian Adverse drug Reaction Monitoring Program.

Risedronate. In: Health Canada, editor(s). Adverse reaction

database. Ottawa, 2005.

Health Canada 2005c

Health Canada. Medeffect [website]. Health Canada YR:

2005. Ottawa.

Higgins 2005

Higgins JPT, Green S, editors. Cochrane Handbook

for Systematic Reviews of Interventions 4.2.5 [updated

May 2005]. In: The Cochrane Library, Issue 3, 2005.

Chichester, UK: John Wiley & Sons, Ltd.

Hodsman 2002

Hodsman AB, Hanley DA, Josse R. Do bisphosphonates

reduce the risk of osteoporotic fractures? An evaluation of

the evidence to date. CMAJ 2002;166(11):1426–30.

Kanis 1994

Kanis JA, Melton LJ, Christiansen C, Johnston CC,

Khaltaev N. The diagnosis of osteoporosis. Journal of Bone

and Mineral Research 1994;9(8):1137–41.

Kherani 2002

Kherani RB, Papaioannou A, Adachi JD. Long-term

tolerability of the bisphosphonates in postmenopausal

osteoporosis: a comparative review. Drug Safety 2002;25

(11):781–90.

Khosla 2007

Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR,

Felsenberg D, et al.Bisphosphonate-associated osteonecrosis

of the jaw: report of a task force of the American Society for

Bone and Mineral Research. Journal of Bone and Minereral

Research 2007;22:1479–91.

Mavrokokki 2007

Mavrokokki T, Cheng A, Stein B, Gross A. Nature and

Frequency of Bisphosphonate-Associated Osteonecrosis of

the Jaws in Australia. Journal of Oral Maxillofacial Surgery

2007;65:415–23.

Mayo Clin Proc 2005

Alendronate and vertebral fracture risk [multiple letters].

Mayo Clinic Proceedings 2005;80:1233–41.

Melton 1989

Melton LJ, III, Kan SH, Frye MA, Wahner HW, O’Fallon

WM, Riggs BL. Epidemiology of vertebral fractures in

women. American Journal of Epidemiology 1989;129(5):

1000–11.

NIH Consensus 2001

NIH Consensus Development Panel on Osteoporosis

Prevention, Diagnosis, Therapy. Osteoporosis prevention,

diagnosis, and therapy. JAMA 2001;285(6):785–95.

Sampson 2003

Sampson M, Barrowman NJ, Moher D, Klassen TP, Pham

B, Platt R, et al.Should meta-analysts search Embase in

addition to Medline?. Journal of Clinical Epidemiology 2003;

56(10):943–55.

Shukla 2003

Shukla V. Treating osteoporosis with teriparatide: many

unknowns? [Issues in emerging health technologies issue

51]. Ottawa: Canadian Coordinating Office of health

Technology Assessment, 2003.

Tugwell 2004

Tugwell P, Shea B, Boers M, Simons L, Strand V, Wells G.

Evidence-based Rheumatology. BMJ Books, 2004.

WHO 1994

WHO. Assessment of fracture risk and its application to

screening for postmenopausal osteoporosis: Report of a

WHO study group. World Health Organ Technical Report

Series 1994;843:1–129.

Woo 2006

Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected]

review: bisphosphonates and osteonecrosis of the jaws.




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References to other published versions of this review

CADTH 2006b

Wells GA, Cranney A, Bouchere M, Peterson J, Shea

B, Robinson V, et al.Bisphosphonates for the primary

and secondary prevention of osteoporotic fractures in

postmenopausal women: a meta-analysis [Technology

report no 69]. Ottawa: Canadian Agency for Drugs and

Technologies in Health 2006.∗ Indicates the major publication for the study



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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Clemmesen 1997




Study length: 2 years

on drug plus 3rd

year drug free follow up

Withdrawals:

Continuous: 15/44 (34.1%)

Cyclic: 11/44 (25.0%)

Placebo: 13/44 (29.5%)

Total: 39/132 (29.5%)

Participants Source: Outpatients attending clinics which specialized in osteoporosis. Study was carried out in two

centres one in Denmark and one in Belgium

Inclusion Criteria: Healthy age 53-81, postmenopausal at least 1 year. Had at least one but no more than

4 vertebral fractures and at least 3 intact lumbar vertebrae

Exclusion Criteria: Estrogen or calcitonin within 12 mos, any bisphosphonate or fluoride, medications

affecting bone metabolism, secondary causes of osteoporosis.

Treatment N: 44, 44

Control N: 44

Age: 68.3 (5.7); YSM: 20.3 (7.3)


BMD: 0.78 (0.14) g/cm2

T-score: -2.4

Fractures: 100%

Interventions Risedronate 2.5 mg/day or cyclical risedronate 2.5 mg/day for 2 wk followed by placebo for 10 wk vs.

placebo

(Calcium 1000 mg/day)

Outcomes This study was not included in the analysis as the assessment period for fractures appeared to include the

off drug treatment period

Vertebral Fractures: Lateral thoracic and lumbar radiographs performed under standardized conditions. At

the end of study radiographs were displayed simultaneously in chronological order for masked assessment

of vertebrae T4 to L5. Vertebral anterior and posterior heights were measured to the nearest millimetre

with a transparent ruler. Belgian site incident fractures were defined as = 15% height reduction in anterior

to posterior ratio or in the anterior or posterior wall as compared to adjacent vertebrae. For the Danish

site the reduction was 25%

Non-vertebral Fractures: Subjects reported all adverse events and were questioned about intercurrent

symptoms and illnesses at every visit

Notes

Risk of bias



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Clemmesen 1997 (Continued)

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Fogelman 2000




Study length: 2

(2.5 mg patients from 9 of 13 centres (N = 76) discontinued prior to the end of the study due to protocol

amendment.)

Withdrawals:

2.5 mg: 111/184 (60.0%)

5.0 mg: 38/177 (21.5%)

Placebo: 37/180 (20.6%)

Total: 186/543 (34.3%)

[not including protocol amendment: 110/467 (23.6%)]

Participants Source: 13 centres in France, UK, the Netherlands, Belgium and Germany

Inclusion Criteria: Women up to 80 years who had been postmenopausal 1 year. Mean lumbar T-score

of -2 or less

Exclusion Criteria: Hyperthyroidism, hyperparathyroidism, or osteomalacia within 1 year, cancer, abnor-

malities affecting lumbar BMD measurement, drugs within 6 - 12 months affecting bone metabolism

including parenteral Vitamin D = 10,000 IU.

Note: patients with previous or ongoing upper GI disease were not excluded

Treatment N: 184, 177

Control N: 180

Age: 64.7 (7.2); YSM: 17.7 (9.4)


BMD: 0.74 (0.08)

t-score: -2.9

Fractures: 30%

Interventions Risedronate 2.5 mg/day or risedronate 5 mg/day vs. placebo.


Outcomes Vertebral Fractures: Lateral and anterior-posterior thoracic and lumbar (T4-L4) radiographs were taken

at baseline and lateral radiographs taken at end of study. Fractures were identified by quantitative mor-

phometry guidelines of US National Osteoporosis Foundation

Working Group on Vertebral Fractures and verified by a radiologist. A fracture was defined by any vertebral

height ratio falling 3 SD of the study population mean

Non-Vertebral: Adverse events (including vertebral and non-vertebral fractures) were assessed throughout

the study via spontaneous reports and direct questioning

Notes

Risk of bias



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Fogelman 2000 (Continued)



Harris 1999



Blinding: double blind, identical placebo, investigators and other study personnel remained blinded

Study length: 3

(2.5 mg/day dose discontinued at 1 year due to protocol amendment.)

Withdrawals:2.5 mg: 238/817 (29.1%)

5.0 mg: 332/821 (40.4%)

Placebo: 370/820 (45.1%)

Total: 940/2458 (38.2%)

Participants Source: 110 centres in North America

Inclusion Criteria: Ambulatory women up to 85 years old who had been post menopausal at least 5 years.

Minimum two radiographically confirmed vertebral T4-L4 fractures (ratio of anterior or middle vertebral

height to the posterior height was = 0.8) or 1 vertebral fracture and lumbar BMD T-score = -2SD of

young adult (0.83g/cm² Hologic or 0.94g/cm² Lunar)

Exclusion Criteria: Conditions that could interfere with evaluation of spinal osteoporosis, calcitonin,

calcitriol or Vitamin D within one month, anabolic steroids, or HRT within 3 months, bisphosphonates,

fluoride within 6 months.

Note: Patients with previous or ongoing upper GI disease or use of medications associated with GI

intolerance (NSAIDS or asprin) were not excluded.

Treatment N: 817

Control N: 821, 820

Age: 69 (7.3); YSM: 24 (9.9)


BMD: 0.83 g/cm2 (0.16)

t-score: -2.4

Fractures: 81%

Interventions Risedronate 2.5 mg/day or risedronate 5 mg/day vs. placebo.

(Calcium 1000 mg/day and if 25-hydroxyvitamin D level was < 40 nmol/L they received up to 500 IU/

day cholecalciferol

Outcomes Vertebral Fractures: Lateral thoracolumbar T4-L4 spine radiographs were obtained at baseline and annu-

ally. Prevalent and incident fractures were diagnosed quantitatively and semi-quantitatively. Quantitative

assessment defined an incident fracture as a 15% decrease of anterior, posterior or middle vertebral height

in a vertebra that was normal at baseline. In the semiquantitative assessment a new fracture was diagnosed

if the grade changed from 0 (normal) to 1(mild) 2 (moderate), or 3 (severe). An independent radiologist

adjudicated discrepancies between methods. Radiologists were blinded

Non-vertebral Fractures: Radiographically confirmed fractures of the clavicle, humerus, wrist, pelvis, hip

or leg, regardless of relationship to trauma

Notes



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Harris 1999 (Continued)

Risk of bias


Allocation concealment? Yes A - Adequate

Hooper 2005


Primary prevention

Blinding: double blind, matching placebo


Withdrawals:

Risedronate 2.5 mg: 28/128 (21.9%)

Risedronate 5 mg: 26/129 (20.2%)

Placebo: 33/126 (26.2%)

Total: 87/383 (22.8%)

Participants Source: 11 centres in Australia.

Inclusion Criteria: Healthy women who were post menopausal 6- 36 months age with FSH > 50 MIU/

ml, and estradiol < 20 pg/ml. BMD T score > -2.5 (0.76g/cm2 Hologic or 0.8 g/cm2 Lunar). Exclusion

Criteria: Hyperparathyroidism, hyperthyroidism, osteomalacia or treatments affecting bone metabolism.

Patients not excluded due to GI disease or medications with potential to irritate GI tract

Treatment N: 2.5 mg 127, 5 mg 129

Control N: 125

Age: 52.6 (3.3); YSM 3.9 (5.6)


BMD: 1.079 (12)

t-score: -0.410 (-0.1073)

Fractures: 18.3%

Interventions Risedronate 2.5 mg/day or 5.0 mg/day vs. placebo


Outcomes Vertebral Fractures: Lumbar and thoracic lateral and anterior-posterior radiographs were taken at baseline

and 2 years. Deformity was confirmed by visual inspection and defined as vertebral height ratio below 3

SD of study population mean. Incident fracture was defined as a loss of 14% or more in anterior, posterior

or middle vertebral height in a vertebra that was normal at baseline

Non-vertebral Fractures: Were monitered as adverse events. At each visit patients were questioned regarding

medically related changes in well being with particular attention to fractures and GI events

Notes

Risk of bias




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Hooper 2005 (Continued)

Allocation concealment? Yes A - Adequate

McClung 2001



Blinding: double blind, identical placebo


Withdrawals:2.5/ 5.0 mg combined: 2197/6197 (35.5%)

placebo: 1127/3134 (35.9%)

Total: 3324/9331 (35.6%)

Participants Source: 2 cohorts from 183 centres in North America, Europe, New Zealand and Australia

Inclusion Criteria: Group 1 - Women age 70-79 with osteoporosis defined as femoral neck BMD T-score

> 4 SD below peak bone mass (originally calculated according to densitometer reference data base and

later according to Third National Health and Nutrition Examination Survey) or > -3 SD and at least

one clinical risk factor i.e. difficulty standing from a sitting position, poor tandem gait, fall-related injury

in previous year, psychomotor score = 5 on Clifton Modified Gibson Spiral Maze test, smoking during

previous 5 years, maternal history of hip fracture, previous hip fracture, hip axis length = 11.1cm.

Group 2 - Women age 80 or older with at least one non-skeletal risk factor for hip fracture, a femoral-

neck t score < -4 or a femoral-neck t score < -3 plus a hip axis length = 11.1cm

Exclusion Criteria: Major medical illness, recent history of cancer, another metabolic bone disease within

1 year, important lab test abnormalities, recent drugs affecting bone, allergy to bisphosphonates, bilateral

hip fractures.

Note: Patients with previous or ongoing upper GI or use of medications associated with GI intolerance

(NSAIDS, asprin, proton pump inhibitors or antacids) were not excluded


Control N: 3134

Age: 78.0 (9.7); YSM: 31.8 (19.3)


BMD: not reported

t-score (femoral): -3.7

Fractures: 42%

Interventions Risedronate 2.5 mg/day or risedronate 5 mg/day vs. placebo

(Calcium 1000 mg/day and if 25-hydroxyvitamin level was < 40 nmol/L, they received vitamin D 500

IU/day)

Outcomes Hip Fractures: Radiographically confirmed.

Non-vertebral Fractures: Radiographically confirmed osteoporotic fractures of wrist leg, humerus, hip,

pelvis or clavicle

Notes

Risk of bias




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McClung 2001 (Continued)


Mortensen 1998


Primary prevention

Blinding: double blind, identical placebo

Study length: 2

on drug plus 3rd year drug free follow up. (Patients given option to continue in study after completing

1st year.)

Withdrawals:

Continuous: 20/37 (54.1%)

Cyclic: 14/38 (36.8%)

Placebo: 15/36 (41.7%)

Total:49/111 (44%)

Participants Source: Two centres - USA and Denmark

Inclusion Criteria: Ambulatory, active women 6-60 month postmenopausal (as measured by FSH and

estradiol) weighing 45-90 kg (within 25% of normal height and weight). Lumbar spine within 2 SD of

age matched bone mass

Exclusion Criteria: Bisphosphonates, thyroid hormone therapy, glucocorticoids = 5 mg/day, anabolic

agents, calcitonin, vitamin D > 400 IU/day, calcium > 1500/day, diuretics, anticonvulsants > 1 month

in previous 6 months, HRT > 1 month in previous 6 months, fluoride > 1 month ever, any bone disease

including hyperparathyroidism, alcohol or drug abuse, psychiatric disease, any evidence of osteoporosis

- vertebral deformity or osteoporosis related fracture of hip or wrist, bilateral oophorectomy, or artificial

menopause.

Note: Nothing in criteria to indicate exclusion of those with upper GI disease.

Treatment N: 37, 38

Control N: 36

Age: 51.2 (3.8); YSM: 2.7 (1.7)

Calcium: 977 (535)mg/d

BMD: 0.94 (0.11) g/cm2

T-score: -1.0

Fractures: 0% (excluded)

Interventions Risedronate 5 mg/day or cyclical risedronate 5 mg/day for 1st 2 wk of every calendar month followed by

placebo for remainder vs. placebo

(Not required to take supplemental calcium.)

Outcomes Vertebral fractures - Thoracic and lumbar radiographs were taken at baseline, 7, 13 and 25 months and

12 months after treatment cessation. Vertebral deformities were defined as a 25% or more decrease in

anterior, mid or posterior, height of a vertebra as compared to baseline and were evaluated for safety

purposes

Non-vertebral fractures- Ascertainment not specified but adverse events were recorded at all patient visits.

This endpoint was not included in the meta-analysis as the evaluation period appeared to include the

follow up time in which patients were off drug

Notes



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Mortensen 1998 (Continued)

Risk of bias



Reginster 2000




Study length: 3

(2.5 mg/dose discontinued at 2 years due to protocol amendment)

Withdrawals:

2.5 mg (at 1 year): 76/408 (18.6%)

5.0 mg (at 3 years): 156/407 (38.3%)

Placebo (at 3 years): 186/407 (45.7%)

Total for 5.0 mg and placebo: 342/814 (40%)

Participants Source: 80 European and Australian centres. VERT study.

Inclusion Criteria: Ambulatory women up to 85 years old who had been post menopausal at least 5 years.

Minimum two radiographically confirmed vertebral T4-L4 fractures

Exclusion Criteria: Conditions that could interfere with evaluation of spinal osteoporosis, calcitonin,

calcitriol or Vitamin D within one month, anabolic steroids, or HRT within 3 months, bisphosphonates,

fluoride within 6 months.

Note: Patients with previous or ongoing upper GI disease or use of medications associated with GI

intolerance (NSAIDS or asprin) were not excluded


Control N: 407

Age: 71.0 (7.0); YSM: 24.4 (8.5)


BMD: 0.79 g/cm2 (0.15)

T-score: -2.7

Fractures: 100%

Interventions Risedronate 2.5 mg/day or risedronate 5 mg/day vs. placebo

(Calcium 1000 mg/day and if 25-hydroxyvitamin level was < 40 nmol/l, they received vitamin D 500

IU/day)

Outcomes Primary Outcome: Vertebral fractures

Vertebral Fractures: Lateral thoracolumbar T4-L4 spine radiographs were obtained at baseline, 1,2 and 3

years and were read in the order they were taken at a single radiology department. Prevalent and incident

fractures were diagnosed quantitatively and semi-quantitatively. Quantitative assessment defined incident

fracture as a 15% decrease of anterior, posterior or middle vertebral height in a vertebra that was normal

at baseline. In the semiquantitative assessment a new fracture was diagnosed if the grade changed from

0 (normal) to 1(mild) 2 (moderate), or 3 (severe). An independent radiologist adjudicated discrepancies

between methods

Non-vertebral Fractures: Radiographically confirmed fractures of the clavicle, humerus, wrist, pelvis, hip



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Reginster 2000 (Continued)

or leg, regardless of relationship to trauma

Notes

Risk of bias



BMD: Lumbar Bone Mineral Density

Calcium: Baseline calcium intake

GI: gastointestinal

HRT: hormone replacement therapy

NSAID: Non steroidal anti inflammatory drugs

Participant Characteristics: Unless othewise specified, participant characteristics are presented as mean (SD)

SD: Standard deviation

t-score calculated using the lumbar spine BMD [(LS BMD -1.047)/0.110]

vs: versus

YSM: Years Since Menopause

Characteristics of excluded studies [ordered by study ID]


Brown 2002 Lack of an appropriate control group.

Delmas 1997 Lack of fracture outcome.

Dobnig 2006 Lack of fracture outcome.

Eastell 2003 Duplicate report or earlier report of another study.

Eriksen 2002 Lack of fracture outcome.

Goa 1998 Non randomized.

Harris 1999b Lack of an appropriate control group.

Harris 2001 Lack of an appropriate control group.

Hooper 1999 Lack of fracture outcome.

Hosking 2003 Lack of appropriate fracture data (i.e. reported as adverse event and unspecified.)



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(Continued)

Hu 2005 Lack of fracture outcome.

Kushida 2004 Lack of an appropriate control group.

Leung 2005 Lack of fracture outcome.

Li 2005 Lack of fracture outcome.

Licata 1997 Non randomized.

McClung 1998 1 No extractable data.

Miller 1999 Duplicate report or earlier report of another study.

Reginster 2001 Duplicate report or earlier report of another study.

Reszka 1999 Non randomized.

Ribot 1999 Duplicate report or earlier report of another study.

Roux 2004 Duplicate report or earlier report of another study.

Singer 1995 Non randomized.

Sorensen 2003 Extension / discontinuation study.

Ste-Marie 2004 Extension study.

Watts 1998 Non randomized.

Watts 1999 Duplicate report or earlier report of another study.

Watts 2003 Duplicate report or earlier report of another study.

Yildirim 2005 Lack of fracture outcome.

Zegels 2001 Duration of therapy < 1 year.



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D A T A A N D A N A L Y S E S

Comparison 1. Risedronate 5 mg vs Control - all years baseline denominators


studies

No. of


1 Vertebral Fractures 5 3139 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.51, 0.77]

1.1 Vertebral Primary 2 327 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.42, 2.25]




studies

No. of


1 Non Vertebral Fractures 5 12397 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.72, 0.90]

1.1 Non Vertebral Primary 1 254 Risk Ratio (M-H, Fixed, 95% CI) 0.81 [0.25, 2.58]




studies

No. of


1 Hip Fractures 4 11859 Risk Ratio (M-H, Fixed, 95% CI) 0.74 [0.59, 0.94]

1.1 Hip primary 1 73 Risk Ratio (M-H, Fixed, 95% CI) Not estimable




studies

No. of


1 Wrist Fractures 3 2528 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.42, 1.07]

1.1 Wrist primary 1 73 Risk Ratio (M-H, Fixed, 95% CI) Not estimable




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Comparison 5. Risedronate 5 mg vs Control - 1 year baseline denominators


studies

No. of



1.1 Vertebral primary 1 73 Risk Ratio (M-H, Fixed, 95% CI) Not estimable



1.4 Wrist primary 1 73 Risk Ratio (M-H, Fixed, 95% CI) Not estimable

Comparison 6. Risedronate 5 mg vs Control - 2 years baseline denominators


studies

No. of








1.6 Wrist secondary 1 73 Risk Ratio (M-H, Fixed, 95% CI) Not estimable



studies

No. of




1.2 Non vertebral 2 611 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.31, 1.28]

1.3 Hip 1 73 Risk Ratio (M-H, Fixed, 95% CI) Not estimable

1.4 Wrist 1 73 Risk Ratio (M-H, Fixed, 95% CI) Not estimable



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studies

No. of







Comparison 9. Risedronate 2.5 mg vs Control - 1 year baseline denominators


studies

No. of




Comparison 10. Risedronate 2.5 mg vs Control - 2 years baseline denominators


studies

No. of




1.2 Non vertebral 2 540 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.21, 1.19]

Comparison 11. Risedronate 2.5 mg vs Control - 2 years baseline denominators


studies

No. of









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Comparison 12. Risedronate 2.5 mg vs Control - all years baseline denominators


studies

No. of


1 Vertebral fractures 4 2992 Risk Ratio (M-H, Fixed, 95% CI) 0.62 [0.46, 0.83]

1.1 Primary prevention 1 252 Risk Ratio (M-H, Fixed, 95% CI) 1.08 [0.48, 2.46]

1.2 Secondary prevention 3 2740 Risk Ratio (M-H, Fixed, 95% CI) 0.57 [0.42, 0.78]

2 Non-vertebral fractures 2 540 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.21, 1.19]

2.1 Primary prevention 1 252 Risk Ratio (M-H, Fixed, 95% CI) 0.49 [0.13, 1.92]

2.2 Secondary prevention 1 288 Risk Ratio (M-H, Fixed, 95% CI) 0.51 [0.17, 1.53]



studies

No. of


1 Withdrawals due to side effects 5 9204 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.88, 1.05]

2 Withdrawals overall 6 12486 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.91, 1.00]


Table 1. Clinical Relevance Table for Fracture Primary Prevention Trials


Trials

Control

Event Rate

Wt Absolute

RD

Wt Rel %

Change

NNTB Statistical Sig Quality of

Evidence

Verte-

bral Fractures

- (Trial Popu-

lation) Pri-

mary Preven-

tion 5mg/day

for 2 yrs

327 (2) 6.2% (6 out of

100)

0% 0 fewer

patients out of

100

-3% (I) Not applicable Not Statis-

tically signifi-

cant

Silver

95% confi-

dence interval

(-5, 5) (-58, 125)

Verte-

bral Fractures

- (Low Risk

Woman) Pri-

mary Preven-

tion 5mg/day

for 2 years

327 (2) 1.2% (1 out of

100)

Not applicable -3% (I) Not applicable Not Statis-

tically signifi-

cant

Silver



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Table 1. Clinical Relevance Table for Fracture Primary Prevention Trials (Continued)

95% confi-

dence interval

(-58, 125)

Verte-

bral Fractures

- (Moderate

Risk Woman)

Primary Pre-

vention 5mg/

day for 2 yrs

327 (2) 5.3% (5 out of

100)


tically signifi-

cant

Silver

95% confi-

dence interval

(-58, 125)

Non Vertebral

Fractures -

(Trial Popula-

tion) Primary

Prevention

(5 mg/day for

2 yrs)

254 (1) 4.8% (5 out of

100)

-1% 1 fewer

patient out of

100

-19% (I) Not applicable Not Statis-

tically signifi-

cant

Silver

95% confi-

dence interval

(-3, 4) (-75, 158)

Non Vertebral

Fractures

- (Low Risk

Woman) Pri-

mary Preven-

tion(5 mg/day

for 2 yrs)

254 (1) 8.9% (9 out of

100)


tically signifi-

cant

Silver

95% confi-

dence interval

(-75, 158)

Non Vertebral

Frac-

tures - (Mod-

erate Risk

Woman) Pri-

mary Preven-

tion(5 mg/day

for 2 yrs)

254 (1) 16.5% (17 out

of 100)


tically signifi-

cant

Silver

95% confi-

dence interval

(-75, 158)



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Hip Fractures

- (Trial Popu-

lation) Pri-

mary Preven-

tion (5mg/day

for 2 yrs)

73 (1) 0.0 (0 out of

100)

0% 0 fewer

patients out of

100

Not estimable Not applicable Not Statis-

tically signifi-

cant

Silver

95% confi-

dence interval

(-5, 5)

Hip Fractures

- (Low Risk

Woman) Pri-

mary Preven-

tion (5mg/day

for 2 yrs)

73 (1) 0.4% (0 out of

100)

Not applicable Not estimable

(I)

Not applicable Not Statis-

tically signifi-

cant

Silver

95% confi-

dence interval

Hip Fractures

- (Moderate

Risk Woman)

Primary Pre-

vention (5mg/

day for 2 yrs)

73 (1) 1.9% (2 out of

100)

Not applicable Not estimable Not applicable Not Statis-

tically signifi-

cant

Silver

95% confi-

dence interval

Wrist Frac-

tures - (Trial

Population)

Primary Pre-

vention (5mg/

day for 2 yrs)

73 (1) 0% (0 out of

100)

-0% 0 fewer

patients out of

100

Not estimable Not applicable Not statis-

tically signifi-

cant

Silver

95% confi-

dence interval

(-5, 5)

Wrist Frac-

tures - (Low

Risk Woman)

Primary Pre-

vention (5mg/

day for 2 yrs)

73 (1) Not available Not applicable Not estimable Not applicable Not statis-

tically signifi-

cant

Silver

95% confi-

dence interval



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Wrist Frac-

tures - (Mod-

erate Risk

Woman) Pri-

mary Preven-

tion (5mg/day

for 2 yrs)

73 (1) Not available Not applicable Not estimable Not applicable Not statis-

tically signifi-

cant

Silver

95% confi-

dence interval

Legend Secondary

prevention =

bone density

of at least 2

SD values be-

low peak bone

mass and/

or one or more

vertebral com-

pression frac-

tures

For Trial Pop-

ulation rates

are based on

the event rate

in the control

group. Low

and Mod-

erate Risk, are

5 year com-

munity popu-

lation risks de-

rived from the

following vari-

ables

in the FRAC-

TURE Index:

age,

fracture after

50 yrs, mater-

nal hip frac-

ture after 50

yrs., weight <

125 lbs, smok-

ing, using

arms to assist

standing and

BMD. Low =

FRACTURE

Index score 1-

2, Moderate =

FRAC-

TURE Index

score 5 (Black

2001) see Fig-

ure 1

Wt =

weighted, RD

= risk differ-

ence

Wt Rel

= weighted rel-

ative percent

change, I = im-

provement

NNT

B = number

needed to ben-

efit

Gold level: At

least one ran-

domised clini-

cal trial meets

all of the fol-

lowing criteria

for the major

outcome

(s) as reported:

Sample sizes of

at least 50 per

group. If a sta-

tistically

significant dif-

ference is not

found they

must be pow-

ered for 20%

relative differ-

ence in the rel-

evant out-

come. Blind-

ing of patients

and as-

sessors for out-

comes. Han-

dling of with-

drawals > 80%

follow up (im-

puta-

tions based on

methods such

as Last Obser-

vation Carried



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For-

ward (LOCF)

acceptable).

Concealment

of treatment

allocation. Sil-

ver level: Ran-

domised trial

does not meet

the above cri-

teria

Table 2. Clinical Relevance Table for Fracture Secondary Prevention Trials


Trials

Control

Event Rate

Wt Absolute

RD

Wt Rel %

Change

NNTB Statistical Sig Quality of

Evidence

Verte-

bral Fractures

- (Trial Pop-

ulation) Sec-

ondary Pre-

vention 5 mg/

day for 3 yrs

2,812 (3) 14.1% (14 out

of 100)

-5% 5 fewer

patients out of

100


significant

Gold

95% confi-

dence interval

(-8, -3) (-50, -24) (15, 30)

Verte-

bral Fractures

- (Moderate

Risk Woman)

Secondary

Prevention 5

mg/day for 3

years

2,812 (3) 5.3% (5 out of

100)


significant

Gold

95% confi-

dence interval

(-50, -24) (38, 79)

Verte-

bral Fractures

- (High Risk

Woman) Sec-

ondary Pre-

vention 5 mg/

day for 3 yrs

2,812 (3) 11.2% (11 out

of 100)


significant

Gold



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Table 2. Clinical Relevance Table for Fracture Secondary Prevention Trials (Continued)

95% confi-

dence interval

(-50, -24) (18, 38)

Non Vertebral

Fractures

- (Trial Pop-

ulation) Sec-

ondary Pre-

vention(5 mg/

day for 2-3

yrs)

12,143 (4) 10.3% (10 out

of 100)

-2% 2 fewer

patients out of

100


significant

Gold

95% confi-

dence interval

(-3, -1) (-28, -10) (35, 98)

Non Vertebral

Frac-

tures - (Mod-

erate Risk

Woman) Sec-

ondary Pre-

vention(5 mg/

day for 2-3

yrs)

12,143 (4) 16.5% (17 out

of 100)


significant

Gold

95% confi-

dence interval

(-28, -10) (22, 61)

Non Vertebral

Fractures

- (High Risk

Woman) Sec-

ondary Pre-

vention(5 mg/

day for 2-3

yrs)

12,143 (4) 27.5% (28 out

of 100)


significant

Gold

95% confi-

dence interval

(-28, -10) (13, 37)

Hip Fractures

- (Trial Pop-

ulation) Sec-

ondary

Prevention (5

mg/day for 3

yrs)

11,786 (3) 2.8 (3 out of

100)

-1% 1 fewer

patient out of

100


significant

Silver



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95% confi-

dence interval

(-1, 0) (-41, -6) (88, 596)

Hip Fractures

- (Moderate

Risk Woman)

Secondary

Prevention (5

mg/day for 3

yrs)

11,786 (3) 1.9% (2 out of

100)


significant

Silver

95% confi-

dence interval

(-41, -6) (129, 878)

Hip Fractures

- (High Risk

Woman) Sec-

ondary

Prevention (5

mg/day for 3

yrs)

11,786 (3) 8.7% (9 out of

100)


significant

Silver

95% confi-

dence interval

(-41, -6) (29, 192)

Wrist Frac-

tures - (Trial

Population)

Secondary

Prevention (5

mg/day for 3

yrs)

2,455 (2) 3.5% (4 out of

100)

-1% 1 fewer

patient out of

100


tically signifi-

cant

Silver

95% confi-

dence interval

(-2, 0) (-58, 7)

Wrist Frac-

tures - (Mod-

erate

Risk Woman)

Secondary

Prevention (5

mg/day for 3

yrs)

2,455 (2) Not available Not applicable -33% (I) Not applicable Not statis-

tically signifi-

cant

Silver

95% confi-

dence interval

(-58, 7) (I)



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Wrist Frac-

tures - (High

Risk Woman)

Secondary

Prevention (5

mg/day for 3

yrs)

2,455 (2) Not available Not applicable -33% (I) Not applicable Not statis-

tically signifi-

cant

Silver

95% confi-

dence interval

(-58, 7)

Legend Secondary

prevention =

bone density

of at least 2

SD values be-

low peak bone

mass and/

or one or more

vertebral com-

pression frac-

tures

For Trial Pop-

ulation

rates are based

on the event

rate in the

control group.

Moderate and

High Risk, are

5 year com-

munity popu-

lation risks de-

rived from the

following vari-

ables

in the FRAC-

TURE Index:

age,

fracture after

50 yrs, mater-

nal hip frac-

ture after 50

yrs, weight <

125 lbs, smok-

ing, using

arms to assist

standing and

BMD. Mod-

erate = FRAC-

TURE Index

score

3-4, High =

FRACTURE

Index score 8-

13 (Black

2001) see Fig-

ure 1

Wt =

weighted, RD

= risk differ-

ence

Wt Rel

= weighted rel-

ative percent

change, I = im-

provement

NNT

B = number

needed to ben-

efit

Gold level: At

least one ran-

domised clini-

cal trial meets

all of the fol-

lowing criteria

for the major

outcome

(s) as reported:

Sample sizes of

at least 50 per

group. If a sta-

tistically

significant dif-

ference is not

found they

must be pow-

ered for 20%

relative differ-

ence in the rel-

evant out-

come. Blind-

ing of patients

and as-

sessors for out-

comes. Han-

dling of with-

drawals > 80%

follow up (im-

puta-

tions based on

methods such

as Last Obser-

vation Carried



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For-

ward (LOCF)

acceptable).

Concealment

of treatment

allocation. Sil-

ver level: Ran-

domised trial

does not meet

the above cri-

teria

W H A T ’ S N E W

Last assessed as up-to-date: 13 November 2007.


13 August 2008 Amended Absolute event rates included in the Plain language summary

28 May 2008 Amended Converted to new review format. CMSG ID C072-R

H I S T O R Y

Review first published: Issue 4, 2003


14 November 2007 New citation required and conclusions have changed See published notes for details on update.



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C O N T R I B U T I O N S O F A U T H O R S

George Wells was involved in the conception, design and implementation of the project and contributed significantly to the writing of

the report.

Ann Cranney was involved with the conception of the review, data abstraction, analysis, interpretation and revision of the final report.

Joan Peterson screened the literature, was involved in the data abstraction, quality assessment and analysis of the primary trials and

contributed significantly to the writing of the report.

Michel Boucher assisted in the design of the analysis, reporting and interpretation of the findings and was involved in the writing of

the report.

Beverley Shea was involved in developing the protocol and conducting the systematic review.

Vivian Robinson was involved in developing the protocol and conducting the systematic review.

Douglas Coyle assisted with the design of the review and reviewed the analysis.

Peter Tugwell provided clinical rheumatology expertise and methodological guidance.

D E C L A R A T I O N S O F I N T E R E S T

None at present.

The Cochrane Funding Arbitration Panel recommended withdrawal of the original review from The Cochrane Library. The original

review was externally supported by Merck and Proctor & Gamble to support research staff.

This current review was updated without the support of any industry sponsor.


Internal sources

• Ottawa Health Research Institute, Canada.

External sources

• Canadian Agency for Drugs and Technologies in Health, Canada.

N O T E S

This review updated a previously published review (Cranney 2003) of risedronate conceived, conducted and completed, in part, by the

authors of this report. There were four general differences in the manner in which the two reviews were conducted. First, the current

review included articles published after the previous review was completed (updated to Feb 2007). Second, although both published

and unpublished data were used in the previous reviews, only published data were used in this review. Third, in the previous review the

random-effects model was always used whereas in the present review the base analysis used the fixed-effect model unless the results were

heterogeneous. Fourth, although the previous review considered both BMD and fracture data, this review was only concerned with

fractures and therefore the definition of primary and secondary prevention put more of an emphasis on the fracture study inclusion

criteria.

Our updated literature search retrieved an additional trial (Hooper 2005) which was published after the previous review. There were

two changes in the choice of the included trials. First, the trials by Mortensen (Mortensen 1998) at 5 mg per day (for non-vertebral

fracture data) and Clemmesen (Clemmesen 1997) at 2.5 mg per day (for vertebral and non-vertebral fracture data) were included

in the previous review but were excluded for the current review since they appeared to include an off drug treatment period. That



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is, the fractures may have occurred during the follow-up period on no treatment and not during the active treatment phase of the

study. Second, in the previous review, additional data were obtained from the authors for the McClung trial (McClung 2001) but this

additional information was not used in the current review.

I N D E X T E R M S

Medical Subject Headings (MeSH)

Bone Density Conservation Agents [adverse effects; ∗therapeutic use]; Etidronic Acid [adverse effects; ∗analogs & derivatives; therapeutic

use]; Fractures, Bone [∗prevention & control]; Hip Fractures [prevention & control]; Osteoporosis, Postmenopausal [∗drug therapy;

prevention & control]; Randomized Controlled Trials as Topic; Spinal Fractures [prevention & control]

MeSH check words

Female; Humans



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Strontium ranelate for preventing and treating

postmenopausal osteoporosis (Review)

O’Donnell S, Cranney A, Wells GA, Adachi JD, Reginster JY



1Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)

Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd

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1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


3BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW . . . . . . . . . . . . . . . . . .

5SEARCH METHODS FOR IDENTIFICATION OF STUDIES . . . . . . . . . . . . . . . . . . .

5METHODS OF THE REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6DESCRIPTION OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7METHODOLOGICAL QUALITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


12POTENTIAL CONFLICT OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . .



12REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15Characteristics of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16Characteristics of excluded studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


17Table 01. Clinical relevance table strontium ranelate 2 g per day: Fractures & safety data . . . . . . . . . .

18Table 02. Clinical relevance table strontium ranelate 2 g per day: BMD data . . . . . . . . . . . . . .

18Table 03. Other adverse events from additional sources (EMEA 2004* and Servier**) . . . . . . . . . . .

19ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19Comparison 01. Fractures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19Comparison 02. BMD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19Comparison 03. Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19COVER SHEET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21GRAPHS AND OTHER TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21Analysis 01.01. Comparison 01 Fractures, Outcome 01 Verterbral fractures . . . . . . . . . . . . . . .

21Analysis 01.02. Comparison 01 Fractures, Outcome 02 Non-vertebral fractures . . . . . . . . . . . . .

22Analysis 02.01. Comparison 02 BMD, Outcome 01 Lumbar spine BMD not adjusted for strontium content . . .

23Analysis 02.02. Comparison 02 BMD, Outcome 02 Lumbar spine adjusted for strontium content . . . . . . .

24Analysis 02.03. Comparison 02 BMD, Outcome 03 Femoral neck . . . . . . . . . . . . . . . . . .

25Analysis 02.04. Comparison 02 BMD, Outcome 04 Total hip . . . . . . . . . . . . . . . . . . .

25Analysis 03.01. Comparison 03 Adverse Events, Outcome 01 Total withdrawls . . . . . . . . . . . . .

26Analysis 03.02. Comparison 03 Adverse Events, Outcome 02 Withdrawals due to adverse events . . . . . . .

27Analysis 03.03. Comparison 03 Adverse Events, Outcome 03 Number of emergent adverse events . . . . . . .

28Analysis 03.04. Comparison 03 Adverse Events, Outcome 04 Serious adverse events . . . . . . . . . . . .

28Analysis 03.05. Comparison 03 Adverse Events, Outcome 05 Diarrhea . . . . . . . . . . . . . . . .

29Analysis 03.06. Comparison 03 Adverse Events, Outcome 06 Gastritis . . . . . . . . . . . . . . . .

29Analysis 03.07. Comparison 03 Adverse Events, Outcome 07 Deaths . . . . . . . . . . . . . . . . .

iStrontium ranelate for preventing and treating postmenopausal osteoporosis (Review)


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Strontium ranelate for preventing and treatingpostmenopausal osteoporosis (Review)

O’Donnell S, Cranney A, Wells GA, Adachi JD, Reginster JY

Status: New

This record should be cited as:

O’Donnell S, Cranney A, Wells GA, Adachi JD, Reginster JY. Strontium ranelate for preventing and treating postmenopausal osteo-

porosis. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD005326. DOI: 10.1002/14651858.CD005326.pub2.

This version first published online: 19 July 2006 in Issue 3, 2006.

Date of most recent substantive amendment: 24 May 2006

A B S T R A C T

Background

Strontium ranelate is a new anti-osteoporosis therapy therefore, its benefits and harms need to be known.

Objectives

To determine the efficacy and safety of strontium ranelate for the treatment and prevention of postmenopausal osteoporosis.

Search strategy

We searched MEDLINE (1996 to March 2005), EMBASE (1996 to week 9 2005), the Cochrane Library (1996 to Issue 1 2005),

reference lists of relevant articles and conference proceedings from the last two years. Additional data was sought from authors and

industry sponsors.

Selection criteria

We included randomized controlled trials (RCTs) of at least one year duration comparing strontium ranelate versus placebo reporting

fracture incidence, bone mineral density (BMD), health related quality of life and/or safety outcomes in postmenopausal women.

Treatment (versus prevention) population was defined as women with prevalent vertebral fractures and/or lumbar spine BMD T score

< -2.5 SD.


Two reviewers independently determined study eligibility, assessed trial quality and extracted the relevant data. Disagreements were

resolved by consensus. RCTs were grouped by dose of strontium ranelate and treatment duration. Where possible, meta-analysis was

conducted using the random effects model.

Main results

A total of four trials met our inclusion criteria, three of which investigated the effects of strontium ranelate compared to placebo in

a treatment population (doses ranged from 0.5 to 2 g daily) and one, in a prevention population (doses 0.125, 0.5 and 1 g daily). In

osteoporotic, postmenopausal women a 37% reduction in vertebral fractures (two trials, n = 5082, RR 0.63, 95% CI 0.56 to 0.71)

and a 14% reduction in non-vertebral fractures (two trials, n = 6572, RR 0.86, 95% CI 0.75 to 0.98) was demonstrated over a three

year period with 2 g of strontium ranelate daily. An increase in BMD at all sites was shown with the same dose: lumbar spine BMD

(two trials, n = 1614, WMD adjusted for strontium content 5.44, 95% CI 3.41 to 7.46 and WMD not adjusted 11.29, 95% CI 10.22

to 12.37 over two years), femoral neck and total hip (two trials, n = 4230, WMD 8.25, 95% CI 7.84 to 8.66 and WMD 9.83, 95%

CI 9.39 to 10.26 respectively over three years). One gram of strontium ranelate daily in postmenopausal women without osteoporosis

increased BMD at all sites over a two year period: lumbar spine (one trial, n = 59, WMD adjusted for strontium content 2.39, 95%

CI 0.15 to 4.63 and WMD not adjusted 6.68, 95% CI 5.16 to 8.20), femoral neck (one trial, n= 60, WMD 2.52, 95%CI 0.96 to

4.09) and total hip (one trial, n = 60, WMD 1.02, 95% CI 0.48 to 1.56). In both the treatment and prevention populations, lower

doses of strontium ranelate were superior to placebo with the highest dose of strontium ranelate demonstrating the greatest reduction



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in vertebral fractures and increase in BMD. There is some evidence to suggest that 2 g of strontium ranelate daily compared to placebo

may have a beneficial effect on health related quality of life in postmenopausal women after three years of treatment. Two grams of

strontium ranelate daily increased the risk of diarrhea (RR 1.38%, 95% CI 1.02 to 1.87); however, adverse events did not affect the

risk of discontinuing strontium ranelate nor did it increase the risk of serious side effects, gastritis or death. Additional data obtained

suggests that the risk of vascular system disorders including venous thromboembolism (two trials, n = 6669, 2.2% versus 1.5%, OR

1.5, 95% CI 1.1 to 2.1) and pulmonary embolism (two trials, n = 6669, 0.8% versus 0.4%, OR 1.7, 95% CI 1.0 to 3.1) as well as

nervous system disorders such as headaches (3.9% versus 2.9%), seizures (0.3% versus 0.1%), memory loss (2.4% versus 1.9%) and

disturbance in consciousness (2.5% versus 2.0%) is slightly increased with taking 2 g of strontium ranelate daily over a 3 to 4 year

period.


There is silver level evidence to support the efficacy of strontium ranelate for the reduction of vertebral fractures (and to a lesser extent

non-vertebral fractures) in postmenopausal osteoporotic women and an increase in BMD (all sites) in postmenopausal women with

and without osteoporosis. Diarrhea may occur however, adverse events leading to study withdrawal were not significantly increased in

the strontium ranelate group. Potential risks to the vascular and neurological system associated with taking 2 g of strontium ranelate

daily need to be further explored and quantified.


Strontium ranelate for osteoporosis in women after menopause

This summary of a Cochrane review presents what we know from research about the effect of strontium ranelate for osteoporosis in

women after menopause. The review shows that:

There is silver level evidence that for treatment of osteoporosis in women after menopause, 2 g of strontium ranelate daily over 3 years

decreases fractures in the spine and slightly decreases fractures not in the spine. Most women do not have side effects that would cause

them to stop taking strontium ranelate. However, other research shows that harms could include a chance of blood clots and seizures,

memory loss and consciousness.

What is osteoporosis and how can strontium ranelate help?

Osteoporosis is a condition in which bone loss occurs. Bone loss leads to weak brittle bones that can break easily, even during everyday

activities. Breaks (fractures) of the spine or non-spine (e.g. wrist and hip) are the most common type. There are many drugs and

minerals that work to treat osteoporosis. Strontium ranelate is a drug that decreases the chance of fractures by slowing the loss of bone

and possibly by building new bone. It is a new drug and therefore its benefits and harms need to be known.

What are the results of this review?

Women in the studies took 2 g of strontium ranelate or a placebo (fake tablets or powder). After 2 to 3 years, the number of fractures

that occurred and bone mineral density was measured. Bone mineral density is a lab test to measure how dense or strong bones are in

the hip, spine or neck. The higher the bone density the better.

Benefits of strontium ranelate

In women after menopause who have osteoporosis:

• strontium ranelate decreases spine fractures

-13 out of 100 women had spine fractures taking strontium ranelate

-21 out of 100 women had spine fractures taking a placebo

• strontium ranelate may decrease fractures that are not in the spine

-11 out of 100 women had non-spine fractures taking strontium ranelate

-13 out of 100 women had non-spine fractures taking a placebo

• strontium ranelate increases bone mineral density

Harms of strontium ranelate

In women after menopause who have osteoporosis:

• strontium ranelate did not cause side effects that would make them stop taking it



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• strontium ranelate did not lead to serious side effects, stomach infections, back pain or death

• strontium ranelate increased diarrhea

-7 out of 100 women had diarrhea taking strontium ranelate

-5 out of 100 women had diarrhea taking a placebo

Other research shows that harms could include a chance of blood clots, and seizures, memory loss and consciousness. The cause of

these neurological side effects are not known.

This review has several limitations which include difficulty interpreting the change in bone mineral density due to the unique aspects

of strontium in bone and incomplete follow-up of some patients within the individual trials.

B A C K G R O U N D

Osteoporosis is a skeletal disorder characterized by low bone mass

and micro-architectural deterioration of bone resulting in an in-

crease in bone fragility and risk of fracture (1993 Consensus; NIH

2001). It most often affects postmenopausal women as reductions

in circulating levels of estrogen lead to accelerated bone turnover

and resorption. The most common sites of osteoporotic fracture

are the wrist, hip and spine however, osteoporotic fractures do oc-

cur at other sites (Seeley 1991). Osteoporotic fractures are a major

burden for the individual, their families and society (Johnell 2004;

Kanis 2003; Cauley 2000). Individuals who suffer osteoporotic

fractures, particularly spine or hip, must deal with the complica-

tions which include reductions in health-related quality-adjusted

life years, increased morbidity and mortality (Cauley 2000; Johnell

2004; Tosteson 2001). Furthermore, the direct and indirect ex-

penditures associated with the care of these individuals, particu-

larly hip fracture patients, is costly (US Dept Health 2004; Ray

1997). In Europe, the number of osteoporotic fractures was esti-

mated to be 3.79 million in 2000 and the associated total direct

costs were 31.7 billion Euros (Kanis 2004). In the United States,

approximately 1.5 million osteoporotic fractures occur each year

(US Dept Health 2004) and the cost of fractures was estimated

to be 20 billion US dollars in 1995 (Ray 1997). With the aging

of the population, and the age-specific increases in osteoporotic

fracture rates, it has been suggested that these costs will more than

double in the coming decades (Burge 2003).

The bone fragility which characterizes this disease is a result of

an imbalance in bone remodeling (bone resorption exceeds bone

formation) and an increase in the rate of remodeling at the tissue

level (Seeman 2002). Risk factors associated with fragility fracture

include advancing age, prior fragility fracture, family history of os-

teoporosis/fracture and low bone mineral density (BMD) (Brown

2002). A working group of the World Health Organization in

1994 proposed that an individual with a BMD more than 2.5

standard deviations (SD) below the young adult mean has osteo-

porosis (WHO 1994). Furthermore, it has been estimated that for

every one SD reduction of BMD, there is an increase in relative

risk of fracture of approximately 1.5 to 2.6 (Marshall 1996).

Effective therapies are available and have been demonstrated to

reduce the relative risk of fracture by 40 to 60% (Cranney 2002).

Pharmacotherapy for prevention and treatment of osteoporosis

includes two primary types of drugs, anti resorptive and anabolic

agents. Anti resorptive agents increase bone strength by decreasing

the number of bone multcellular units. This reduces resporption

and prevents further structural damage of trabecular bone and by

reducing cortical porosity. In contrast, anabolic agents increase

bone strength by increasing bone mass due to an increase in the

number of bone multicellular units. As result the magnitude of

the formation phase is greater than the resorption phase (Riggs

2005).

The majority of the agents currently available for the treatment

of osteoporosis are anti resorptive (e.g. bisphosphonates, estrogen,

selective estrogen modulators and calcitonin) and there are a few

anabolic agents (e.g. intermittent recombinant human parathy-

roid hormone and fluoride) (Sorbera 2003). A novel oral agent,

strontium ranelate, has been suggested to simultaneously decrease

bone resorption and stimulate bone formation although there is

some controversy surrounding its mechanism of action.

Strontium ranelate consists of two divalent cation atoms of sta-

ble strontium (natural element) and an organic moiety (ranelic

acid) which dissociates at the gastro-intestinal level. Strontium is a

cation (i.e. positively charged ion) and physically closely related to

calcium, an active component of the skeleton. Ranelic acid is an

organic, highly polar molecule without pharmacological activity

(EMEA 2004). In vitro, strontium ranelate has been suggested to

have a dual effect on bone however, in vivo long term dosing of

strontium ranelate in OVX rats and monkeys resulted in increased

bone formation but non-significant trends of bone resorption. In

human studies (phase III trials), there is some evidence of increases

in bone formation markers (serum bone-specific alkaline phos-

phatase and C-terminal propeptide of type I procollagen) and de-

creases in markers of bone resorption (serum C-telopeptide and

urinary N-telopeptide cross links) from the third month of treat-

ment (2 g of strontium ranelate daily) up to three years. Poten-

tial mechanisms of action include activation of calcium-sensing

receptor or induction of cellular differentiation. The proposed in-



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dication is for treatment of postmenopausal osteoporosis in order

to reduce the risk of fracture (EMEA 2004).

Different doses of strontium ranelate have been tested. In a two

year randomized controlled trial doses from 0.5 g to 2 g per day

were tested in 353 women with postmenopausal osteoporosis (Me-

unier 2002) and in another two year randomized controlled trial,

doses from 0.125 g to 1 g per day were evaluated in 160 early post-

menopausal women (Reginster 2002-1). In both trials, the pri-

mary efficacy endpoint was BMD and results showed a clear dose

response. All tested doses were superior to placebo with the highest

dose of strontium ranelate (2 g per day) demonstrating the greatest

increase in BMD after adjusting for bone strontium content over

two years (Reginster 2003-1). As a result, 2 g of strontium ranelate

per day is considered the recommended daily dose and was the

only dose evaluated in the two phase III trials (Meunier 2004-1;

Reginster 2005).

Given the potential advantages of strontium ranelate in the pre-

vention and treatment of osteoporosis, and that it is a new ther-

apeutic agent, it is important that the benefits and harms of this

therapy are fully explored through a systematic review of the lit-

erature.

O B J E C T I V E S

To assess the clinical efficacy and safety of strontium ranelate in

the prevention and treatment of osteoporosis compared to placebo

or active comparator in postmenopausal women through a sys-

tematic review of the literature. The following major endpoints

were used for this purpose: 1) Fractures (vertebral and non-ver-

tebral); 2) BMD; 3) Health related quality of life and; 4) Safety.

A treatment (versus prevention) population was defined as post-

menopausal women with prevalent vertebral fractures and/or lum-

bar spine BMD T score < -2.5 SD.

C R I T E R I A F O R C O N S I D E R I N G

S T U D I E S F O R T H I S R E V I E W

Types of studies

Randomized placebo or active comparator-controlled trials of at

least one year duration were included in this review. Studies were

excluded if they were not truly randomized (e.g. patients random-

ized using date of birth) but not on the basis of language of pub-

lication.


Postmenopausal women, in which menopause was either surgically

or naturally induced, were included.

Types of intervention

Trials that investigated the effect of strontium ranelate versus

placebo or an active comparator were included however, trials that

investigated multiple interventions where the effect of strontium

ranelate could not be separated out were not included.


Efficacy measures:

1. The primary efficacy outcome was the number of women with

incident vertebral and non-vertebral fractures (a feasible outcome

for a treatment population). Asymptomatic vertebral fractures

were included if they were either quantitatively or semiquanta-

tively ascertained via a radiographic examination as well, symp-

tomatic (or clinical) vertebral fractures as defined by acute back

pain and radiographical findings were also included. Non-verte-

bral fractures included all appendicular type fractures except frac-

tures of the coccyx, skull, jaw, face, ankle, fingers or toes as they

are not considered to be osteoporotic related (Meunier 2004-1;

Reginster 2005).

2. The secondary efficacy outcome to fractures (or surrogate out-

come) was the mean percent change in BMD of the lumbar spine,

femoral neck and total hip measured by Dual Energy X-Ray Ab-

sorptiometry (DXA) at baseline and yearly intervals (a relevant

outcome for both prevention and treatment populations). Stron-

tium ranelate has a higher atomic number than calcium. When

present in bone as it attenuates x-rays to a greater extent than cal-

cium resulting in an overestimation of BMD as measured by DXA

(Blake 2005). As a result, BMD measurements should be adjusted

for strontium content in order to avoid such an artifactual increase

in BMD. The correction used to adjust for the strontium con-

tent in bone in the lumbar spine BMD measurements has been

described as an indirect method and based on: 1) the correlation

between the strontium content measured in the iliac crest on bone

biopsy and the area under the curve of the integrated strontium

plasma curve; and 2) the correlation between the bone strontium

content measured in lumbar vertebrae and the iliac crest in mon-

keys. However, given that no correlation has been established be-

tween femoral neck and iliac crest bone strontium content is not

adjusted for at the other BMD sites (Meunier 2002).

3. Health Related Quality of Life (a relevant outcome for a treat-

ment population).

4. Safety measures include the following (relevant for both pre-

vention and treatment populations):

i) Total withdrawals (the total number of withdrawals after enrol-

ment in the study).

ii) Withdrawals due to adverse events (withdrawals as a result of

an adverse event)

iii) Number of emergent adverse events (adverse events that de-

veloped during the study).

iv) Serious adverse events (adverse events that were immediately

life-threatening, or resulted in hospitalization, disability, malig-

nant disease or death) (Reginster 2002-1).

v) Number of adverse events affecting the gastrointestinal system

(e.g. diarrhea or gastritis)



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vi) Deaths

S E A R C H M E T H O D S F O R

I D E N T I F I C A T I O N O F S T U D I E S

See: methods used in reviews.

Strontium ranelate is a relatively new drug and it was anticipated

that most of the trials would have been published in the past five

years therefore, our search focused on this time period only. Our

search aimed to identify all trials of strontium ranelate for either

the prevention or treatment of postmenopausal osteoporosis

and we employed the following approaches (based on Cochrane

search strategy outlined by Robinson and Dickersin) (Robinson

2002):

• An electronic search of MEDLINE (1996 to March 2005),

EMBASE (1996 to week 9 2005) and the Cochrane Library

(1996 to Issue 1 2005). Our search strategy included MeSH

terms such as osteoporosis, postmenopausal and strontium

ranelate in addition, complementary free text words. We

limited the search to randomized controlled trials and

supplemented it to include previously completed systematic

reviews.

• A review of reference lists of relevant articles for additional

published trials.

• A hand search of abstracts from Osteoporosis International,

Journal of Bone and Mineral Research, Calcified Tissue

International and FDA proceedings from the last two years.

• Lastly, additional information was sought from authors and

industry sponsors.

MEDLINE Search Strategy

1 *Osteoporosis/

2 osteoporos#s.tw.

3 bone loss$.tw.

4 Bone Density/

5 (bone adj2 (density or fragil$)).tw.

6 bone mass.tw.

7 bmd.tw.

8 exp Fractures, Bone/

9 fracture$.tw.

10 or/1-9

11 Postmenopause/

12 (post menopaus$ or postmenopaus$ or post-menopaus$).tw.

13 11 or 12

14 10 and 13

15 clinical trial.pt.

16 randomized controlled trial.pt.

17 tu.fs.

18 dt.fs.

19 random$.tw.

20 (double adj blind$).tw.

21 placebo$.tw.

22 or/15-21

23 22 and 14

24 Strontium/

25 strontium.tw.

26 ranelate.tw.

27 prevos.tw.

28 or/24-27

29 28 and 23

30 limit 29 to yr=“1996 - 2005”

Embase Search Strategy

1 exp osteoporosis/

2 bone loss$.tw.

3 osteoporos#s.tw.

4 bone density/

5 (bone adj2 (density or fragil$)).tw.

6 bone mass.tw.

7 bmd.tw.

8 exp Fracture/

9 fracture$.tw.

10 or/1-9

11 postmenopause/

12 (post menopaus$ or postmenopaus$ or post-menopaus$).tw.

13 11 or 12

14 10 and 13

15 random$.tw.

16 factorial$.tw.

17 crossover$.tw.

18 placebo$.tw.

19 (singl$ adj blind$).tw.

20 (doubl$ adj blind$).tw.

21 assign$.tw.

22 allocat$.tw.

23 volunteer$.tw.

24 randomized controlled trials/

25 double-blind method/

26 single-blind method/

27 or/15-26

28 27 and 14

29 STRONTIUM/

30 strontium.tw.

31 ranelate.tw.

32 prevos.tw.

33 or/29-32

34 27 and 33

35 limit 34 to yr=“1996 - 2005”

M E T H O D S O F T H E R E V I E W

Study selection, quality assessment and data extraction:



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The bibliographic record (i.e. title, authors, keywords and abstract)

retrieved from the search were assessed by two independent

reviewers (SO’D, AC) for potential eligibility based on the review’s

a priori eligibility criteria. Those records deemed potentially

eligible, or those in which there was not enough information,

underwent a full text review to confirm their inclusion.

Methodological quality was assessed by two independent reviewers

(SO’D, AC) using a validated instrument by Jadad (Jadad 1996).

This checklist includes three items pertaining to descriptions of

randomization, blinding, and the inclusion of data for dropouts

and withdrawals, with a total score of five. Studies with a score

less than or equal to two were considered low quality studies.

Allocation concealment was also evaluated by two independent

reviewers (SO’D, AC) using the allocation component of a

validated instrument (Schulz 1995). As outlined in the Cochrane

Reviewer’s Handbook, the allocation concealment was determined

to be: A) adequate i.e. central randomization; numbered or coded

bottles or containers; drugs prepared by the pharmacy; serially

numbered, opaque, sealed envelopes; or other description that

contained elements convincing of concealment, B) unclear i.e.

authors either did not report an allocation concealment approach

at all or reported an approach that was neither adequate nor

inadequate, C) inadequate i.e. alternation or reference to case

record numbers or to dates of birth, and D) not used. Next,

data were independently extracted by both reviewers (SO’D, AC)

using a data extraction form designed specifically for this review.

Details of the study population, duration of intervention, baseline

demographic data, and the outcomes were collected. Differences

with respect to article eligibility, quality assessment and data

extraction were resolved by referring to the original publication

and establishing consensus (Alderson 2003).

Grading the strength of the evidence per outcome:

We used the ribbon grading system as described in the 2004

Evidence-based Rheumatology BMJ book (Tugwell 2004) to grade

the strength of the evidence per outcome. The ribbon grading

system uses four categories to rank the evidence from research

studies: Platinum, Gold, Silver and Bronze. The ranking is given

according to different criteria, including sample size, blinding,

handling of withdrawals and concealment allocation (Tugwell

2004). The ranking of the efficacy outcomes (i.e. fractures and

BMD) is included in the synopsis, methodological quality of

included studies and the clinical relevance tables (see Additional

Tables - 01 and 02) of this review.

Data analysis:

Prior to the pooling, we developed hypotheses that might account

for heterogeneity of study results and compared groups according

to: 1) treatment duration, 2) dose and, 3) prevention versus

treatment populations. Where possible, the analyses were based

on intention-to-treat data from the individual clinical trials.

For fractures and safety outcomes, a weighted relative risk was

determined for the number of women with either incident

fractures or adverse events using Review Manager 4.2.7 (Fleiss

1993). For BMD, a weighted mean difference (WMD) of the

percent change between treatment and control groups for different

BMD sites including lumbar spine, femoral neck and total hip

was calculated. Analyses of the four trials were conducted using

an available data set as it was not possible to carry out an

intention to treat analysis with the published data. Meta-analysis

was conducted according to random effects model. Heterogeneity

of the treatment effect was calculated using a chi-square test with

n -1 degrees of freedom; where n is the number of studies and

the I2 statistic (Fleiss 1993; Higgins 2003). In addition to relative

measures, the absolute risk reduction (ARR) was calculated and

for those outcomes that were statistically significant, the number

needed to treat (NNT) was determined. The NNT was calculated

by taking the inverse of the ARR (NNT = 1/ARR) where ARR is

the control event rate minus the treatment event rate. These results

are summarized in the clinical relevance tables of this review (see

Additional Tables - 01 and 02).

D E S C R I P T I O N O F S T U D I E S

A total of 80 potentially relevant studies were identified from the

electronic and hand search strategy outlined above and screened

for retrieval. Of these, 62 were excluded as they did not meet the

review’s eligibility criteria and 18 underwent a full text review (Me-

unier 2003; Meunier 2004-3; Meunier 2002; Meunier 2004-1;

Reginster 2002-1; Reginster 2005; Boivin 2003; Meunier 2004-

2; Naveau 2004; Pors 2004; Reginster 2002-2; Reginster 2003-

1; Reginster 2003-2; Reginster 2004; Reginster 2004-1; Sorbera

2003; Uebelhart 2003; Marquis 2005). Of these 18 records, a to-

tal of 13 were excluded as a result of being either a review pub-

lication (Meunier 2004-2; Reginster 2003-1; Meunier 2004-3;

Boivin 2003; Naveau 2004; Pors 2004; Reginster 2002-2; Re-

ginster 2003-2; Reginster 2004; Reginster 2004-1; Sorbera 2003;

Uebelhart 2003) or a description of the study protocol (Meunier

2003). The remaining five studies met our eligibility criteria, four

of which were primary studies (Meunier 2002; Meunier 2004-1;

Reginster 2002-1; Reginster 2005) and one, an abstract, that was

a companion paper to the included study by Meuneir et al., 2004

(Marquis 2005). There was no previous systematic review on this

topic.

All four included primary studies were randomized placebo con-

trolled trials (Meunier 2002; Meunier 2004-1; Reginster 2002-

1; Reginster 2005). Three investigated the efficacy of strontium

ranelate in a treatment population (Meunier 2002; Meunier 2004-

1; Reginster 2005) and one included a prevention population (Re-

ginster 2002-1). The mean age of the postmenopausal women

studied ranged from 54.2 (Reginster 2002-1) to 76.7 years (Regin-

ster 2005). None of the women had a previous vertebral fracture in

one study (Reginster 2002-1), approximately half had a prior ver-

tebral fracture in one (Reginster 2005) and all of the women had

a prior vertebral fracture in two (Meunier 2002; Meunier 2004-



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1). The women’s mean BMD T score was < - 2.5 SD in three

(Meunier 2002; Meunier 2004-1; Reginster 2005) and > - 2.5 SD

in one (Reginster 2002-1). With respect to dosages of strontium

ranelate received, the three treatment studies included the recom-

mended daily dose of strontium ranelate (2g) (Meunier 2002; Me-

unier 2004-1; Reginster 2005) whereas in the prevention trial; the

highest daily dose was 1 g (Reginster 2002-1). The compliance

rate ranged from 80% (Reginster 2005) to 93% (Meunier 2002).

All four studies included a calcium supplement in both treatment

and control groups which ranged in dose from 500 mg (Meunier

2002; Reginster 2002-1) to 1000 mg (Meunier 2004-1; Reginster

2005) daily. In three trials, women in the treatment and control

groups also received vitamin D supplements which ranged from

400 to 800 IU daily based on serum concentrations of 25-hydrox-

yvitamin D (Reginster 2005; Meunier 2004-1) or 800 IU daily

(Meunier 2002). No other osteoporotic treatments were admin-

istered. Three studies assessed vertebral fractures (Meunier 2002;

Meunier 2004-1; Reginster 2005) and two included non-vertebral

fractures (Meunier 2004-2; Reginster 2005). All four studies mea-

sured BMD, three of which assessed BMD of the lumbar spine

(Meunier 2002; Reginster 2002-1; Meunier 2004-1), three at the

total hip (Reginster 2002-1; Meunier 2004-1; Reginster 2005)

and four at the femoral neck (Meunier 2002; Reginster 2002-1;

Meunier 2004-1; Reginster 2005). Quality of life was assessed in

two trials (Meunier 2004-1; Reginster 2005). Total withdrawals,

withdrawals due to adverse events, emergent adverse events, se-

rious adverse events and deaths were reported in all four stud-

ies (Meunier 2004-1; Reginster 2002-1; Reginster 2005; Meunier

2002) whereas the number of individuals that developed diarrhea

or gastritis was reported in three (Meunier 2002; Meunier 2004-

1; Reginster 2005). Additional details regarding the characteris-

tics of the included studies are presented in the Characteristics of

Included Studies Table of this review.

M E T H O D O L O G I C A L Q U A L I T Y

The quality of the included studies was assessed using the Jadad

instrument (Jadad 1996). Quality scores, percent lost to follow-up

and allocation concealment grades are summarized in the Charac-

teristics of Included Studies Table of this review. All four studies

were adequately reported as randomized and described adequate

methods regarding the sequence of randomization. All reported

that the trial was double blind and of these, two indicated that the

recipients of care were unaware of their assigned intervention (Re-

ginster 2002-1; Reginster 2005). One reported that the persons

responsible for assessing outcomes were unaware of the assigned

intervention (Meunier 2004-1) and one reported that the recipi-

ents, those providing the care and persons responsible for assessing

outcomes were all unaware of the assigned intervention (Meunier

2002). A description of withdrawals was adequately provided in

all trials. All trials had a methodological quality score of greater

than three out five on the Jadad checklist (mean 4.25, range 4-5).

Despite the high quality of the included studies, three had losses

to follow-up greater than 20% (Meunier 2002; Meunier 2004-1;

Reginster 2005) and only one provided an adequate description of

allocation concealment (Meunier 2002). Lastly, the analyses of the

four trials were conducted using an available analysis set, which is

not preferred but close to the intention to treat’ principle (Alder-

son 2003). For the efficacy outcomes of this review (fractures and

BMD), a “silver” level of evidence has been assigned as none of the

randomized trials met all of the criteria required for a gold level

ranking i.e. sample size of at least 50 in each group, blinding of

patients and assessors for outcomes, loss to follow-up < 20% and

adequate allocation concealment (Tugwell 2004).

R E S U L T S

FRACTURES:

Vertebral Fractures:

Vertebral fractures were determined by the quantitative morpho-

metric assessment method by Genant (Meunier 2002; Meunier

2004-1) and semi-quantative visual assessments (Meunier 2004-

1; Reginster 2005). Patients were not obligated to undergo a ver-

tebral x-ray in one of the phase III trials however, x-rays were ob-

tained for the largest number of patients as possible (total of 3640

patients or 71%) (Reginster 2005).

In osteoporotic women, 2 g of strontium ranelate per day demon-

strated a 41% relative reduction in radiographic vertebral fractures

over a one year period (three trials, n=5254, RR 0.59, 95% CI

0.46 to 0.74) (Meunier 2002; Meunier 2004-1; Reginster 2005)

and a 37% relative reduction over a three year period (two trials,

n = 5082, RR 0.63, 95% CI 0.56 to 0.71) compared to placebo

(Meunier 2004-1; Reginster 2005). The chi-square test for het-

erogeneity of treatment effect was not significant in either of these

analyses (i.e. p > 0.1).

There was only one trial (n=1442) that investigated the effects of

2 g of strontium ranelate versus placebo per day on symptomatic

or clinical vertebral fractures in osteoporotic women (Meunier

2004-1). The results from this trial demonstrated a 52% relative

reduction in risk of a symptomatic fracture (RR 0.48, 95% CI

0.29 to 0.80) over a one year period and a 38% relative reduction

(RR 0.62, 95% CI 0.47 to 0.83) over three years.

With respect to the lower doses of strontium ranelate, one trial

demonstrated a 31% relative reduction in radiographic vertebral

fractures in osteoporotic women using 0.5 g of strontium ranelate

versus placebo per day over a two year period however, this was

not statistically significant (RR 0.69, 95% CI 0.47 to 1.01) (Me-

unier 2004-1). The same study showed a 6% relative reduction in

radiographic vertebral fractures using 1.0 g of strontium ranelate

daily over the same time frame again, this was not statistically sig-

nificant (RR 0.94, 95% CI 0.68 to 1.30) (Meunier 2004-1).

Non-vertebral Fractures:



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Non-vertebral fractures were reported by study investigators based

on radiographic evaluation or written documentation provided

e.g. radiological report, copy of the hospitalization/emergency de-

partment report (Meunier 2004-1, Reginster 2005).

In osteoporotic women, 2 g of strontium ranelate per day demon-

strated a 14% relative reduction in all non-vertebral fractures (in-

cluding hip but excluding fractures of the coccyx, skull, jaw, face,

ankle, fingers and toes) over a three year period compared to

placebo (two trials, n = 6572, RR 0.86, 95% CI 0.75 to 0.98)

(Meunier 2004-1; Reginster 2005). However, the upper boundary

of the confidence interval approximates one. The chi-square test

for heterogeneity of treatment effect was not significant.

One study (n = 4932) reported on major osteoporotic non-verte-

bral fractures defined as fractures of the wrist, pelvis and sacrum,

ribs-sternum, clavicle, humerus or hip only in women with osteo-

porosis and found a 19% relative reduction taking 2 g strontium

ranelate daily compared to placebo although the upper boundary

of the confidence interval approaches one (RR 0.81, 95% CI 0.66

to 0.98) (Reginster 2005).

There were no studies that evaluated the effects of lower doses of

strontium ranelate on the incidence of non-vertebral fractures.

Hip:

There was only one trial that assessed the efficacy of 2 g of stron-

tium ranelate per day versus placebo on the relative reduction of

hip fractures in women with osteoporosis (Reginster 2005) there-

fore, we were unable to estimate a pooled relative risk. Hip frac-

tures, similar to other non-vertebral fractures, were determined

by a radiological evaluation or by a report from a hospitalization.

After three years, the relative risk of a hip fracture was 15% (RR

0.85, 95% CI 0.61 to 1.19) in the total group of women (n=4932)

versus 36% for a subgroup at high risk of hip fracture (n=1977)

defined by age > 74 years and a femoral neck BMD T-score < - 3

(Looker 1991) (RR 0.64, 95% CI 0.41 to 0.99). In both instances

the treatment effect was not statistically significant. However, this

study was not powered for this efficacy outcome.

BMD:

Lumbar Spine BMD:

Using 2 g of strontium ranelate daily versus placebo, an increase

in lumbar spine BMD was demonstrated in osteoporotic women

over a two year period (two trials, n = 1614, WMD adjusted for

strontium content 5.44, 95% CI 3.41 to 7.46 and WMD, not

adjusted for strontium content 11.29, 95% CI 10.22 to 12.37)

(Meunier 2002; Meunier 2004-1). However, the chi-square test

for heterogeneity of treatment effect was significant for the anal-

ysis involving the results adjusted for strontium content (p=0.04)

and I2 = 76.6%. We investigated sources of clinical heterogeneity

and a possible explanation relates to the difference in timing and

methods of the strontium content calculation from bone-biopsy

samples between the two trials (Meunier 2004-1; Meunier 2002).

There was only one trial (n=1442) that investigated the effects

of 2 g of strontium ranelate daily versus placebo in osteoporotic

women on lumbar spine BMD over a three year period and the

WMD demonstrated an increase in lumbar spine BMD relative

to placebo (WMD adjusted for strontium content 8.09, 95% CI

7.22 to 8.96 and WMD not adjusted for strontium content 14.39,

95% CI 13.40 to 15.38) (Meunier 2004-1).

In terms of the lower doses of strontium ranelate, one study (n=63)

investigated the effects of 0.125 g of strontium ranelate daily ver-

sus placebo on women without osteoporosis and found a non-

significant increase in lumbar spine BMD over a two year period

(WMD not adjusted for strontium content 0.37, 95% CI -1.57 to

2.31) (Reginster 2002-1). Women, with and without osteoporo-

sis, taking 0.5 g of strontium ranelate daily compared to placebo

showed a non-significant increase in lumbar spine BMD over a

two year period when BMD was adjusted for strontium content

(two trials, n = 232, WMD 1.01, 95% CI -0.63 to 2.66). However,

when BMD was not adjusted for strontium content, the increase

was significant (WMD 3.59, 95% CI 1.66 to 5.51) (Meunier

2002; Reginster 2002-1). The chi square test for heterogeneity

of treatment effect for the analyses where BMD was not adjusted

for strontium content was approaching significance (p=0.16) and

I2 = 49.5%. The inclusion of a treatment (Meunier 2002) versus

prevention (Reginster 2002-1) population may explain this find-

ing. Lastly, women with and without osteoporosis, taking 1 g of

strontium ranelate daily compared to placebo demonstrated an

increase in lumbar spine BMD over a two year period (Meunier

2002; Reginster 2002-1) (two trials, n = 232, WMD adjusted for

strontium content 2.14, 95% CI 0.70 to 3.58 and WMD, not

adjusted for strontium content 6.68, 5.16 to 8.20). The chi square

test for heterogeneity of treatment effect was not significant.

Femoral Neck BMD:

The effects of taking 2 g of strontium ranelate daily versus placebo

in osteoporotic women demonstrated an increase in femoral neck

BMD over two year (two trials, n=1614, WMD 5.73, 95% CI

5.15 to 6.32) (Meunier 2002; Meunier 2004-1) and three year

period (two trials, n=4230, WMD 8.25%, 95% CI 7.84 to 8.66)

(Meunier 2004-1; Reginster 2005). The chi-square test for het-

erogeneity of the treatment effect was not significant for both of

these analyses.

With respect to the lower doses of strontium ranelate, one trial

(n = 63) explored the effects of 0.125 g/day in women without

osteoporosis and found a non significant increase in femoral neck

BMD in favour of those receiving the placebo over a two year

period (WMD -1.47, 95% CI -3.68 to 0.74) (Reginster 2002-

1). The effects of 0.5 g of strontium ranelate daily versus placebo

demonstrated a non-significant increase in femoral neck BMD

(two trials, n = 232, WMD 1.00, 95% CI -0.52 to 2.52) whereas

1 g of strontium ranelate daily versus placebo showed a significant

increase (two trials, n = 233, WMD 2.52, 95% CI 0.96 to 4.09)

over a two year period (Meunier 2002; Reginster 2002-1). The chi



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square test for heterogeneity of treatment effect was not significant

for either of these analyses.

Total Hip BMD:

One study (n=1442) demonstrated an increase in total hip BMD in

osteoporotic women on 2 g of strontium ranelate daily compared

to placebo over a two year period (WMD 1.16, 95% CI 1.05-

1.27) (Meunier 2004-1) and two trials (n=4230) demonstrated an

increase in total hip BMD over a three year period (WMD 9.83,

95% CI 9.39 to 10.26). The chi-square test for heterogeneity of

treatment effect for the latter analyses was not significant.

Only one trial investigated the effects of lower doses of strontium

ranelate on total hip BMD and found a non-significant increase

with 0.125 g of strontium ranelate daily (n= 63, WMD 0.67, 95%

CI -1.18 to 2.52) and significant increases with 0.5 g/day (n=65,

WMD 2.02, 95% CI 0.47 to 3.57) and 1 g/day (n=60, WMD

4.09, 95% CI 2.09 to 6.09) over a two year period (Reginster

2002-1).

Health Related Quality of Life:

Quality of life was assessed using the SF-36 questionnaire in two

trials (Meunier 2004-1; Reginster 2005) as well as the Quality of

Life questionnaire in Osteoporosis (QUALIOST) in one (Meu-

nier 2004-1). The QUALIOST is a 23 item, disease specific (verte-

bral osteoporosis) questionnaire, with a global score and two sub-

scores: physical and emotional. In both trials, women completed

the quality of life assessments at baseline and every six months

throughout the duration of the trial (Meunier 2003). The results

are not within the published literature however, unpublished data

demonstrated that 2 g of strontium ranelate daily compared to

placebo has a beneficial effect on quality of life as defined by the

QUALIOST in a subset of osteoporotic women (n=1240) after

three years of treatment (global score p = 0.016, emotional and

physical scores p = 0.019 and 0.032 respectively) (Marquis 2005).

Furthermore, results from a back pain assessment included in the

QUALIOST questionnaire conducted every six months, revealed

that the occurrence of back pain was significantly reduced by 29%

in the strontium ranelate group as compared to the placebo group

over three years with a significant effect in the first year (p = 0.006)

(Marquis 2005).

ADVERSE EVENTS:

All adverse event data was reported by dose regardless of study

duration i.e. two years (Meunier 2002; Reginster 2002-1) and

three years (Meunier 2004-1; Reginster 2005).

Total withdrawals:

A total of three trials (n = 6847) using the recommended dose of

2 g strontium ranelate versus placebo daily did not find a signifi-

cant difference in the risk of withdrawals (RR 0.98, 95% CI 0.91

to 1.05) (Meunier 2002; Meunier 2004-1; Reginster 2005). The

chi-square test for heterogeneity of the treatment effect was not

significant. Similarly, two trials (n=256) using 0.5 g of strontium

ranelate versus placebo daily did not demonstrate a significant dif-

ference in the risk of withdrawal (RR 0.87, 95% CI 0.36 to 2.11)

(Meunier 2002; Reginster 2002-1). The chi square test was ap-

proaching significance (p=0.11) and I2 = 60.7% which may be

explained by the inclusion of a treatment (Meunier 2002) versus

prevention (Reginster 2002-1) population.

Withdrawals due to adverse events:

A total of three trials (n = 6847) reported the safety of using the

recommended daily dose of 2 g strontium ranelate versus placebo

through withdrawals due to adverse events (Meunier 2002; Meu-

nier 2004-1; Reginster 2005). The pooled estimate of the relative

risk was 1.20 (95% CI 0.96 to 1.50) with 22% of the strontium

ranelate treated patients versus 19.1% of the controls having with-

drawn due to an adverse event however, this finding was not signif-

icant (p=0.12). The chi-square test for heterogeneity of the treat-

ment effect was borderline significant (p=0.10) and I2=57.0%.

This may be attributed to differences in the study populations

baseline characteristics including age and frailty (i.e. fracture preva-

lence). Similarly, for those women taking 0.5 g/day, there was no

significant difference in the risk of withdrawals due to adverse

events (two trials, n=256, RR 1.10, 95% CI 0.56 to 1.80) (Meu-

nier 2002; Reginster 2002-1). The chi square test for heterogene-

ity was not significant.

Number of emergent adverse events:

A total of three trials (n = 6847) using the recommended daily

dose of 2 g of strontium ranelate versus placebo daily did not find

a significant difference in the number of emergent adverse events

(RR 0.99, 95% CI 0.98 to 1.01). (Meunier 2004-1; Meunier

2004-1; Reginster 2005). Similarly, two trials (n=256) using 0.5 g

of strontium ranelate versus placebo daily did not find a significant

difference in the risk of developing an adverse event (RR 0.93,

95% CI 0.86 to 1.00) (Meunier 2002; Reginster 2002-1). The

chi-square test for heterogeneity of the treatment effect was not

significant for either of these analyses.

Serious adverse events:

A total of three trials (n = 6847) reported the number of partic-

ipants that developed a serious adverse event using 2 g of stron-

tium ranelate daily versus placebo (Meunier 2002; Meunier 2004-

1; Reginster 2005). Serious adverse events occurred in 24.09% of

the strontium ranelate treated patients versus 23.97% of the con-

trols. The pooled estimate of the relative risk was 1.01 (95% CI

0.92 to 1.09) demonstrating a non significant difference between

the two groups. Similarly, two trials (n=256) reported the number

of serious adverse events using 0.5 g of strontium ranelate versus

placebo daily and found no significant difference in the relative

risk of developing a serious adverse event (RR 0.81, 95% CI 0.44

to 1.48) (Meunier 2002; Reginster 2002-1). The chi-square test

for heterogeneity of the treatment effect was not significant for

either of these analyses.

Diarrhea:

A total of three trials (n = 6847) reported the number of partic-

ipants that developed diarrhea using the recommended dose of



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strontium ranelate versus placebo daily (Meunier 2004-1; Meu-

nier 2002; Reginster 2005). Diarrhea occurred in 6.5% of the

strontium ranelate treated patients versus 4.7% in the controls.

The pooled estimate of the relative risk was 1.38 (95% CI 1.02 to

1.87) with an overall significant effect (p = 0.04). The chi-square

test for heterogeneity of the treatment effect was not significant.

Gastritis:

A total of three trials (n = 6847) reported the number of partici-

pants that developed gastritis using 2 g of strontium ranelate versus

placebo daily (Meunier 2002; Meunier 2004-1; Reginster 2005).

Gastritis occurred in 2.7% of the strontium ranelate treated pa-

tients and 3.4% of the controls. The pooled estimate of the rela-

tive risk was 0.81 (95% CI 0.56 to 1.17). The chi-square test for

heterogeneity of the treatment effect was not significant.

Deaths:

A total of three trials (n = 6847) reported the total number of deaths

using 2 g of strontium ranelate versus placebo daily (Meunier

2002; Meunier 2004-1; Reginster 2005). A total of 4.97% of the

strontium ranelate treated patients versus 5.37% of the controls

died during the follow-up period. The pooled estimate of the

relative risk was 0.99 (95% CI 0.64 to 1.53). The chi-square test

for heterogeneity of the treatment effect was borderline significant

with p= 0.17 and I2= 42.8%. This may be attributed to differences

in the mean age of the study population in addition to their frailty.

Additional data obtained suggests that the risk of vascular sys-

tem disorders including venous thromboembolism (two trials, n

= 6669, 2.2% versus 1.5%, OR 1.5, 95% CI 1.1 to 2.1) and pul-

monary embolism (two trials, n = 6669, 0.8% versus 0.4%, OR

1.7, 95% CI 1.0 to 3.1) as well as nervous system disorders such

as headaches (3.9% versus 2.9%), seizures (0.3% versus 0.1%),

memory loss (2.4% versus 1.9%) and disturbance in conscious-

ness (2.5% versus 2.0%) is slightly increased with taking 2 g of

strontium ranelate daily over a 3 to 4 year period.

D I S C U S S I O N

A total of four trials met our inclusion criteria, three of which

investigated the effects of strontium ranelate compared to placebo

in a treatment population (doses ranged from 0.5 to 2 g daily) and

one, in a prevention population (doses 0.125, 0.5 and 1 g daily).

The included studies were presumably conducted in calcium and

vitamin D replete postmenopausal women.

There is silver level evidence to support the use of 2 g of strontium

ranelate daily in osteoporotic postmenopausal women to reduce

the risk of vertebral and to a lesser extent, non-vertebral fractures.

The pooled estimate of the relative risk for vertebral and non-ver-

tebral fractures over a three year follow-up period were consistent

with a reduction of 37% for vertebral fractures and 14% for non-

vertebral fractures. Both estimates were statistically significant and

there was little heterogeneity of treatment effect however, the up-

per boundary of the confidence interval of the non-vertebral frac-

tures approaches one indicating that the data may be consistent

with a null effect. Furthermore, the impact that 2 g of strontium

ranelate daily has on reducing the risk of a hip fracture remains un-

clear as the only included study with data was not powered for this

outcome. Although data from direct comparisons with other anti-

osteoporotic treatments are lacking, the reduction in the relative

risk of vertebral fracture seems similar to the other available thera-

pies which have been shown to reduce the relative risk of recurrent

fracture by 40 to 60% (Cranney 2002). The greater reduction in

risk of vertebral fractures compared to non-vertebral fractures may

be explained by the greater effect that strontium ranelate has on

the vertebral versus non-vertebral bone mineral density.

The results of this review support the use of 2 g of strontium

ranelate daily in osteoporotic postmenopausal women for increas-

ing BMD at all sites over a two to three year period. In a preven-

tion population, 1 g of strontium ranelate daily was demonstrated

to increase BMD at all sites compared to placebo over a two year

period. In both the treatment and prevention populations, lower

doses of strontium ranelate were superior to placebo with the high-

est dose of strontium ranelate demonstrating the greatest increase

in BMD over a two year period. While the increase in BMD in

patients taking 2 g of strontium ranelate daily is impressive, cau-

tion is necessary when in interpreting these results. As previously

mentioned, the combined effect of strontium distribution in bone

and increased x-ray absorption of strontium compared to calcium

leads to an amplification of BMD measurement by DXA (Or-

tolani 2006). While the included trials described and performed

a correction to adjust for the strontium content in bone for the

lumbar spine BMD measurements, there is considerable uncer-

tainty about the accuracy of the results which arises from the small

number of participants in whom iliac crest bone biopsy was per-

formed and the reliance on animal data for the correction factor

for inferring bone strontium content in the spine (Blake 2005).

Although limited, there is evidence from one phase III trial to

suggest that 2 g of strontium ranelate daily compared to placebo

has a beneficial effect on health related quality of life in a subset of

postmenopausal women (n=1240) after three years of treatment.

In keeping with this, results from a back pain assessment included

in the quality of life questionnaire revealed that the occurrence

of back pain was significantly reduced by 29% in the strontium

ranelate group as compared to the placebo group over three years

with a significant effect in the first year (p = 0.006) (Marquis

2005). These findings are presumably due to a reduction in the

consequences related to osteoporosis such as vertebral fractures.

Overall incidence rates for adverse events with strontium ranelate

did not differ from placebo regardless of dose. There was a statisti-

cally significant increase in the risk for diarrhea in patients treated

with 2 g of strontium ranelate daily relative to placebo. However;

there was no significant difference in the number of withdrawals



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due to side effects, number of emergent events, serious adverse

events, gastritis or deaths regardless of the dose analyzed. Addi-

tional data obtained from the scientific report by the European

Agency for the Evaluation of Medicinal Products (EMEA 2004),

in addition to the industry sponsor (Servier), has illustrated some

concern of a slight increased risk in vascular and neurological dis-

orders as well as abnormal laboratory findings. This information

is based on results from the two phase III trials which focused on

the recommended dose of 2 g of strontium ranelate daily (Meu-

nier 2004-1; Reginster 2005) and has been summarized below and

within the appended table entitled “Other adverse events from

additional sources” (see Additional Tables -02).

Disorders of the vascular system were present in 26.3% of the pa-

tients in the strontium ranelate group versus 24.4% in the placebo;

Estimated difference = 1.9% (95% CI -0.2 to 4.0) with an in-

creased reporting rate of adverse events of venous thromboem-

bolism (2.2% versus 1.5%, OR 1.5, 95% CI 1.1 to 2.1) and pul-

monary embolism (0.8% versus 4.5%, OR 1.7, 95% CI 1.0 to

3.1) over a three year period. Furthermore, the absolute number

of patients that suffered a pulmonary embolism resulting in dis-

continuation of treatment or death was slightly increased in the

strontium ranelate group compared to controls (i.e. 0.2% versus

0.1%). The cause of this increased risk of vascular disorders is not

understood. Nervous system disorders were found in 20.9% of

the patients in the strontium ranelate group versus 18.9% in the

placebo; Estimated difference = 2.0 % (95% CI 0.1 to 3.9) with

an increased reporting of seizures (0.3% versus 0.1%), memory

loss (2.4% versus 1.9%) and disturbances in consciousness (2.5%

versus 2.0%) over a four year period. Again, the etiology of the

increased risk in neurological disorders is not clear. Lastly, mean

baseline serum creatine kinase levels increased in both groups how-

ever, this increase was significantly greater in the strontium ranelate

group (31.3 + 80.8 IU/L) compared to the controls (13.1 + 46.6

IU/L); Estimated difference = 18.2 IU/L (95% CI 14.8 to 21.6).

The serum creatine kinase levels was greater than the upper limit

of normal on at least one occasion in 29.4% (789/2680) of the

women in the strontium ranelate group versus 17.6% (475/2705)

of the controls (RR 1.68, 95% CI 1.52 to 1.85) providing evidence

of strontium ranelate impacting skeletal muscle cell integrity. In

light of these findings targetted surveillance will be needed (EMEA

2004).

Our systematic review has several limitations. Firstly, while the

methodological quality of the included studies was high based on

the Jadad instrument, three of the four studies had losses to follow-

up greater than 20% (Meunier 2002; Meunier 2004-1; Reginster

2005) and three had unclear descriptions of allocation conceal-

ment (Meunier 2004-1; Meunier 2004-1; Reginster 2005). Losses

to follow-up can threaten the validity of the trial since the event

rate may be very different in those lost to follow-up versus those

who completed the trial and failure to conceal the participants’

treatment allocation could also bias the treatment effect in either

direction. Secondly, access to aggregate data only within the pub-

lished studies resulting in pooling of proportions and limiting our

ability to adjust for differences in patient populations.

This review will be updated every two years (or earlier) depending

on the emergence of new evidence. Review updates will entail re-

peating, at periodic intervals, the steps involved in the original re-

view. If new evidence addresses important variables that were not

included in the original review we will consider including them.

In such instances, we will recheck whether any of their earlier

identified studies had such information that was overlooked. Fur-

thermore, should we decide to include a new analysis strategy in

our updated review we understand that any new analysis strategies

represents a substantive change to the review requiring editorial

critique through the Cochrane Collaboration’s established edito-

rial process.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

There is silver level evidence to support the usefulness of strontium

ranelate in reducing fractures in postmenopausal osteoporotic

women and increasing BMD in women with/without osteoporo-

sis. Pooled estimates using 2 g of strontium ranelate daily com-

pared to placebo in osteoporotic women over a three year period

are consistent with a reduction in vertebral fractures (37%); how-

ever, there is less of a reduction in non-vertebral fractures (14%)

and the effect on hip fractures remains unclear. Strontium ranelate

increased BMD at all sites in both treatment and prevention pop-

ulations and while lower doses of strontium ranelate were superior

to placebo, the highest dose demonstrated the greatest increase.

There is some evidence to suggest that 2 g of strontium ranelate

daily compared to placebo may have a beneficial effect on health

related quality of life in postmenopausal women after three years

of treatment. Diarrhea may occur however, adverse events leading

to study withdrawal were not significantly increased in the stron-

tium ranelate group. Potential risks to the vascular and neurolog-

ical system associated with taking 2 g of strontium ranelate daily

need to be further explored and quantified.


Further monitoring of the quality, effectiveness and safety of stron-

tium ranelate is essential especially in the prevention of osteo-

porosis. Additional research is required to confirm its mechanism

of action. Long term fracture data are needed to confirm the ef-

fect that strontium ranelate has on bone health in both preven-

tion and treatment populations. Long term safety data is required

with particular attention to be paid to bone mineralization, con-

tinued fracture efficacy, neurological and vascular system disor-

ders, specifically venous and pulmonary thromboembolism and

skeletal muscle integrity. Future trials to evaluate the impact of

strontium ranelate treatment on BMD, including the effect on

the elimination of bone strontium in patients switching to other



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anti-resorptive treatments, are needed. In addition, comparative

trials evaluating the efficacy of strontium ranelate relative to other

osteoporosis therapies such as bisphosphonates and intermittent

recombinant human parathyroid hormone are required.

P O T E N T I A L C O N F L I C T O F

I N T E R E S T

None known.


The authors would like to thank Louise Falzon of the Cochrane

Musculoskeletal Group for her assistance in developing the search

strategy and Patricia Chatelain from Servier who provided addi-

tional data not found within the published literature.


External sources of support

• Canadian Institutes for Health Research CANADA

Internal sources of support

• Ottawa Health Research Institute CANADA

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brands in a multicenter clinical trial. Journal of clinical densitometry

1999;2:37–44.

Tosteson 2001

Tosteson AN, Gabriel SE, Grove MR, Moncur MM, Kneeland TS,

Melton LJ, III. Impact of hip and vertebral fractures on quality-

adjusted life years. Osteoporosis international 2001;12:1042–1049.

Tugwell 2004

Tugwell P, Shea B, Boers M, Brooks P, Simon LS, Strand V, et

al.Evidence-based rheumatology. BMJ Publishing Group, 2004.

US Dept Health 2004

U.S. Department of Health and Human Service. Bone health and

osteoporosis: a report of the surgeon general. Office of the Surgeon

General, Rockville, and MD 2004:1–436.

WHO 1994

WHO Study Group. Assessment of fracture risk and its application

to screening for postmenopausal osteoporosis. Report of a WHO

study group. World Health Organization technical report 1994; Vol.

843:1–129.



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T A B L E S

Characteristics of included studies

Study Meunier 2002

Methods Randomized placebo controlled trial

Duration = 2 years

N = 353

Participants Postmenopausal women

(mean age 66.2, mean (SD) Lumbar spine (LS) T-score by group: -3.80 (0.94) to -.3.97 (0.95), previous

vertebral fracture 100%)

Treatment

Primary outcome: LS bone mineral density (BMD)

Interventions Strontium ranelate 0.5 g OR 1 g OR 2 g VERSUS placebo daily

(calcium supplement 500 mg daily and vitamin D 800 IU daily)

Outcomes BMD: Lumbar spine and femoral neck

Fractures: vertebral (deformities)

Notes Lost to follow-up: 81/353 (22.9%)

Quality Score: 5/5

Allocation concealment A – Adequate

Study Meunier 2004-1


Duration = 3 years

N = 1649


(mean age 69.3, mean (SD) LS T-score by group: -3.5 (1.3) to -3.6 (1.2), previous vertebral fracture 100%)

Treatment

Primary outcome: Vertebral fractures

Interventions Strontium ranelate 2g VERSUS placebo daily

(calcium supplement up to 1000 mg daily based upon dietary intake and vitamin D 400-800 IU daily based

on serum concentration of 25-hydroxyvitamin D)

Outcomes BMD: Lumbar spine, femoral neck and total hip

Fracture: Vertebral and non-vertebral


Quality score: 4/5

Allocation concealment B – Unclear

Study Reginster 2002-1


Duration = 2 years

N = 160


(mean age 54.2, mean LS T-score by group: -1.3 to -1.5, previous vertebral fracture 0%)

Prevention

Primary outcome: LS BMD



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Interventions Strontium ranelate 125 mg OR 500 mg OR 1 g VERSUS placebo daily

(calcium supplement 500 mg daily as calcium carbonate)

Outcomes BMD: Lumbar spine, femoral neck and total hip


Quality score: 4/5


Study Reginster 2005


Duration = 5 years (main statistical analysis over 3 years)

N = 5091


(mean age 76.7, mean (SD) LS T-score -2.83 (1.63) to -3.24 (1.53), previous vertebral and non-vertebral

fracture 55.4 VERSUS 54.2%)

Treatment

Primary outcome: Non-vertebral fractures

Interventions Strontium ranelate 2 g VERSUS placebo daily

(calcium supplement up to 1000 mg daily based upon dietary intake and vitamin D 400-800 IU daily based

on serum concentration of 25-hydroxyvitamin D)

Outcomes BMD: Femoral neck and total hip

Fracture: Vertebral, non-vertebral, major non-vertebral (hip, wrist, pelvis and sacrum, ribs and sternum,

clavicle, humerus) and hip

Notes Lost to follow-up:

1771/5091 (34.8%)

Quality Score: 4/5


Characteristics of excluded studies


Boivin 2003 Review publication

Meunier 2003 Review of study design

Meunier 2004-2 Review publication

Meunier 2004-3 Review publication

Naveau 2004 Review publication

Pors 2004 Review publication

Reginster 2002-2 Review publication



Reginster 2004 Review publication


Sorbera 2003 Review publication

Uebelhart 2003 Review publication



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Characteristics of excluded studies (Continued )


Table 01. Clinical relevance table strontium ranelate 2 g per day: Fractures & safety data

Outcome

ER in Sr

grp (%)

ER in Ctrl

grp (%)

RR (95%

CI)

ARD

(95% CI)

NNT/NNH

(95% CI)

Sr grp: #

of women

Ctrl grp:

# of

women

Rel %

Improve-

ment

Quality of

evidence

Vertebral

fracture (1

year)

117/2621

(4.5%)

206/2633

(7.8%)

0.59

(0.46,

0.74)

-4% (-7 , -

1)

25 (14, 1) 4/100 7/100 41% Silver

Vertebral

fracture (3

years)

341/2536

(13.4%)

543/2546

(21.3%)

0.63

(0.56,

0.71)

-9% (-13,

-4)

11 (8, 25) 13/100 21/100 37% Silver

Non-

vertebral

fracture (3

years)

345/3305

(10.4%)

398/3267

(12.5%)

0.86

(0.75,

0.98)

-2% (-3,

0)

50 (33, 0) 11/100 13/100 14% Silver

With-

drawals

due to

adverse

events

762/3439

(22.1%)

650/3408

(19.1%)

1.20

(0.96,

1.50)

3% (1, 6) - - - - Silver

Serious

adverse

events

828/3437

(24.1%)

816/3404

(24.0%)

1.01

(0.92,

1.09)

0% (-2, 2) - - - - Silver

Emergent

adverse

events

3028/3439

(88.0%)

3019/3408

(88.6%)

0.99

(0.98,

1.01)

-1% (-2,

1)

- - - - Silver

Gastritis 93/3439

(2.7%)

115/3408

(3.4%)

0.81

(0.56,

1.17)

-1% (-2,

1)

- - - - Silver

Diarrhea 222/3439

(6.5%)

160/3408

(4.7%)

1.38

(1.02,

1.87)

2% (0, 3) 50 (0, 33) 6/100 4/100 -38% Silver

Legend: ER =

Event rate

Ctrl =

Controls

RR =

Relative

risk

ARD =

Absolute

risk

difference

NNT =

Number

needed to

treat

# =

Number

Rel =

Relative

Sr =

Strontium

ranelate

CI = Con-

fidence

interval

NNH =

Number

needed to

harm



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Table 02. Clinical relevance table strontium ranelate 2 g per day: BMD data

Outcome (scale)

# in Sr: Ctrl

group Mean (SD) Ctrl WMD (95% CI) Abs change Rel change

Quality of

Evidence

Lumbar spine

BMD - not

adjusted (2 years)

804:810 -1.02 (6.10)* 11.29 (10.22,

12.37)

11.29 -11.1% Silver

Lumbar spine

BMD - adjusted

(2 years)

804:810 -1.18 (6.26)* 5.44 (3.41, 7.46) 5.44 -4.6% Silver

Femoral neck

BMD (2 years)

804:810 -2.18 (5.06)* 5.73 (5.15, 6.32) 5.73 -2.6% Silver

Femoral neck

BMD (3 years)

2112:2118 -2.57 (5.80)** 8.25 (7.84, 8.66) 8.25 -3.2% Silver

Total hip BMD

(3 years)

2112:2118 -2.74 (5.80)** 9.83 (9.39,

10.26)

9.83 -3.6% Silver

most

representative

study:

# = Number SD = Standard

deviation

WMD =

Weighted mean

difference

Abs = Absolute Rel = Relative

Meunier, 2004-

1*; Reginster,

2005**

Sr = Strontium

ranelate

Ctrl = Controls

Table 03. Other adverse events from additional sources (EMEA 2004* and Servier**)

Adverse event (AE) Sr (n = 3352) Control (n= 3317) ED (95% CI) OR (95% CI)

VASCULAR SYSTEM

DISORDERS

880 (26.3%)* 809 (24.4%)* 1.9% (-0.2, 4.0)* -

Thrombosis 111 (3.3%)* 72 (2.2%)* 1.1% (0.4, 1.9)* -

Venous thromboembolism at 3

years

75 (2.2%)** 50 (1.5%)** - 1.5 (1.1, 2.1)*

Venous thromboembolism at 4

years

87 (2.6%)** 61 (1.8%)** - -

Pulmonary embolism (PE) 25 (0.8%)** 15 (0.4%)** - 1.7 (1.0, 3.1)*

Fatal PE 6 (0.2%)* 3 (0.1%)* - -

PE leading to treatment

discontinuation

7 (0.2%)* 3 (0.1%)* - -

NERVOUS SYSTEM

DISORDERS

699 (20.9%)* 627 (18.9%)* 2.0% (0.1, 3.0)* -

Headaches 131 (3.9%)* 97 (2.9%)* 1.0% (0.1, 1.9)* -

Seizures at 4 years 9 (0.3%)** 3 (0.1%)** - -

Memory loss at 4 years 79 (2.4%)** 63 (1.9%)** - -

Disturbance in consciousness 83 (2.5%)** 66 (2.0%)** - -



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Table 03. Other adverse events from additional sources (EMEA 2004* and Servier**) (Continued )

Adverse event (AE) Sr (n = 3352) Control (n= 3317) ED (95% CI) OR (95% CI)

at 4 years

LABORATORY RESULTS

Serum creatine kinase 31.3 (80.8) IU/L* 13.1 (46.6) IU/L* 18.2 (14.8; 21.6) IU/L* -

Data obtained from the

EMEA* and Servier**

Sr = Strontium ranelate ED= Estimated difference OR = Odds ratio

CI = Confidence interval

A N A L Y S E S

Comparison 01. Fractures

Outcome titleNo. of

studies

No. of


01 Verterbral fractures Relative Risk (Random) 95% CI Subtotals only

02 Non-vertebral fractures Relative Risk (Random) 95% CI Subtotals only

Comparison 02. BMD

Outcome titleNo. of

studies

No. of


01 Lumbar spine BMD not

adjusted for strontium content

Weighted Mean Difference (Random) 95% CI Subtotals only

02 Lumbar spine adjusted for

strontium content

Weighted Mean Difference (Random) 95% CI Subtotals only

03 Femoral neck Weighted Mean Difference (Random) 95% CI Subtotals only

04 Total hip Weighted Mean Difference (Random) 95% CI Subtotals only

Comparison 03. Adverse Events

Outcome titleNo. of

studies

No. of


01 Total withdrawls Relative Risk (Random) 95% CI Subtotals only

02 Withdrawals due to adverse

events

Relative Risk (Random) 95% CI Subtotals only

03 Number of emergent adverse

events

Relative Risk (Random) 95% CI Subtotals only

04 Serious adverse events Relative Risk (Random) 95% CI Subtotals only

05 Diarrhea Relative Risk (Random) 95% CI Subtotals only

06 Gastritis Relative Risk (Random) 95% CI Subtotals only

07 Deaths Relative Risk (Random) 95% CI Subtotals only

C O V E R S H E E T

Title Strontium ranelate for preventing and treating postmenopausal osteoporosis

Authors O’Donnell S, Cranney A, Wells GA, Adachi JD, Reginster JY

Contribution of author(s) Siobhan O’Donnell prepared the protocol and review for submission.



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Ann Cranney conceptualized the idea and supervised all stages of the review.

George Wells provided statistical support.

Jonathan Adachi provided feedback on drafts.

Jean-Yves Reginster facilitated the attainment of unpublished data and provided feedback

on drafts.

All co-reviewers reviewed and approved the final review.

Issue protocol first published 2005/2

Review first published 2006/3

Date of most recent amendment 24 May 2006

Date of most recent

SUBSTANTIVE amendment

24 May 2006

What’s New Information not supplied by author

Date new studies sought but

none found

Information not supplied by author

Date new studies found but not

yet included/excluded


Date new studies found and

included/excluded


Date authors’ conclusions

section amended


Contact address Ms Siobhan O’Donnell

Research Coordinator

Clinical Epidemiology Program

Ottawa Health Research Institute

1053 Carling Avenue, C-414

Ottawa

ON

K1Y 4E9

CANADA

E-mail: [email protected]

Tel: 613-798-5555

Fax: 613-761-5492

DOI 10.1002/14651858.CD005326.pub2

Cochrane Library number CD005326

Editorial group Cochrane Musculoskeletal Group

Editorial group code HM-MUSKEL



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G R A P H S A N D O T H E R T A B L E S

Analysis 01.01. Comparison 01 Fractures, Outcome 01 Verterbral fractures

Review: Strontium ranelate for preventing and treating postmenopausal osteoporosis

Comparison: 01 Fractures

Outcome: 01 Verterbral fractures

Study Strontium Placebo Relative Risk (Random) Weight Relative Risk (Random)

n/N n/N 95% CI (%) 95% CI

01 2 g/day - 1 Year

Meunier 2002 22/85 28/87 22.2 0.80 [ 0.50, 1.29 ]

Meunier 2004-1 44/719 85/723 37.6 0.52 [ 0.37, 0.74 ]

Reginster 2005 51/1817 93/1823 40.2 0.55 [ 0.39, 0.77 ]

Subtotal (95% CI) 2621 2633 100.0 0.59 [ 0.46, 0.74 ]

Total events: 117 (Strontium), 206 (Placebo)

Test for heterogeneity chi-square=2.34 df=2 p=0.31 I =14.4%

Test for overall effect z=4.47 p<0.00001

02 2 g/day - 3 Years

Meunier 2004-1 139/719 222/723 43.8 0.63 [ 0.52, 0.76 ]

Reginster 2005 202/1817 321/1823 56.2 0.63 [ 0.54, 0.74 ]

Subtotal (95% CI) 2536 2546 100.0 0.63 [ 0.56, 0.71 ]

Total events: 341 (Strontium), 543 (Placebo)



0.1 0.2 0.5 1 2 5 10

Favours strontium Favours placebo

Analysis 01.02. Comparison 01 Fractures, Outcome 02 Non-vertebral fractures


Comparison: 01 Fractures

Outcome: 02 Non-vertebral fractures

Study Strontium ranelate Placebo Relative Risk (Random) Weight Relative Risk (Random)

n/N n/N 95% CI (%) 95% CI


Meunier 2004-1 112/826 122/814 32.6 0.90 [ 0.71, 1.15 ]

Reginster 2005 233/2479 276/2453 67.4 0.84 [ 0.71, 0.99 ]

Subtotal (95% CI) 3305 3267 100.0 0.86 [ 0.75, 0.98 ]

Total events: 345 (Strontium ranelate), 398 (Placebo)


Test for overall effect z=2.22 p=0.03

0.1 0.2 0.5 1 2 5 10




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Analysis 02.01. Comparison 02 BMD, Outcome 01 Lumbar spine BMD not adjusted for strontium content


Comparison: 02 BMD

Outcome: 01 Lumbar spine BMD not adjusted for strontium content

Study Strontium Ranelate Placebo Weighted Mean Difference (Random) Weight Weighted Mean Difference (Random)

N Mean(SD) N Mean(SD) 95% CI (%) 95% CI

01 0.5 g/day - 2 Years

Meunier 2002 80 5.87 (6.59) 87 1.25 (5.30) 47.5 4.62 [ 2.80, 6.44 ]

Reginster 2002-1 35 1.90 (3.59) 30 -0.75 (3.02) 52.5 2.65 [ 1.04, 4.26 ]

Subtotal (95% CI) 115 117 100.0 3.59 [ 1.66, 5.51 ]



02 1 g/d - 2 Years

Meunier 2002 86 8.33 (8.65) 87 1.25 (5.30) 50.3 7.08 [ 4.94, 9.22 ]

Reginster 2002-1 29 5.53 (5.12) 30 -0.75 (3.02) 49.7 6.28 [ 4.13, 8.43 ]

Subtotal (95% CI) 115 117 100.0 6.68 [ 5.16, 8.20 ]




Meunier 2002 85 13.61 (8.87) 87 1.25 (5.30) 20.8 12.36 [ 10.17, 14.55 ]

Meunier 2004-1 719 9.99 (9.83) 723 -1.02 (6.10) 79.2 11.01 [ 10.17, 11.85 ]

Subtotal (95% CI) 804 810 100.0 11.29 [ 10.22, 12.37 ]



-100.0 -50.0 0 50.0 100.0

Favours placebo Favours strontium



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Analysis 02.02. Comparison 02 BMD, Outcome 02 Lumbar spine adjusted for strontium content


Comparison: 02 BMD

Outcome: 02 Lumbar spine adjusted for strontium content




Meunier 2002 80 3.11 (5.92) 87 1.23 (5.31) 48.2 1.88 [ 0.17, 3.59 ]

Reginster 2002-1 35 -0.78 (3.42) 30 -0.98 (3.14) 51.8 0.20 [ -1.40, 1.80 ]

Subtotal (95% CI) 115 117 100.0 1.01 [ -0.63, 2.66 ]




Meunier 2002 86 3.20 (7.16) 87 1.23 (5.31) 58.7 1.97 [ 0.09, 3.85 ]

Reginster 2002-1 29 1.41 (5.33) 30 -0.98 (3.14) 41.3 2.39 [ 0.15, 4.63 ]

Subtotal (95% CI) 115 117 100.0 2.14 [ 0.70, 3.58 ]




Meunier 2002 85 5.45 (6.80) 87 1.23 (5.31) 41.9 4.22 [ 2.39, 6.05 ]

Meunier 2004-1 719 5.13 (8.56) 723 -1.18 (6.26) 58.1 6.31 [ 5.54, 7.08 ]

Subtotal (95% CI) 804 810 100.0 5.44 [ 3.41, 7.46 ]



-10.0 -5.0 0 5.0 10.0




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Analysis 02.03. Comparison 02 BMD, Outcome 03 Femoral neck


Comparison: 02 BMD

Outcome: 03 Femoral neck




Meunier 2002 80 0.24 (3.01) 87 -0.47 (9.39) 53.5 0.71 [ -1.37, 2.79 ]

Reginster 2002-1 35 0.46 (4.70) 30 -0.87 (4.46) 46.5 1.33 [ -0.90, 3.56 ]

Subtotal (95% CI) 115 117 100.0 1.00 [ -0.52, 2.52 ]




Meunier 2002 86 1.41 (3.45) 87 -0.47 (9.39) 55.3 1.88 [ -0.22, 3.98 ]

Reginster 2002-1 30 2.45 (4.78) 30 -0.87 (4.46) 44.7 3.32 [ 0.98, 5.66 ]

Subtotal (95% CI) 116 117 100.0 2.52 [ 0.96, 4.09 ]




Meunier 2002 85 5.36 (8.22) 87 -0.47 (9.39) 4.9 5.83 [ 3.19, 8.47 ]

Meunier 2004-1 719 3.55 (6.47) 723 -2.18 (5.06) 95.1 5.73 [ 5.13, 6.33 ]

Subtotal (95% CI) 804 810 100.0 5.73 [ 5.15, 6.32 ]




Meunier 2004-1 719 5.51 (7.58) 723 -2.79 (5.67) 35.7 8.30 [ 7.61, 8.99 ]

Reginster 2005 1393 5.65 (7.90) 1395 -2.57 (5.80) 64.3 8.22 [ 7.71, 8.73 ]

Subtotal (95% CI) 2112 2118 100.0 8.25 [ 7.84, 8.66 ]



-10.0 -5.0 0 5.0 10.0




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Analysis 02.04. Comparison 02 BMD, Outcome 04 Total hip


Comparison: 02 BMD

Outcome: 04 Total hip

Study Strontium ranelate Placebo Weighted Mean Difference (Random) Weight Weighted Mean Difference (Random)



Meunier 2004-1 719 7.33 (7.67) 723 -2.49 (5.84) 38.8 9.82 [ 9.12, 10.52 ]

Reginster 2005 1393 7.09 (8.71) 1395 -2.74 (6.19) 61.2 9.83 [ 9.27, 10.39 ]

Subtotal (95% CI) 2112 2118 100.0 9.83 [ 9.39, 10.26 ]



-100.0 -50.0 0 50.0 100.0


Analysis 03.01. Comparison 03 Adverse Events, Outcome 01 Total withdrawls


Comparison: 03 Adverse Events

Outcome: 01 Total withdrawls


n/N n/N 95% CI (%) 95% CI

01 0.5 g/d

Meunier 2002 20/85 17/91 59.6 1.26 [ 0.71, 2.24 ]

Reginster 2002-1 5/40 10/40 40.4 0.50 [ 0.19, 1.33 ]

Subtotal (95% CI) 125 131 100.0 0.87 [ 0.36, 2.11 ]




02 2 g/d

Meunier 2002 20/87 17/91 1.5 1.23 [ 0.69, 2.19 ]

Meunier 2004-1 198/826 182/814 16.0 1.07 [ 0.90, 1.28 ]

Reginster 2005 839/2526 870/2503 82.5 0.96 [ 0.88, 1.03 ]

Subtotal (95% CI) 3439 3408 100.0 0.98 [ 0.91, 1.05 ]




0.1 0.2 0.5 1 2 5 10




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Analysis 03.02. Comparison 03 Adverse Events, Outcome 02 Withdrawals due to adverse events



Outcome: 02 Withdrawals due to adverse events


n/N n/N 95% CI (%) 95% CI

01 0.5 g/d

Meunier 2002 15/85 14/91 76.1 1.15 [ 0.59, 2.23 ]

Reginster 2002-1 4/40 6/40 23.9 0.67 [ 0.20, 2.18 ]

Subtotal (95% CI) 125 131 100.0 1.01 [ 0.56, 1.80 ]



Test for overall effect z=0.02 p=1

02 2 g/d

Meunier 2002 11/87 14/91 8.3 0.82 [ 0.39, 1.71 ]

Meunier 2004-1 140/826 95/814 36.4 1.45 [ 1.14, 1.85 ]

Reginster 2005 611/2526 541/2503 55.4 1.12 [ 1.01, 1.24 ]

Subtotal (95% CI) 3439 3408 100.0 1.20 [ 0.96, 1.50 ]




0.1 0.2 0.5 1 2 5 10




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Analysis 03.03. Comparison 03 Adverse Events, Outcome 03 Number of emergent adverse events



Outcome: 03 Number of emergent adverse events


n/N n/N 95% CI (%) 95% CI

01 0.5 g/d

Meunier 2002 70/85 83/91 42.7 0.90 [ 0.80, 1.02 ]

Reginster 2002-1 37/40 39/40 57.3 0.95 [ 0.86, 1.05 ]

Subtotal (95% CI) 125 131 100.0 0.93 [ 0.86, 1.00 ]




02 2 g/d

Meunier 2002 78/87 83/91 3.2 0.98 [ 0.89, 1.08 ]

Meunier 2004-1 730/826 711/814 22.9 1.01 [ 0.98, 1.05 ]

Reginster 2005 2220/2526 2225/2503 73.9 0.99 [ 0.97, 1.01 ]

Subtotal (95% CI) 3439 3408 100.0 0.99 [ 0.98, 1.01 ]




0.1 0.2 0.5 1 2 5 10




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Analysis 03.04. Comparison 03 Adverse Events, Outcome 04 Serious adverse events



Outcome: 04 Serious adverse events


n/N n/N 95% CI (%) 95% CI

01 0.5 g/d

Meunier 2002 11/80 17/87 76.1 0.70 [ 0.35, 1.41 ]

Reginster 2002-1 5/40 4/40 23.9 1.25 [ 0.36, 4.32 ]

Subtotal (95% CI) 120 127 100.0 0.81 [ 0.44, 1.48 ]




02 2 g/d

Meunier 2002 16/85 17/87 1.9 0.96 [ 0.52, 1.78 ]

Meunier 2004-1 188/826 188/814 22.5 0.99 [ 0.83, 1.18 ]

Reginster 2005 624/2526 611/2503 75.6 1.01 [ 0.92, 1.11 ]

Subtotal (95% CI) 3437 3404 100.0 1.01 [ 0.92, 1.09 ]




0.1 0.2 0.5 1 2 5 10


Analysis 03.05. Comparison 03 Adverse Events, Outcome 05 Diarrhea



Outcome: 05 Diarrhea


n/N n/N 95% CI (%) 95% CI

01 2 g/d

Meunier 2002 3/87 6/91 4.9 0.52 [ 0.13, 2.03 ]

Meunier 2004-1 50/826 29/814 31.6 1.70 [ 1.09, 2.66 ]

Reginster 2005 169/2526 125/2503 63.5 1.34 [ 1.07, 1.68 ]

Subtotal (95% CI) 3439 3408 100.0 1.38 [ 1.02, 1.87 ]




0.1 0.2 0.5 1 2 5 10




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Analysis 03.06. Comparison 03 Adverse Events, Outcome 06 Gastritis



Outcome: 06 Gastritis


n/N n/N 95% CI (%) 95% CI

01 2 g/d

Meunier 2002 5/87 2/91 5.0 2.61 [ 0.52, 13.12 ]

Meunier 2004-1 30/826 45/814 40.7 0.66 [ 0.42, 1.03 ]

Reginster 2005 58/2526 68/2503 54.3 0.85 [ 0.60, 1.19 ]

Subtotal (95% CI) 3439 3408 100.0 0.81 [ 0.56, 1.17 ]




0.01 0.1 1 10 100


Analysis 03.07. Comparison 03 Adverse Events, Outcome 07 Deaths



Outcome: 07 Deaths


n/N n/N 95% CI (%) 95% CI

01 0.5 g/d

Meunier 2002 4/85 3/91 100.0 1.43 [ 0.33, 6.19 ]

x Reginster 2002-1 0/40 0/40 0.0 Not estimable

Subtotal (95% CI) 125 131 100.0 1.43 [ 0.33, 6.19 ]


Test for heterogeneity: not applicable


02 2 g/d

Meunier 2002 0/87 3/91 2.2 0.15 [ 0.01, 2.85 ]

Meunier 2004-1 29/826 21/814 34.3 1.36 [ 0.78, 2.37 ]

Reginster 2005 142/2526 159/2503 63.5 0.88 [ 0.71, 1.10 ]

Subtotal (95% CI) 3439 3408 100.0 0.99 [ 0.64, 1.53 ]



Test for overall effect z=0.06 p=1

0.001 0.01 0.1 1 10 100 1000




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cochrane alendronate, risendronate systematic review

Documents

methods figure

university of ottawa

cochrane collaboration

cochrane review

cochrane library2011

cochrane musculoskeletal

postmenopausal womengeorge

shea b