vitamin d for the prevention of osteoporotic fractures

8/2/2019 Vitamin D for the Prevention of Osteoporotic Fractures

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TITLE: Vitamin D for the Prevention of Osteoporotic Fractures

AUTHOR: Jeffrey A. Tice, MD

Assistant Professor of Medicine

Division of General Internal Medicine

Department of Medicine

University of California San Francisco

PUBLISHER: California Technology Assessment Forum

DATE OF PUBLICATION: February 16, 2011

PLACE OF PUBLICATION: San Francisco, CA


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VITAMIN D FOR THE PREVENTION OF OSTEOPOROTIC FRACTURES

A Technology Assessment

INTRODUCTION

The California Technology Assessment Forum (CTAF) was asked to assess the evidence for the use of

vitamin D to prevent osteoporotic fractures. There has been increasing interest and controversy surrounding

vitamin D deficiency in the United States and the use of vitamin D supplements to prevent a myriad of

diseases.1-5The Institute of Medicine reviewed the new literature and updated their dietary

recommendations about dietary intake of vitamin D and calcium in 2011.6The primary use of vitamin D has

been in promoting healthy bones and preventing osteoporosis. However, several recent randomized trialshave questioned the utility of vitamin D for the prevention of osteoporotic fractures,7-9and the most recent

large trial reported a significant increase in the risk of both falls and fractures in patients randomized to

receive supplemental vitamin D.10

BACKGROUND

Osteoporotic fractures

People with poor bone quality and low bone mass, usually assessed by bone mineral density (BMD) aresaid to have osteoporosis. Osteoporosis itself is asymptomatic, but it increases an individuals risk for

fractures. The most common fracture sites associated with osteoporosis are the hip, the distal forearm

(wrist), and the vertebrae (spine). Hip fractures have the greatest impact on patients quality of life: half of

patients have permanent limitations to their physical activity; 20% require long-term care in a nursing home,

and up to 20% die in the year following the fracture.11-15In the United States, the lifetime risk for a hip

fracture is approximately 18% in Caucasian women and 6% in men.16Similarly, the lifetime risk for a

fracture of the distal forearm is approximately 16% in Caucasian women and 5% in men. Finally, the lifetime

risk for at least one vertebral fracture diagnosed by a physician is approximately 16% in Caucasian womenand 2.5% in men.16Moreover, the majority of vertebral fractures are not diagnosed clinically, but still may

cause significant pain and limitations to physical activity.17Approximately nine million women and three

million men in the United States have osteoporosis. In 2005, there were approximately two million fractures

due to osteoporosis with annual direct costs exceeding $17 billion.18This includes approximately 300,000

hip fractures and 550,000 vertebral fractures, but does not include indirect costs associated with fractures


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such as long-term rehabilitation programs or nursing home placement.18

Bone density, an important risk factor for fracture, increases as children grow and reaches its peak at about

age 30 years and declines thereafter. Osteoporosis is usually defined as a BMD at least 2.5 standard

deviations below the average bone density for a 30 year old of the same sex. The number of standarddeviation units from peak bone mass is called the T-score. Dual x-ray absorptiometry (DXA), a special form

of low dose x-rays, is the preferred method to measure BMD. DXA measurements of BMD are usually done

at the hip and lumbar spine as those are the most common sites for osteoporotic fractures.

As described above, the majority of osteoporotic fractures occur in women. Other important risk factors for

osteoporosis include older age, race (Caucasians and Asians are at increased risk), family history of hip

fracture, early menopause, smoking, drinking three or more alcoholic beverages per day, limited physical

activity, falls, low body weight, corticosteroid use, and hyperthyroidism.19Everyone loses bone mass as they

age, but bone loss accelerates for women at the time of menopause. Estrogen therapy has been shown to

slow the bone loss associated with menopause and to reduce a womans risk for osteoporotic fractures.

Parathyroid hormone analogs, bisphosphonates, nasal calcitonin, and selective estrogen receptor

modulators are other classes of medications that can reduce a womans risk for fractures.20Less expensive

alternatives may include calcium and vitamin D.

Vitamin D

Vitamin D is the most important cause of nutritional rickets worldwide. Rickets is a disease of childrencharacterized by stunted growth and soft bones that lead to bowing of the legs and arms. It results from

inadequate mineralization of the bones primarily due to inadequate vitamin D, although inadequate calcium

and phosphorous in the diet can also cause the disease. This led to the classification of vitamin D as a

vitamin.

As the biology of vitamin D and bone physiology was understood in greater detail, it became clear that

vitamin D is better thought of as a pro-hormone. The activated form of vitamin D requires the addition of two

hydroxyl groups. The liver adds the first hydroxyl group to form 25-hydroxyvitamin D (25(OH(D). The kidney

adds the second hydroxyl group to form 1,25-dihydroxyvitamin D or calcitriol. Calcitriol is the biologically

active form of vitamin D.

Calcitriol acts on the intestines, kidneys, and bones to increase plasma levels of calcium and phosphate,

which are required for bone mineralization. It primarily promotes calcium and phosphate absorption

throughout the intestines. In combination with parathyroid hormone (PTH), calcitriol promotes resorption of


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the bone matrix, which releases calcium and phosphate into the circulation. Calcitriol also slightly increases

renal reabsorption of calcium. These activities cause plasma calcium levels to rise, which in turn decreases

PTH secretion. Thus, the actions and levels of vitamin D, calcium and PTH are intimately linked. Many of

the trials described below randomized patients to a combination of vitamin D and calcium and report the

effect of supplementation on PTH levels. PTH levels should fall, thus decreasing bone resorption that is

stimulated by high levels of PTH.

Calcium and vitamin D also play a role in muscle function.21Recent meta-analyses of randomized trials

report that vitamin D supplementation reduces the risk of fall in the elderly.22-24Since most fractures follow

falls, a reduction in falls should translate into a reduction in fractures.

The primary source of vitamin D in the human body is de novo synthesis of the vitamin by the skin when

exposed to the ultraviolet B radiation from sunlight. This natural form of vitamin D, made by the skin, is

called cholecalciferol, and is also known as vitamin D3. A synthetic form, derived from plant sterols, is called

ergocalciferol or vitamin D2. Vitamin D2 has been commonly used in dietary supplements in the United

States, although recent controversy about the bioequivalence of vitamins D2 and D3 has led to more

frequent use of vitamin D3.25-30

Serum 25(OH)D is considered the best measure of overall vitamin D status. It reflects both dietary intake of

vitamin D and endogenous production of vitamin D by the skin. Low serum 25(OH)D levels are associated

with osteoporosis and predict future fractures.31-35The cutpoint for a normal serum 25(OH)D level is

controversial. There is consensus that individuals with levels below 20 ng/ml are deficient in vitamin D.

However, many experts argue that optimal levels are above 30 mg/ml.26

Serum 25(OH)D levels tend to fall in populations during the winter compared to the summer months

because of the shorter hours of daylight.36Additionally, in the developed world, individuals spend less time

outside in sunlight and when outside are encouraged to keep their skin covered or to use sun block in order

to prevent skin cancer. This limits the bodys ability to naturally produce vitamin D. In order to prevent

rickets, dairy products have been fortified with vitamin D. But many individuals consume very little dairy in

their diet. Older individuals in particular have limited sun exposure and minimal vitamin D in their diet.

Serum 25(OH)D levels clearly decrease with aging in the United States.36Thus, low 25(OH)D levels are

very common, especially in the elderly, and may contribute to the increased incidence of fractures in this

population. Recent data suggest that 35% to 40% of Americans over the age of 50 have vitamin D levels

below 20 ng/ml and approximately 80% have levels below 30 ng/ml.6

The Institute of Medicine (IOM) recently released updated recommendations about vitamin D intake.6The


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Recommended Daily Allowance (RDA) represents the intake requirement that meets the needs of 97.5% of

the population. The new RDA levels are 600 International Units (IU) per day for people ages 1 through 70

and 800 IU per day for people over the age of 70. Both were increased by 200 IU per day compared with

their 1997 recommendations. The new RDA should be sufficient to maintain serum 25(OH)D levels above

20 ng/mL without significant sun exposure or dietary intake. The Tolerable Upper Intake Level (UL) is the

intake level above which the potential for harm increases. The new UL is 4000 IU per day, up from 2000 IU

per day.

Low 25(OH)D levels are common and have been shown to predict bone loss, osteoporosis, and fractures.

Vitamin D supplementation is also inexpensive and relatively safe. Thus, supplementation with vitamin D

may be an important therapy to prevent fractures. However, excitement about the efficacy of high doses of

other vitamins for the prevention of chronic diseases of aging has been tempered by the results of large

clinical trials demonstrating either no benefits (folic acid, vitamin C) or increased mortality and net harm(vitamin E, beta carotene).37This assessment summarizes the randomized trial literature on vitamin D

supplementation to prevent fractures.

TECHNOLOGY ASSESSMENT (TA)

TA Criterion 1: The technology must have final approval from the appropriate government

regulatory bodies.

The Food and Drug Administration (FDA) has regulatory responsibility for dietary supplements (includingvitamins). However, a different set of regulations is used than that used for foods and drugs.

Under the Dietary Supplement Health and Education Act of 1994 (DSHEA) the dietary supplement

manufacturer is responsible for ensuring the supplement is safe prior to bringing it to market. The

manufacturer is also responsible to ensure that the product label information is truthful. The FDA is

responsible for post-marketing monitoring to ensure that unsafe products are removed from the market and

that labeling is accurate. The Federal Trade Commission (FTC) regulates advertising of dietary

supplements.

There are some preparations of Vitamin D, both Calcitriol and Ergocalciferol which have been approved by

the FDA for prescription use only. These preparations may be injectable, oral or nasal spray.

TA Criterion 1 is met.


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TA Criterion 2: The scientific evidence must permit conclusions concerning the effectiveness of

the technology regarding health outcomes.

The Medline database, Embase, Cochrane clinical trials database, Cochrane reviews database and the

Database of Abstracts of Reviews of Effects (DARE) were searched using the key words ergocalciferol,

cholecalciferol, vitamin D, vitamin D2, or vitamin D3. The results were crossed with the results from a

search on fracture. The search was performed for the period from 1945 through January 2011. The

bibliographies of systematic reviews and key articles were manually searched for additional references.

References were also solicited from the manufacturers and local experts. The abstracts of citations were

reviewed for relevance and all potentially relevant articles were reviewed in full. This review focuses on the

effect of vitamin D on osteoporotic fractures as well as potential harms including hypercalcemia, kidney

stones, renal function, and death.

The search identified 996 potentially relevant studies (Figure 1). After elimination of duplicate and non-

relevant references including studies of fractures in young women and studies of activated forms of vitamin

D, the search identified multiple publications describing 25 randomized or pseudo-randomized trials that

reported osteoporotic fractures as one of their outcomes.7-10,38-61The search included pseudo-randomized

trials38,40,47in which allocation to the intervention or control arm was primarily determined by date of birth as

well as cluster randomized trials53,56, even though both designs may introduce some selection bias.

Sensitivity analyses were performed eliminating these trials from the meta-analyses. These 25 trials

randomized 87,577 participants who developed 1,520 hip fractures, 480 clinical vertebral fractures, and

8,790 fractures in total. One trial, the Womens Health Initiative, contributed 36,282 participants, 374 hip

fractures, and 4,260 total fractures.8


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Figure 1: Selection of studies for inclusion in review

Level of Evidence: 1 through 5.

TA Criterion 2 is met.

TA Criterion 3: The technology must improve net health outcomes.

The primary harm arising from osteoporosis is fracture. Hip fractures have the largest impact on patients

quality of life including long-term disability, loss of mobility, nursing home placement, and a significantly

increased risk of death. Vertebral fractures can result in significant back pain, at times requiringhospitalization, as well as depression, reduced quality of life, and reduced respiratory function. However the

majority of vertebral fractures are clinically silent. For that reason, the primary outcome reported in many

trials is non-vertebral fractures. This assessment will summarize the outcomes in clinical trials that report

data on hip fractures, non-vertebral fractures, symptomatic vertebral fractures, and total fractures.

996 potentially relevantreferences screened

196 abstracts for assessment

25 studies included inassessment:

25 RCTs

87 studies for full text review

476 duplicate citations excluded324 excluded: not randomized; reviews,abstracts only; other interventions

109 studies excluded(Editorials, reviews, abstracts, no

clinical outcomes)

62 studies excluded: young military

recruits; no fracture outcomes; activatedvitamin D interventions


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The data from the randomized trials are described in Tables 1 through 5 below. For trials with multiple arms

or a factorial design, either the vitamin D groups were combined and compared to the untreated controls or

mutually exclusive groups were directly compared in two separate rows of the Tables. For example, the

RECORD trial has been divided into two sub-studies: the results from the vitamin D only group were

compared to those from the group that received neither supplemental vitamin D or calcium (Grant 2005a

RECORD) and the results from vitamin D plus calcium group were compared to the calcium only group

(Grant 2005b RECORD). Table 1 summarizes the methodological characteristics of the trials that primarily

determine the quality of the trials. Table 2 summarizes the study characteristics including the size of the

study, details of the intervention and control, the length of follow-up, and the primary outcomes. Table 3

describes the characteristics of the patients that reflect the inclusion and exclusion criteria of the trials. Table

4 describes the primary outcomes of the trials and Table 5 describes the reported adverse events.


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Table 1: Randomized trials of vitamin D2 or D3 to prevent fractures Methodological Quality

Study Randomization Allocationconcealment

Groups comparable Outcome assessmentblinded

Follow-up >80%

Intention to treatanalysis

Quality

Inkovaara 1983a PseudoBy birthdate

Yes Yes Yes Yes Yes Poor

Inkovaara 1983b PseudoBy birthdate

Yes Yes Yes Yes Yes Poor

Heikinheimo 1992 PseudoBy birthdate

NR Yes NR Yes No Poor

Chapuy 1992, 1994 Yes NR Small difference inheight (153 versus154 cm, p=0.003)

NR Yes Yes Fair

Lips 1996 Yes Yes Yes Yes Yes Yes Good

Dawson Hughes1997

Yes Yes Yes Yes Yes Yes Good

Komulainen 1998 Yes Yes Yes No Yes Yes Fair

Pfeifer 2000 Yes NR Yes NR Yes Yes Fair

Chapuy 2002 Yes NR Yes NR Yes Yes Fair

Meyer 2002 PseudoBy birthdate

Yes Yes NR Yes Yes Poor

Bischoff 2003 Yes Yes Yes Yes No Yes Fair


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Follow-up >80%


Quality

Trivedi 2003 Yes Yes Yes Yes Yes Yes Good

Avenell 2004 Yes No Yes No Yes Yes Fair

Harwood 2004 Yes Yes No, differences inbaseline vitamin D

and fractures

No Yes NR Poor

Larsen 2004 Yes NR No, Vitamin D groupolder (p


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Follow-up >80%


Quality

Smith 2007 Yes Yes Yes Yes No Yes Fair

Prince 2008 Yes NR No, vitamin D groupshorter in height

(p


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Table 2: Randomized trials of vitamin D2 or D3 to prevent fractures - Study Characteristics

Study N Location Randomization D2/D3 Vitamin Ddose, IU

DoseFrequency

Calcium, mg Control Adherence FU, mo 1 endpo

Inkovaara1983a

87 Finland

1 center

Pseudo D3 1000 Daily 0 Placebo NR 12 NR

Inkovaara

1983b

88 Finland

1 center

Pseudo D3 1000 Daily 1000 Calcium

1000

NR 12 NR

Heikinheimo1992

799 Finland

1 center

Pseudo D2 150,000300,000

Annually 0 No placebo NR 41 Totalfracture

Chapuy 1992,1994

3270 France180 nursinghomes

Simple D3 800 Daily 1200 Placebo 83% 18 Hip fractu

Lips 1996 2578 Netherlands

1 center


DawsonHughes 1997

389 United States

1 center

Simple D3 700 Daily 500 Placebo 93% 36 NR

Komulainen1998

232 Finland

1 center

Factorial withhormone therapy

D3 300 Daily 93 Calcium 93 NR 60 BMD

Pfeifer 2000 137 Germany

1 center

Simple D3 800 Daily 1200 Calcium1200

96% 12 Body sw

Chapuy 2002 583 France55 apartmentfor elderly

Simple D3 800 Daily 1200 Placebo 95% 24 NR

Meyer 2002 1144 Norway51 nursinghomes

Pseudo D3 400 Daily 0 Placebo 62% 24 Hip fractu


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DoseFrequency


Bischoff 2003 122 Switzerland

2 hospitals


NR 3 Falls

Trivedi 2003 2686 England

No center

Simple D3 100,000 Every 4months

0 Placebo 80% 60 NR

Avenell 2004

134

Scotland

1 center

Simple

D3

800

Daily

100

No placebo

85%

12

Recruitm

Harwood 2004 150 England

1 center

Simple, 4 groups D2D3

300,000800

AnnuallyDaily

10001000

No placebo NR 12 BMD

Larsen 2004 7073 Denmark

1 town

Cluster D3 400 Daily 1000 No placebo < 56% 42 Osteoporfracture

Flicker 2005 625 Australia

Multiple


67% 24 Falls

Grant 2005aRECORD

2675 UnitedKingdom21 hospitals

Factorial D3 800 Daily 0 Placebo 80% 45 Osteoporfracture

Grant 2005bRECORD

2617 UnitedKingdom21 hospitals

Factorial D3 800 Daily 1000 Placebo +calcium

1000

77% 45 Osteoporfracture

Porthouse2005

3314 England107 generalpractices

Simple D3 800 Daily 1000 No placebo 63% 25 All fractu

Jackson 2006WHI

36282 North AmericaMulticenter


Law 2006 3717 UnitedKingdom 118care homes

Cluster D2 100,000 Every 3months

0 No placebo 98% 10 Falls


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DoseFrequency


Lyons 2007 3440 Wales497 carehomes

Simple D2 100,000 Every 4months

0 Placebo 80% 36 Fracture

Smith 2007 9440 UnitedKingdom 111practices

Simple D2 300,000 Annually 0 Placebo 98% 36 Non-vertebrafracture

Prince 2008

302

Australia

1 center

Simple

D2

1000

Daily

1000

Placebo +calcium

1000

86%

12

Falls

Pfeifer 2009 242 Germany andAustria2 centers


87% 20 Falls

Salovaara2010

3195 FinlandPopulation-based

Simple D3 800 Daily 1000 No placebo < 86% 36 Any fract

Sanders 2010VITAL D

2256 Australia

1 center

Simple D3 500,000 Annually 0 Placebo 97% 36 Any fract


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Table 3: Randomized trials of vitamin D2 or D3 to prevent fractures - Patient Characteristics

Study N Age, years Female, % Prior Fx Baseline25(OH)D

level, ng/ml

BaselineBMD

Institutionalized(I) or living in thecommunity (C)

Inkovaara1983a

87 79 82 NR NR NR I

Inkovaara

1983b

88 80 82 NR NR NR I

Heikinheimo1992

799 84 80 NR NR NR 60% C40% I

Chapuy 1992,1994

3270 84 100 NR 14 ng/ml NR I

Lips 1996 2578 80 74 Hip fractureexcluded

11 NR C

DawsonHughes 1997

389 71 55 NR 30 0.89 g/cm2 atfemoral neck

C

Komulainen1998

232 53 100 NR NR 0.94 g/cm2 atfemoral neck

C

Pfeifer 2000 137 75 100 Osteoporoticfracturesexcluded

10 NR C

Chapuy 2002 583 85 100 NR 9 0.69 g/cm2 atfemoral neck

C

Meyer 2002 1144 85 75 27% prior hipfx

20 NR I


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level, ng/ml

BaselineBMD


Bischoff 2003 122 85 100 None in prior3 months

12 NR I

Trivedi 2003 2686 75 24 Not excluded NR NR C

Avenell 2004

134

77

82

100%: 92%in past 3months

NR

NR

C

Harwood 2004 150 81 100 100% hip fxw/surgery inpast 7 days

12 0.57 g/cm2 atfemoral neck

C

Larsen 2004 7073 75 60 Not excluded 14 NR C

Flicker 2005 625 83 95 25% Excluded ifless than 10 or

greater than36

NR I

Grant 2005aRECORD

2675 77 85 100%, mostin past 1

month

15 NR C

Grant 2005bRECORD

2617 77 85 100%, mostin past 1month

15 NR C

Porthouse 2005 3314 77 100 58% NR NR C

Jackson 2006WHI

36282 62 100 12% afterage 55

19 0.9 g/cm2 attotal hip

C

Law 2006 3717 85 76 NR 19 NR I


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level, ng/ml

BaselineBMD


Lyons 2007 3440 84 76 NR NR NR I

Smith 2007 9440 79 54 38% 23 NR C

Prince 2008

302

77

100

NR

18

NR

C

Pfeifer 2009 242 77 75 NR 22 NR C

Salovaara 2010 3195 67 100 35% 20 0.87 g/cm2 atfemoral neck

C

Sanders 2010VITAL D

2256 76 100 35% sinceage 50

20 NR C


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Table 4: Randomized trials of vitamin D2 or D3 to prevent fractures - Study outcomes

Study Vitamin D, n

Control, n

Hipfracture, %

Vertebralfracture, %

Non-vertebralfracture, %

Total fracture, % 25(OH)D, ng/mlduring follow-up

BMD, % change PTH, pg/ml

Inkovaara1983a

45

42

NR

NR

NR

NR

NR

NR

2.2%

7.1%

NR

NR

NR

NR

NR

NRInkovaara

1983b

46

42

NR

NR

NR

NR

NR

NR

0%

2.4%

NR

NR

NR

NR

NR

NRHeikinheimo1992

341

458

7.3%

9.4%

2.3%

1.3%

NR

NR

16%

22%

19

9

NR

NR

NR

NRChapuy 1992,1994

1634

1636

4.9%

6.7%

NR

NR

10%

13%

NR

NR

42

11

+2.7%

-4.6%

30

56Lips 1996 1291

1287

4.5%

3.7%

NR

NR

10%

9.5%

NR

NR

25

9

NR

NR

NR

NRDawsonHughes 1997

187

202

0%

0.5%

NR

NR

5.9%

13%

NR

NR

45

28

+1.1%

-0.4%

32

45Komulainen

1998

116

116

0.9%

1.7%

NR

NR

9.5%

13%

NR

NR

NR

NR

-4.1%

-4.4%

NR

NRPfeifer 2000 70

67

0%

1.5%

NR

NR

4.3%

9.0%

NR

NR

26

17

NR

NR

40

48Chapuy 2002 393

190

6.9%

11%

NR

NR

25%

29%

NR

NR

31

6

+0.3%

-2.4%

~45, estimatefrom graph

~90

Meyer 2002 569

575

8.8%

8.2%

NR

NR

12%

13%

NR

NR

26

18

NR

NR

68

65


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Study Vitamin D, n

Control, n

Hipfracture, %





Bischoff 2003 62

60

3.2%

1.7%

NR

NR

NR

NR

NR

NR

26

11

NR

NR

26

34Trivedi 2003 1345

1341

1.6%

1.8%

1.3%

2.1%

7.5%

9.0%

8.8%

11%

30

21

74.4by heel ultrasound

72.3

47

50Avenell 2004 99

35

NR

NR

NR

NR

NR

NR

6.1%

8.6%

NR

NR

NR

NR

NR

NRHarwood 2004 113

37

NR

NR

NR

NR

NR

NR

8.0%

14%

20

11

0.65 g/cm2 at totalhip

0.63 g/cm2

42

56Larsen 2004 4957

2116

NR

NR

NR

NR

NR

NR

6.4%

7.9%

19

15

NR

NR

37

50Flicker 2005 313

312

NR

NR

NR

NR

8.0%

11%

NR

NR

NR

NR

NR

NR

NR

NRGrant 2005aRECORD

1343

1332

3.5%

3.1%

0.3%

0.1%

16%

15%

16%

15%

25

18

NR

NR

44

44

Grant 2005bRECORD 1306

1311

3.5%

3.7%

0%

0.2%

14%

14%

14%

14%

25

17

NR

NR

31

35Porthouse 2005 1321

1993

0.6%

0.9%

NR

NR

4.4%

4.6%

4.4%

4.6%

NR

NR

NR

NR

NR

NRJackson 2006WHI

18176

18106

1.0%

1.1%

1.0%

1.1%

11%

11%

12%

12%

NR

NR

Increase at year 60.86% greater inVitamin D group

(p


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Study Vitamin D, n

Control, n

Hipfracture, %





Lyons 2007 1725

1715

6.5%

6.1%

0.2%

0.5%

12%

12%

12%

13%

32

22

NR

NR

45

60Smith 2007 4727

4713

1.4%

0.9%

NR

NR

6.5%

5.9%

NR

NR

27

NS different

NR

NR

Non-significandecrease from

baseline or con

Prince 2008 151

151

NR

NR

NR

NR

NR

NR

2.6%

2.0%

NR

NR

NR

NR

NR

NRPfeifer 2009 121

121

NR

NR

NR

NR

NR

NR

5.8%

11%

34

23

NR

NR

35

39Salovaara 2010 1586

1609

0.3%

0.1%

NR

NR

4.5%

5.1%

4.9%

5.8%

30

22

NR

NR

NR

NRSanders 2010VITAL D

1131

1125

NR

NR

0.6%

0.8%

NR

NR

14%

11%

~28Estimate from graph

~16

NR

NR

NR

NR


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Table 5: Randomized trials of vitamin D2 or D3 to prevent fractures - Potential harms

Study Vitamin D, n

Control, n

Hypercalcemia, % Kidney stones, % Kidneydysfunction, %

GI distress, % Death, %

Inkovaara 1983a 45

42

2

0

NR

NR

0

0

NR

NR

16

12Inkovaara 1983b 46

42

0

0

NR

NR

0

0

NR

NR

15

12Heikinheimo 1992 341

458

0

0

NR

NR

NR

NR

NR

NR

44

42Chapuy 1992, 1994 1634

1636

0.1

0

0

0

NR

NR

2.4

2.1

16

17Lips 1996 1291

1287

NR

NR

NR

NR

NR

NR

NR

NR

17

20Dawson Hughes1997

187

202

NR

NR

NR

NR

NR

NR

2.1

1.0

NR

NR

Komulainen 1998 116

116

NR

NR

NR

NR

NR

NR

NR

NR

NR

NRPfeifer 2000 70

67

NR

NR

NR

NR

NR

NR

NR

NR

NR

NRChapuy 2002 393

190

0.8

0

0

0

No significant effect 6.1

8.4

18

24Meyer 2002 569

575

NR

NR

NR

NR

NR

NR

NR

NR

30

28


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Study Vitamin D, n

Control, n



Bischoff 2003 62

60

0

0

NR

NR

NR

NR

3.2

0

NR

NRTrivedi 2003 1345

1341

NR

NR

NR

NR

NR

NR

NR

NR

17

18Avenell 2004 99

35

NR

NR

NR

NR

NR

NR

NR

NR

1.0

2.9Harwood 2004 113

37

0

0

NR

NR

NR

NR

NR

NR

27

14Larsen 2004 4957

2116

NR

NR

NR

NR

NR

NR

NR

NR

NR

NRFlicker 2005 313

312

NR

NR

NR

NR

NR

NR

NR

NR

24

27Grant 2005aRECORD

1343

1332


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Study Vitamin D, n

Control, n



Lyons 2007 1725

1715

NR

NR

NR

NR

NR

NR

NR

NR

41

42Smith 2007 4727

4713

NR

NR

NR

NR

NR

NR

NR

NR

NR

NRPrince 2008 151

151

0.7

0

NR

NR

NR

NR

11

12

0

0.7Pfeiffer 2009 121

121

NR

NR

NR

NR

NR

NR

NR

NR

NR

NRSalovaara 2010 1586

1609

NR

NR

NR

NR

NR

NR

4

NR

0.9

0.8Sanders 2010VITAL D

1131

1125

NR

NR

NR

NR

NR

NR

NR

NR

3.5

4.2

NR Not reportedBMD Bone mineral densityI Living in an institutional settingC Living independently in the communityFx FractureNS Not significant


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Comments on the trials

The quality of the randomized trials was uneven. Four of the trials used pseudo-randomization by birthdate

to allocate patients to either vitamin D or the control group which may have introduced some selection bias

as the staff and investigators could predict a potential participants allocation based on their birthdate.

Another two trials used cluster randomization, but one had a small number of clusters and neither adjusted

for clustering effects in their primary analysis. Seven of the trials did not use a placebo in the control group,

effectively unblinding the study. Despite randomization, five of the trials had significant differences between

the intervention and control groups. In addition, eleven of the trials did not blind their outcome assessment

or did not report blinding for the assessment of study outcomes.

There was significant heterogeneity in the patient populations studied, the interventions used, and the length

of follow-up. Some trials included only individuals living in nursing homes, assisted living facilities, and other

institutional settings. Other trials recruited individuals who lived independently in the community. The

average age of participants ranged from 53 years in one trial that focused on recently menopausal women

to 85 years in several of the trials that randomized patients in institutional settings. The proportion of women

ranged from 24% in one study to 100% in eleven of the studies. Some trials excluded patients with prior

fractures while others specifically studied patients with recent osteoporotic or hip fractures. Not all studies

reported baseline vitamin D levels or bone density measurements and those that did primarily reported on a

small sample of the participants. The average 25(OH) vitamin D levels in the studies ranged from 9 ng/ml to

30 ng/ml. Similarly, the average bone density at the femoral neck in the studies ranged from 0.57 g/cm2 to

0.94 g/cm2. Thus, some of the trials studied older institutionalized individuals with severe vitamin deficiency,

osteoporosis, and prior fractures while others studied relatively young individuals with normal vitamin D

levels and no prior fractures. Interventions included vitamin D2 and D3 at doses ranging from 300 IU per

day to 500,000 IU annually. This dose range is much greater than the range typically tested in drug trials.

Some of the trials included calcium as part of the intervention and some included calcium as part of the

control intervention. Differences in the location of studies may also have influenced the results because the

United States and Canada are the only countries that fortify dairy products with vitamin D. That is why

vitamin D levels are typically much lower in studies performed in European countries compared to studies

performed in the United States and Canada. Finally, in some trials the intervention lasted for only a few

months with follow-up for less than 12 months. Other trials continued the intervention and follow-up for five

years or more. If there is a time lag between the initiation of vitamin therapy and any beneficial effects on

fracture incidence or adverse events, there may be heterogeneity in the outcomes based on length of follow-

up. Because of the potential for effect modification in subgroups based on the patient populations studied

and the differing interventions, meta-regression was used to assess important subgroup effects. Meta-


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regression is a statistical technique that can help identify whether any of the differences in the patient

populations studied or the study methods explain heterogeneity in the results of the different trials.


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Primary meta-analysis

All trials were included in the primary meta-analysis. Separate meta-analyses were performed for the

following outcomes: all fractures (total fractures or non-vertebral fractures if total fractures were not

reported), hip fractures, and vertebral fractures. Because of the heterogeneity in the patient populations and

interventions, random effect models were used for all meta-analyses.

Figure 2 is the Forest plot for all fractures. The diamonds represent the point estimates for the relative risk

(RR) for fracture of vitamin D compared to the control intervention from each of the studies. The width of the

horizontal lines represents the 95% confidence interval for each point estimate. A relative risk less than 1 (to

the left of the vertical line) indicates that there was a lower incidence of fractures in the vitamin D group

compared to the control group. The summary estimate indicates that there was a significant 7% overall

reduction in fractures for participants in the vitamin D groups (RR 0.93, 95% CI 0.86 to 1.00, p = 0.04). Only

four of the 26 studies had point estimates greater than 1. However 42% of the total variation across studies

is due to heterogeneity rather than chance (I2 = 42%, p=0.013). This suggests that results of some of the

studies are so different that they should not be combined in a meta-analysis because they are likely

measuring different biological phenomena. For instance, the 95% confidence intervals for the Chapuy trial

(0.61 to 0.90) and for the Sanders trial (0.99 to 1.54) do not overlap at all. Potential explanations for the

heterogeneity will be explored in the next section (Meta-regression results and stratified analyses).


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Figure 2: Meta-analysis for all fractures


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Figure 3 presents the results of the same analysis for hip fractures. Fewer studies reported hip fracture

outcomes. Overall, there was a non-significant trend towards fewer hip fractures in the vitamin D groups

(RR 0.97, 95% CI 0.86 to 1.09, p = 0.60). Eight of the 18 studies had point estimates greater than 1. There

was less heterogeneity in the hip fracture outcomes (I2 = 15%, p=0.272).

Figure 3: Meta-analysis for hip fractures


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Figure 4 summarizes the results for studies reporting non-vertebral fractures. Similar to hip fractures, there

was a non-significant trend towards a 5% reduction in non-vertebral fractures (RR 0.95, 95% CI 0.88 to

1.02, p = 0.17). Only three of the 17 studies had point estimates greater than 1. However there was

borderline significant heterogeneity in the studies reporting non-vertebral fracture outcomes (I2 = 39%,

p=0.053).

Figure 4: Meta-analysis for non-vertebral fractures


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Only seven studies reported vertebral fracture outcomes and all were clinically apparent fractures, not

fractures detected solely by x-rays. Figure 5 summarizes the results. There was a larger, 18% reduction in

vertebral fractures, but it was not statistically significant (RR 0.82, 95% CI 0.57 to 1.18, p = 0.29). Two of the

seven studies had point estimates greater than 1. Even though the p-value for heterogeneity in the studies

was not significant, the percentage of the variation beyond that expected by chance was modestly large (I2 =

31%, p=0.19).

Figure 5: Meta-analysis for vertebral fractures

Thus, for all fracture outcomes there was a trend towards benefit, but also significant heterogeneity in the

trials contributing to the summary estimate of the effect. In the next section, meta-regression was used to

identify factors that strongly contribute to that heterogeneity.

Meta-regression results and stratified analyses to understand heterogeneity

Potential sources of heterogeneity in the results of these randomized trials arise from both the patient


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populations studied and the differences in the therapies given to the intervention and control groups. Meta-

regression was performed to assess whether the average age of the study participants ( 75 years versus >

75 years), independence of the participants (community living versus institutionalized), average baseline

25(OH)D level (< 18 ng/ml versus 18 ng/ml), vitamin D dose ( 400 IU per day versus > 400 IU), vitamin

D type (D2 versus D3), dose frequency (daily versus every three months or less), calcium supplementation

for the vitamin D group (yes versus no), or calcium supplementation for the control group (yes versus no)

significantly explained any of the heterogeneity in the results of the different studies. Only one of these

characteristics reached statistical significance in the meta-regression: the use of calcium supplementation in

the active control group reached statistical significance (p=0.009). Thus, the association between vitamin D

and fracture in studies that gave a combination of vitamin D and calcium to the intervention group differed

significantly from the association between vitamin D and fracture in studies that did not give supplemental

calcium to the intervention group.

Importantly, all of the studies that studied the combination of vitamin D plus calcium used daily dosing.

However, meta-regression evaluating daily dosing versus intermittent dosing without calcium dosing in the

model did not reach statistical significance (p = 0.21). Whether the participants were drawn from

independently living individuals in the community or from nursing homes or assisted living institutions was

borderline significant in the meta-regression model (p = 0.07) and will be explored further below. The meta-

regression did not suggest any significant heterogeneity in fracture outcomes based on the age of

participants, vitamin D dose, vitamin D2 versus D3, baseline 25(OH)D levels, or calcium supplementation

for the controls (p > 0.40 for each), although the power to detect an effect was low. Low power wasparticularly problematic for the baseline 25(OH)D level as most studies did not measure or report baseline

levels. Furthermore, the individual data on patient characteristics such as age, sex, and 25(OH) D level are

required to fully explore heterogeneity based on individual patient characteristics. One of the published

meta-analyses62described in the section below (Comparison with published meta-analyses) obtained

individual level data for participants in seven of the largest trials and should be considered the more

definitive evaluation for individual patient characteristics.

Stratified analyses help to make the results of the meta-regression analyses more clinically meaningful. The

meta-analysis for all fractures stratified by the use of calcium supplements found the following. There was a

significant reduction in fractures in the vitamin D group when the intervention included calcium

supplementation (RR 0.95, 95% CI 0.92 to 0.99). There was not even a trend towards benefit from vitamin D

when calcium supplementation was not included (RR 1.02, 95% CI 0.95 to 1.10). This suggests that vitamin

D does not reduce fractures without concomitant supplementation with calcium.


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Even though the meta-regression coefficients were not significant, when stratified by dosing, there was a

significant reduction in fractures for the daily vitamin D group (RR 0.94, 95% CI 0.94 to 0.98), but not for

vitamin D groups with therapy given every three, four or twelve months (RR 1.01). Again, it is difficult to

separate this effect from that of calcium because all of the studies using intermittent vitamin D dosing did not

give supplemental calcium to the vitamin D group.

Similarly, there was a suggestion that studies that recruited participants from populations that had average

baseline 25(OH)D levels below 18 ng/ml found benefit from vitamin D therapy (RR 0.90, 95% CI 0.83 to

0.98) while those with higher average baseline 25(OH)D levels did not find benefit (RR 0.99, 95% CI 0.94 to

1.04). However the test for interaction by baseline 25(OH)D level was not significant (p = 0.67). There was

little power to detect an interaction because few studies measured baseline 25(OH)D levels and those that

measured 25(OH)D only did so for a small subgroup of patients in each trial. Furthermore, only group

average values could be used for stratification. Thus studies with low average 25(OH)D levels includedparticipants with individual values greater than 18 ng/ml and studies with high average 25(OH)D levels

included participants with individual values lower than 18 ng/ml. Thus, the result of our analysis stratified by

25(OH)D level must be interpreted cautiously.


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Meta-analysis results for trials of daily vitamin D plus calcium stratified by institutional setting

Based on the meta-regression, the original meta-analyses were repeated for studies of daily vitamin D plus

calcium stratified by whether or not the participants were sampled from an institutional setting or not. Figure

6 summarizes the updated meta-analysis for all fractures. For studies that sampled participants living ininstitutional settings, daily vitamin D plus calcium reduced all fractures by 26% (RR 0.74, 95% CI 0.62 to

0.88, p = 0.001) without any unexplained heterogeneity beyond that expected by chance (I2 = 0%, p for

heterogeneity = 0.85). For studies that sampled participants living in the community, the summary relative

risk for daily vitamin D plus calcium reduced the incidence of all fractures by 9% (RR 0.91, 95% CI 0.84 to

0.98, p = 0.019) with minimal unexplained heterogeneity (I2 = 13%, p for heterogeneity = 0.32). If all of these

studies are combined, there was a 14% reduction in all fractures (p = 0.001) with moderate, though non-

significant heterogeneity.

Figure 6: Stratified meta-analysis for all fractures


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Figure 7 summarizes the updated meta-analysis for hip fractures. For studies that sampled participants

living in institutional settings, daily vitamin D plus calcium reduced hip fractures by 26% (RR 0.74, 95% CI

0.56 to 0.97, p = 0.032) without any unexplained heterogeneity beyond that expected by chance (I2 = 0%, p

for heterogeneity = 0.42). For studies that sampled participants living in the community, daily vitamin D plus

calcium reduced the incidence of hip fractures by 15% (RR 0.85, 95% CI 0.72 to 1.01, p = 0.059) with no

unexplained heterogeneity (I2 = 0%, p for heterogeneity = 0.82). If all studies are combined, there was a

statistically and clinically significant 18% reduction in hip fractures (p = 0.007) with no heterogeneity (I2 =

0%, p for heterogeneity = 0.83).

Figure 7: Stratified meta-analysis for hip fractures


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Figure 8 summarizes the updated meta-analysis for non-vertebral fractures. For studies that sampled

participants living in institutional settings, daily vitamin D plus calcium reduced non-vertebral fractures by

26% (RR 0.74, 95% CI 0.62 to 0.89, p = 0.001) without any unexplained heterogeneity beyond that

expected by chance (I2 = 0%, p for heterogeneity = 0.86). For studies that sampled participants living in the

community, daily vitamin D plus calcium reduced the incidence of non-vertebral fractures by a non-

significant 5% (RR 0.95, 95% CI 0.88 to 1.02, p = 0.174) with minimal heterogeneity (I2 = 0%, p for

heterogeneity = 0.37). If all studies are combined, there was a statistically and clinically significant 12%

reduction in non-vertebral fractures (p = 0.018), but there was moderate heterogeneity (I2 = 40%, p for

heterogeneity = 0.09).

Figure 8: Stratified meta-analysis for non-vertebral fractures


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Figure 9 summarizes the updated meta-analysis for vertebral fractures. None of the studies that sampled

participants living in institutional settings reported vertebral fractures separately. For studies that sampled

participants living in the community, daily vitamin D plus calcium reduced the incidence of vertebral fractures

by 10% (RR 0.90, 95% CI 0.74 to 1.1, p = 0.27) with no unexplained heterogeneity (I2 = 0%, p for

heterogeneity = 0.40).

Figure 9: Stratified meta-analysis for vertebral fractures

In summary, daily vitamin D plus calcium significantly reduced the risk of incident fractures for individuals

living in either an institutional or community setting. The reduction was greater for individuals in institutions

than for patients in the community and was stronger for hip fractures than for vertebral fractures or other

non-vertebral fractures. The results did not change during sensitivity analyses that dropped each study

individually and dropped the poor quality studies.

Harms

High levels of vitamin D can cause hypercalcemia and if prolonged can result in soft tissue calcification with

eventual damage to the kidneys and heart.63-68Recently, there has been increased concern that even high


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normal levels of calcium in patients receiving calcium supplements with or without vitamin D may increase

the risk for heart attacks and death from heart disease.69,70Table 5 summarizes the harms reported in the

randomized trials. Hypercalcemia was rare (


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Mortality

Mortality outcomes are also summarized in Table 5. Mortality in the trials varied from 0% to 42% reflecting

the large differences in the age and frailty between the populations studied in the trials of vitamin D therapy.

Figure 10 summarizes the mortality data for all of the clinical trials. There was a trend towards an overall 6%reduction in total mortality (p = 0.17), but there was significant unexplained variation between the studies (I2

= 67%, p for heterogeneity < 0.001).

Figure 10: Meta-analysis for all-cause mortality in all studies of vitamin D therapy

Figure 11 summarizes the mortality outcomes for the studies of daily vitamin D plus calcium. For studies

that sampled participants living in institutional settings, daily vitamin D plus calcium did not significantly

reduce mortality (RR 0.95, 95% CI 0.81 to 1.10, p = 0.48), although there was no unexplained heterogeneity


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beyond that expected by chance (I2 = 0%, p for heterogeneity = 0.81). For studies that sampled participants

living in the community, daily vitamin D plus calcium reduced mortality by a non-significant 19% (RR 0.81,

95% CI 0.63 to 1.05, p = 0.11), but there was significant heterogeneity (I2 = 81%, p for heterogeneity

vitamin d for the prevention of osteoporotic fractures

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