Osteoporosis and osteopenia:implications for periodontal andimplant therapy

JO A N OT O M O-CO R G E L

According to the National Osteoporosis Foundation,

osteoporosis is a major public health threat for an

estimated 44 million of the US population (55% of

people ‡50 years of age) (163). In the USA, 10 million

individuals are estimated to already have the disease

and almost 34 million more are estimated to have low

bone mass and thus are at risk for osteoporosis. In

Europe, the USA and Japan, osteoporosis is estimated

to affect 75 million people (64). One third of women

and one-fifth of men over 50 years of age will

experience osteoporotic fractures, (103, 147). The

combined lifetime risk for hip, forearm and vertebral

fractures is approximately 40%, equivalent to the risk

for cardiovascular disease (147).

Bone mineral density is quantified using dual-en-

ergy X-ray absorptiometry scans to define a T score.

The T score compares bone mineral density with the

mean peak bone density for an individual of the same

gender and is reported as the number of standard

deviations below that average. A T score of )2.5 or less

is diagnostic for osteoporosis. Scores of )1.0 to )2.5

indicate osteopenia, and scores of 0 to )1.0 are con-

sidered normal (61). T scores are used to determine

an individual�s fracture risk primarily at the lumbar

spine, total hip, femoral neck or trochanter. Some

clinicians evaluate Z scores, which are also deter-

mined by a dual-energy X-ray absorptiometry scan,

but compare the bone mineral density results with

persons of the same age, weight, ethnicity and gender.

Z scores are used to determine if there is an unusual

reason for the alteration in bone mineral density (e.g.

a systemic etiology such as thyrotoxicosis).

The incidence of osteoporosis is higher in women

(80%) than in men (20%). Women have a lower

total bone mass than men, and peak bone levels

occur at an earlier age in women (�25 years of age,

with 98% of the skeletal mass built by age 20) than

in men (�30 years of age). Women reach meno-

pause at a mean age of 50–51 years, and a decrease

in estrogen perimenopausally (3–5 years before

menopause) and a few years after menopause

(1 year without a menstrual cycle) causes acceler-

ated bone loss (Table 1). In women, two stages of

primary bone loss occur. The first stage is rapid

trabecular bone loss as a result of estrogen defi-

ciency initiated with the onset of menopause that

occurs for a duration of approximately 4–8 years

and is characterized by high bone resorption and

reduced bone formation. The second stage involves

slower trabecular and cortical bone loss that occurs

as a result of decreased bone formation. In men,

bone loss generally occurs at a slower rate, as a

result of lower levels of bioavailable testosterone

and estrogen.

Among white women, the lifetime risk of hip

fracture is one in six (compared with, for example, a

one in nine risk of a diagnosis of breast cancer) (45).

The greatest morbidity associated with osteoporosis

is related to hip fractures, with 20–24% mortality

within the first year after a hip fracture (120). Of

those who survive, 40–60% are unable to walk

unassisted 1 year later. Although osteoporosis is

more prevalent in women, the mortality rate for men

with a hip fracture is double that in women of a

similar age (104). Men acquire osteoporosis at a later

age with a sharp increase in incidence observed at

70 years of age and older, and therefore complica-

tions of the hip fracture that result from immobility,

for example thrombophlebitis, are more likely to

occur in men.

Risk factors for osteoporosis can be classed as

nonmodifiable or modifiable (Table 2). Gender

(female), hereditary factors, ethnicity, small body

frame (<127 lbs), and early or surgical menopause are

111

Periodontology 2000, Vol. 59, 2012, 111–139

Printed in Singapore. All rights reserved

� 2012 John Wiley & Sons A/S

PERIODONTOLOGY 2000

nonmodifiable risk factors for osteoporosis. Exercise,

diet, alcohol intake, smoking, hormone replacement

therapy, immobility and lack of weight-bearing

exercise are modifiable risk factors. Medications

(Table 3) used routinely in clinical medicine may

have detrimental effects on bone remodeling.

Recently, a �prescriptiome� analysis of 62,865 men of

50+ years of age with a fracture indicated that the

largest impact on fracture risk at a population level

was exerted by loop diuretics and analgesics (1). A

multitude of systemic diseases are also associated

with an increased risk of osteoporosis, including

hypogonadal states (anorexia nervosa, female athletic

triad, Turner�s syndrome and Klinefelter�s syndrome),

endocrine disorders (Cushing�s syndrome, hyper-

parathyroidism, thyrotoxicosis, diabetes mellitus,

adrenal insufficiency and acromegaly), gastrointesti-

nal disorders (severe hepatic disease, malabsorption,

pernicious anemia, malnutrition and gastrectomy),

rheumatologic disorders (rheumatoid arthritis),

certain inherited diseases (osteogenesis imperfecta,

Table 1. Effects of estrogen on bone remodeling

• Enhanced numbers of remodeling sites as a result of enhanced bone formation of osteoclasts and decreased formation of

new bone in the resorption lacunae, eventually causing decreased bone mass and increased risk for osteoporosis

• Increased bone resorption is caused by decreased inhibition of estrogen on osteoclastogenesis and osteoclastic activity

• Estrogen receptors may be present in osteoclast progenitor cell and multinucleated osteoclasts. Note that marrow cells

(macrophages, monocytes, osteoclast precursors and mast cells) and bone cells (osteoblasts, osteocytes and osteoclasts)

have estrogen receptors a and b. Estrogen receptor-a is the dominant estrogen receptor in cortical bone and estrogen

receptor-b is the dominant receptor in cancellous bone

• Estrogen suppresses the synthesis of cytokines responsible for stimulating osteoblast apoptosis and reducing osteoclast

cell death.

• Stimulatory effect of estrogen on bone formation may be mediated by estrogen receptor-responsive elements on

promoters in genes involved in bone matrix biosynthesis, including type I collagen or cytokine genetics

• Estrogen may play a role in the longevity of bone cells by controlling the rate of apoptosis and reducing osteoclast cell

death

Table 2. Risk factors for osteoporosis

Nonmodifiable

Female

Thin skeletal frame

Family history

History of fracture in first relative

Caucasian or Asian

Advanced age

Adult fracture

Early menopause (<45 years of age) or bilateral

ovariectomy

Modifiable

Cigarette smoking

Low body weight (<57.6 kg)

Estrogen deficiency

Premenstrual amenorrhea (for >1 year)

Inadequate calcium intake

Alcoholism

Physical inactivity

Imbalance or vertigo

Lactose intolerance

Table 3. Medications ⁄ drugs associated with secondaryosteoporosis

Glucocorticoids

Anticonvulsants (i.e. phenytoin)

Ciclosporin

Cytotoxic drugs (i.e. methotrexate)

Lithium

Coumadin

Heparin therapy (long term)

Aluminum

Gonadotropin-releasing hormone agonists

Thyroid hormone (in excess)

Excessive alcohol

Proton pump inhibitors

112

Otomo-Corgel

hemochromatosis, hypophosphatasia and porphy-

ria), hematologic ⁄ malignant disorders (multiple

myeloma, leukemia, lymphoma, hemophilia and

thalassemia), and other disorders such as lactose

intolerance, chronic obstructive pulmonary disease,

breastfeeding, pregnancy and sarcoidosis.

Osteoporosis and osteopenia:physiology

Osteoporosis is a systemic skeletal disease charac-

terized by loss of bone mass and micro-architectural

deterioration with a consequent increase in bone

fragility and susceptibility to fracture (61). It results

from bone loss as a result of changes in remodeling

during normal aging, but may be accelerated by

extrinsic and intrinsic factors. Although bone appears

inert, it is a dynamic tissue that receives about 10% of

the cardiac output and remodels throughout life

(129). Bone consists of both compact and trabecular

bone. The extracellular bone components include a

solid mineral phase associated with an organic type I

(90–95%) collagen matrix. This part of the organic

matrix, which is noncollagenous, contains serum

proteins such as albumin, cell attachment ⁄ signaling

proteins (thrombospondin, osteopontin and fibro-

nectin), calcium-binding proteins (matrix gla protein

and osteocalcin) and proteoglycans (biglycan and

decorin). The serum proteins are responsible for the

organization of collagen fibrils, initiation of miner-

alization and ⁄ or bonding of the mineral phase to the

matrix.

The mineral phase contains calcium and phos-

phate in the form of a poorly crystalline hydroxyap-

atite. Sodium, potassium and magnesium are also

present in small amounts. The skeleton contains over

99% of the calcium in the adult human body. The

remaining 1% is in the extracellular fluid and serum,

and calcium homeostasis is imperative for critical

functions such as neurologic activity, clotting and

muscular contraction. Skeletal calcium accretion

accelerates throughout childhood and adolescence,

reaches a peak in early adulthood and gradually

declines thereafter at rates that rarely exceed 1–2%

per year (129). In contrast, there are high daily rates

of calcium flux into and out of bone, mediated by

coupled osteoblastic and osteoclastic activity, of the

0.5–1.0% of freely exchangeable skeletal calcium

within the extracellular fluid. Calcium channels can

be activated by hormones, metabolites or neuro-

transmitters affecting the 50% of total serum calcium

that is ionized. The concentration of ionized calcium

in the extracellular fluid is usually controlled by

adjusting the rates of calcium movement across

intestinal and renal epithelia, mediated primarily by

changes in the levels of parathyroid hormone,

1,25(OH)2D-vitamin D3 and calcitonin. Current

studies seek to understand vitamin D-mediated

activation and to identify vitamin D-regulated genes

that mediate osteoblast and osteoclast functions

(179). Proteins, either uncomplexed (albumin and

immunoglobulins) or loosely complexed with phos-

phate, citrate, sulfate or other anions, are bound to

the remaining nonionized calcium. Therefore, serum

proteins also directly affect the total blood calcium

concentration.

Bone tissues are dynamic, and healthy bone

models and remodels throughout life. Modeling is a

process in which the skeleton increases in size in a

linear manner in response to the stresses placed

upon it. This involves new bone formation that is

independent of prior bone resorption, and the skel-

eton can thus assume a new shape or cortical thick-

ening. On the other hand, remodeling is initiated by

resorption and is followed by new bone formation at

the same resorptive site. Bone remodeling repairs

micro-damage in the skeleton to preserve strength

and supplies serum calcium from the skeleton for

mineral homeostasis. Signals from mechanical

stresses are sensed by osteocytes and are then

transmitted to osteoclasts or osteoblasts, or to their

precursors. Bone resorption reflects the sum of

osteoclast recruitment and death, and the rate at

which the average cell degrades matrix (171).

When remodeling becomes unbalanced, osteoporo-

sis (a loss of bone) or osteopetrosis (a gain of bone)

occurs (Fig. 1) (34). This remodeling occurs at bone

multicellular units. Riggs & Parfitt (195) estimated that

the human skeleton has 1–2 · 106 of these units. In

postmenopausal osteoporosis, the number of activated

multicellular units is increased, leading to increased

numbers of osteoclasts and resorption lacunae in the

skeleton. There are also increased numbers of forma-

tion sites and osteoblasts, but as a result of estrogen

deficiency, the osteoblasts do not function effectively.

There are estrogen receptors on osteoblasts and oste-

oclasts, and therefore estrogen can inhibit osteoclast

formation, may indirectly affect receptor activator of

nuclear factor-jB ligand (RANKL) expression by

cytokine regulation and may influence osteoclast

formation by decreasing the expression of macrophage

colony-stimulating factor. Decreased estrogen also

results in reduced inhibition of osteoclastogenesis and

more osteoclastic activity (226). The net result is

decreased bone mass and reduced strength.

113

Osteoporosis and osteopenia: implications for periodontal and implant therapy

Current clinical therapies

Clinical therapy for osteoporosis is a lifelong inter-

vention. It is therefore important to understand not

only what medications the patient is currently taking,

but what medications they have previously taken, the

side effects, compliance, duration and how effective

the therapies have been. The current medications

approved for osteoporosis include calcium, vitamin

D, bisphosphonates, parathyroid hormone, selective

estrogen receptor modulators, calcitonin, hormone

therapy, denosumab and strontium ranelate (Ta-

ble 4). Controversies exist regarding the optimal cal-

cium dose and calcium sources.

With increasing longevity, it is important to

remember that osteoporosis is not only a female

disease. Owing to the increase of US veterans suf-

fering from osteoporosis, the Veterans Administra-

tion has developed an algorithm for the treatment of

male osteoporosis (Fig. 2) (53).

Calcium

Calcium intake in the USA is inadequate according to

the Harvard Medical Report, which identified that

only 45% of adult men and 22% of adult women

receive the recommended intake of calcium (216).

Among 9- to 17-year-old subjects, just 25% of boys

and 10% of girls receive sufficient calcium. Calcium

alone may be partially effective in preventing bone

loss, especially in elderly women with an inadequate

calcium intake (185, 190). In a 2002 review, 68 of 70

�investigator controlled� studies found that calcium

supplementation resulted in greater gains in bone

during growth, less loss of bone with age, and ⁄ or

reduced fracture risk (88). The National Academy of

Sciences, National Institutes of Health and the Na-

tional Osteoporosis Foundation support the recom-

mendations in Table 5. The best sources of calcium

are foods, especially dairy products (milk, yogurt,

cheese and ice cream), nuts ⁄ seed (peanuts, sesame

paste and almonds), legumes (soy and baked beans,

tofu), vegetables (spinach, broccoli, artichokes and

A

OsteoblastsOsteoclast

progen.

Initiation Resorption

2–4 weeks 4–6 months

Reversal Boneformation

Remodelingcompleted

“cleaningcells”

Osteoblastprogen.

OsteoblastsCouplingfactors?

B C D E

Fig. 1. Normal bone remodeling. (A) Bone remodeling is

initiated by osteoclastic resorption, but osteoclast formation

and activation are controlled by osteoblasts on the bone

surface. Next, the inactive osteoblasts or pre-osteoblasts

cover the surfaces of bone tissues where activation leads to

osteoblastic degradation of unmineralized osteoid sand-

wiched between the mineralized bone. (B) Osteoblasts now

increase their expression of receptor activator of nuclear

factor-jB ligand (RANKL) and macrophage colony-stimu-

lating factor, while decreasing osteoprotegerin (the inhibitor

of RANK). This process creates an increase in the osteoclast

progenitor pool and initiates the differentiation that allows

the development of latent multinucleated osteoclasts. Once

the surface osteoblasts retract from the surface, multinu-

cleated osteoclasts have access to the mineralized bone.

Here the osteoclasts develop a ruffled border and dissolve

hydroxyapatite crystals forming resorption lacunae. (C)

When osteoclasts leave the lacunae, mononuclear cells ap-

pear and they remove the organic matrix debris. (D) Osteo-

blast precursors are differentiated into active osteoblasts that

fill the lacunae with new bone. (E) Remodeling is complete.

Permission granted from U. H. Lerner (123).

Table 4. Medications approved for the treatment ofosteoporosis

Calcium supplementation

Vitamin D supplementation

Bisphosphonates*

Selective estrogen receptor modulators

Tamoxifen

Raloxifen

Calcitonin

Hormone therapy

Parathyroid hormone (teriparatide)

Denosumab

Strontium ranelate

*See Table 6.

114

Otomo-Corgel

snow peas), fruits ⁄ fortified fruit juices (fortified

orange juice, rhubarb and dried fruit), fish (salmon

with bones, sardines with bones, bass and ocean

perch) and shellfish (steamed clams, lobster and

shrimp). Some food constituents may affect the

absorption of calcium. For example, oxalic acid in

spinach and rhubarb may combine with the calcium

in these plants so that it is not readily absorbed.

The other sources of calcium are supplements. They

are usually administered as calcium carbonate or

calcium citrate; however, phosphate, lactate and

gluconate forms may also be found. Calcium pills are

compounds in which the actual amount of calcium is

�elemental calcium�. For example, calcium carbonate

contains 40% calcium by weight; thus, a 500-mg pill of

calcium carbonate contains 200 mg of calcium, and

therefore the labeling will indicate that each pill con-

tains 200 mg of elemental calcium. Calcium citrate

contains 21% calcium by weight. Calcium carbonate

is best taken with food because it requires stomach

acid for absorption. Although it is usually tolerated by

most people, it has been reported to cause bloating

and constipation in some. Calcium citrate is easier to

absorb, especially in the elderly, and can be taken with

food or on an empty stomach. One must remember

that approximately 500 mg of calcium can be

absorbed at one time, so if supplementing, the dose

should be spread throughout the day. Also, recom-

Glucocorticoid therapy (5 mg daily for 3 months)Low trauma fracture after age 45 yearsRadiographic evidence of vertebral osteopenia or fractureAndrogen deprivation therapy or other hypogonadismAnticonvulsant therapy (2 years or more)Gastrectomy, malabsorption, celiac disease, bariatric surgeryExcess alcohol consumptionOther conditions and medications

Indications present?

Reassess in 2 yearsDual-energy X-ray absorptiometry (spineand hip ♦)

T-score –2.5 or lessin spine or hip⁺

T-score between –1and –2.5

T-score –1 or higherin spine or hip

History, examination basic laboratory

analyses, serum and urine calcium, 25

hydroxyvitamin D

Secondary causesConsider evaluation and

treatmentRepeat bone mineral

density scan at 1–2 years

Low trauma fractureEvaluate and consider

treatment

No secondary causes or effectsRe-evaluate in 2 yearsLifestyle counselingEnsure adequate calcium/vitamin D

No osteoporosisLifestyle counselingEnsure adequate calcium/vitamin D

Treat abnormalities and/or refer patient

Re-evaluate fortreatment

Ensure adequate calcium:1.2 g dailyEnsure adequate vitamin D:800+ units dailyNonpharmacologic interventions to reducefracture riskOral bisphosphonates

Refer to metabolic bone specialist if bisphosphonates are contraindicated or patientintolerant or not responsive

YesNo

NormalAbnormal

⁺ For T-score less than –2.5 and multiple fracture or T-scoreless than –3.5, consider referral to a Metabolic Bone Specialist.♦ Do a forearm bone mineral density if spine or hip cannot beinterpreted.

Fig. 2. 2011 Veterans Administration algorithm for treat-

ing male osteoporosis. Owing to the increasing incidence

of osteoporosis among patients at the Veteran�s Adminis-

tration Hospitals, this algorithm was developed through

the office of the Under Secretary for Health (53). It is to be

used as a guide when selecting which men need to be

screened for osteoporosis, treatment recommendations

and management of complications.

Table 5. Calcium recommendations

Age National Academy of

Sciences

Calcium intake

recommendations

(mg ⁄ day)

Birth to 6 months 210

7 months to 1 year 270

1–3 years 500

4–8 years 800

9–18 years 1,300

19–50 years 1,000

51 years or older 1,200

Pregnant ⁄ lactating 14–18 years 1,300

Pregnant ⁄ lactating 19–50 years 1,000

115

Osteoporosis and osteopenia: implications for periodontal and implant therapy

mended doses should not exceed 2,500 mg ⁄ day

because of the possible increased risk for kidney stones.

Vitamin D

Vitamin D plays a vital role in calcium absorption in

the gastrointestinal tract. Vitamin D levels have been

shown to be inadequate in over half of the women

treated for osteoporosis in the USA and Europe (183).

7-Dehydrocholesterol is absorbed into the systemic

circulation via the skin or from the diet. It is then

hydroxylated in the liver to form 25-hydroxy vitamin D

or calcidiol. In order to be metabolically active, 25-

hydroxy vitamin D is hydroxylated in the kidney to

form the active hormone calcitriol or 1,25-hydroxy

vitamin. Calcitriol is responsible for maintaining

serum calcium and phosphate concentrations by

controlling absorption in the small intestine (52).

Parathyroid hormone is secreted when serum calcium

levels fall in order to increase 1,25-hydroxy vitamin D

synthesis and, as a result, calcium absorption from the

intestine increases. Although most studies show a

strong effect of vitamin D on reducing fracture risk

when supplemented in conjunction with calcium,

there are reports of increased bone density or reduced

fracture with vitamin D alone (26, 167, 176).

The recommended amount of vitamin D supple-

ment is under constant revision. The 2006 recom-

mended daily allowance (RDA) was 200 IU ⁄ day

(5.0 lg) for adults 19–50 years of age, 400 IU ⁄ day

(10.0 lg) for those 50–70 years of age and 600 IU ⁄ day

(15.0 lg) for those over 70 years of age. Most refer-

ences at that time indicated that the current vitamin D

intake was not optimal and recommendations were

made to increase the guidelines. Accordingly, in 2010

the US Institute of Medicine (IOM) revised the guide-

lines to the following: 1–3 years of age, 600 IU ⁄ day

with an upper limit of 2,500 IU ⁄ day; 4–8 years of age,

600 IU ⁄ day with an upper limit of 3000 IU ⁄ day; 9–

69 years of age, 600 IU ⁄ day with an upper limit of

4,000 IU ⁄ day; and>70 years of age, 800 IU ⁄ day with

an upper limit of 4,000 IU ⁄ day (204). End-points

associated with improved bone mineral density, such

as lower-extremity function, dental health, risk of

fractures and reduction in colorectal cancer, require

1,000 IU ⁄ day of vitamin D (20, 90). Also, a recent re-

view found that the safe upper limit for vitamin D

consumption by adults was 10,000 IU ⁄ day or >10

times any current recommended intakes (87, 230). It is

difficult to obtain an adequate intake of vitamin D from

the human diet; exposure of skin to ultraviolet light

provides the greatest effect. This means that geogra-

phy, season, skin color and sun-related behavior are

the main predictors of vitamin D nutritional status

(143, 225, 233). Vitamin D supplementation should

therefore be adjusted according to these factors.

Bisphosphonates

Bisphosphonates are analogs of inorganic pyrophos-

phates. They have low intestinal absorption, are ex-

creted via the kidneys without metabolic alteration and

have a high affinity for hydroxyapatite crystals (71, 217).

They are powerful inhibitors of osteoclastic activity,

have a high affinity to bone and are preferentially

delivered to sites of increased bone formation or

resorption. Clinical trials have shown that oral alendr-

onate, risedronate and, recently, ibandronate, reduce

hip fracture and increase bone mineral density in the

hip, spine and wrist (30, 31, 202). Despite data that

indicate good tolerance of oral bisphosphonates for up

to 10 years, it is unclear as to which patients need to

stay on medication in the long term. Pharmacokinetic

studies in humans and animal studies have demon-

strated that the tight binding of bisphosphonates to

hydroxyapatite results in the retention of bisphospho-

nates for prolonged periods in the bone, and they be-

come locally active again when that bone packet is

resorbed (128). This property raises the possibility of

both prolonged clinical effectiveness and prolonged

risk of harm (44). The Fracture Intervention Trial Long-

term Extension (FLEX) indicated that women who have

had a good response to 5 years of bisphosphonate

therapy (a 3–5% increase in hip bone mineral density,

an 8–10% increase in spine bone mineral density and a

T score of >)3.5) and who are not otherwise at in-

creased risk of vertebral fracture can consider a �holi-

day� off the drug for up to 5 years (28). In experimental

animals, alendronate has been shown to inhibit repair

of normal microdamage, so microdamage accumula-

tion may occur (125, 140). Note also that several bis-

phosphonates were approved by the US Food and Drug

Administration after 2001, and the long-term effects of

these drugs on bone suppression are not yet known.

There are differences in the physical and chemical

structure of available bisphosphonates that may

explain variations in clinical observations. Potency at

the enzyme level, binding affinity, distribution

accumulation and release vary among the different

bisphosphonates (Table 6). Low-affinity bisphospho-

nates do not bind as tightly and are available on the

surface of the bone for removal by osteoclasts; thus,

the drug �comes off� the bone more easily and its

effects may be shorter in duration. The chemical

differences between the bisphosphonates result in

differences in: uptake and retention by the skeleton;

116

Otomo-Corgel

diffusion of the drug within bone; release of the

adsorbed drug from bone; potential recycling of the

desorbed drug back onto bone surfaces; and on min-

eral dynamics and cellular functions (161). To date, in

bisphosphonate trials, specific gains in bone quality

(architecture, turnover, damage accumulation and

mineralization) have not been reported in the human

maxilla or mandible. Further research regarding the

distribution of the medication in individual patients

and distribution to oral bone is needed.

The term �bisphosphonate� is derived from the base

of the drug, namely two phosphate (PO3) groups

covalently linked to a central carbon. The carbon

atom confers resistance to hydrolysis and allows two

R side-chains to attach. The short side-chain, R1,

influences the chemical properties and pharmacoki-

netics of the drug.

R1O

P

R2

CP

O

O-

O- O-

O-

This chain usually has a hydroxyl moiety, which pro-

vides a strong affinity for calcium crystals and bone

mineral. The long side-chain, R2, determines the

chemical properties, the mode of action and the

strength of the bisphosphonate. Bisphosphonates in-

hibit osteoclasts by two mechanisms, depending on

whether the R2 side chain contains nitrogen side

groups. The nonaminobisphosphonates (etidronate,

clodronate and tiludronate) lack a �nitrogen� in their side

chains and are metabolized by osteoclasts to inactive

nonhydrolyzable ATP analogs that interfere with

osteoclast cellular energy and thus induce apoptosis.

The more potent aminobisphosphonates (pamidronate,

alendronate, ibandronate, risedronate and zoledronate),

with �nitrogen�-containing side groups, have four activ-

ities: inactivation of ATP; inhibition of farnesyl diph-

osphonate synthase (part of the mevalonate pathway in

cholesterol synthesis) resulting in osteoclast cytoskeletal

disruption, dysregulation of intracellular transport and

inhibition of cell proliferation; reduction of osteoclast

recruitment; and induction of osteoblasts to produce an

osteoclast-inhibiting factor.

Over 750,000 prescriptions for bisphosphonates

were written each week in 2006 in the USA. In 2010

the number of prescriptions had dropped to

approximately 702,000 per week, although this still

equates to 36.5 million per year. Bisphosphonates are

available in oral doses (daily, weekly, monthly and

quarterly) and in intravenous yearly doses. The long-

term effects of the newer medications are unknown.

Table 6. Dosage and US Food and Drug Administration approval dates of bisphosphonates for use in the USA

Agent Dosage forms Approved Potency

Etidronate (Didronel�; Warner-Chilcott

Laboratories, Rockaway, NY, USA)

200 ⁄ 400 mg tablets 1977 1·

Clodronate (Bonefos�; Bayer Healthcare,

Morristown, NJ, USA)

400 ⁄ 800 mg tablets

60 mg ⁄ ml ampules

Not approved in USA

(Canada only)

10·

Tiludronate (Skelid�; Sanofi-aventis,

Bridgewater, NJ, USA)

200 mg tablets 1977 10·

Pamidronate (Aredia�; Novartis

Cambridge, MA, USA)

20 ⁄ 60 ⁄ 90 mg vials 1991 100·

Alendronate (Fosamax�; Merck & Co.,

Whitehouse Station, NJ, USA)

5 ⁄ 10 ⁄ 35 ⁄ 40 ⁄ 70 mg tablets

70 mg ⁄ 75 ml oral solution

1995 100·

Alendronate + D 70 mg and 2800 U cholecalciferol tablets 2005

Ibandronate (Boniva�; Roche

Laboratories, Burlington, NC, USA)

2.5 mg tablets

150 mg tablets

3 mg ⁄ 3 ml vials

2003

2005

2006

500·

Risedronate (Actonel�; Procter & Gamble,

Cincinnati, OH, USA)

5 ⁄ 30 ⁄ 35 mg tablets

35 mg and 500 calcium

1998

2005

2,000·

Risedronate + (Actonel + calcium�) 35 mg ⁄ 1,250 mg calcium carbonate 2005

Zoledronate (Zometa�; Novartis

Cambridge, MA, USA)

Reclast�

4 mg vials

5 mg vial

2001

2007

10,000·

117

Osteoporosis and osteopenia: implications for periodontal and implant therapy

The oral doses have been associated with gastroin-

testinal side effects such as dysphagia, esophagitis,

esophageal ulcers and gastric ulcers. Bisphospho-

nates are recommended to be taken on an empty

stomach with a full glass of water while remaining

upright for 30 min afterwards. For this reason, com-

pliance has been a consistent problem.

In August 2007, the US Food and Drug

Administration approved once-per-year intravenous

zoledronic acid for the treatment of osteoporosis. In a

36-month trial, atrial fibrillation and arrhythmia were

observed among more patients on once-per-year

zoledronic acid (1.3%) than those on placebo (0.5%),

but the overall incidence was not significant (38).

Also, a growing number of atypical femur fractures in

patients taking oral bisphosphonates are a new con-

cern (208). Intravenous doses of pamidronate and

zolendronate for the treatment of multiple myeloma

and metastatic breast ⁄ prostate cancer that has

metastasized to bone have also been associated with

osteonecrosis of the jaw.

Parathyroid hormone

Human parathyroid hormone has shown significant

reductions in both vertebral and appendicular fracture

rates. Parathyroid hormone was approved by the US

Food and Drug Administration in 2002 as a re-

combinant parathyroid hormone 1–34 with the name

teriparatide. It is delivered as a 20 lg subcutaneous

injection indicated daily for postmenopausal women

and men with osteoporosis. Most osteoporosis thera-

pies act to primarily inhibit bone resorption and

reduce bone remodeling; however, parathyroid hor-

mone has the potential to enhance skeletal microar-

chitecture. The initial animal study showed that daily

injection of parathyroid hormone for several weeks or

months increased bone mass and strength (158).

Human studies indicate that parathyroid hormone

increases bone mineral density and decreases the risk

of vertebral and nonvertebral fractures (130, 164, 169,

213). The current recommendation is that, to avoid

decreases in bone density (27, 107), patients should be

treated with an antiresorptive medication (e.g. a bi-

sphosphonate) only after intermittent parathyroid

hormone therapy has been discontinued, and that bi-

sphosphonates should not be used concomitantly with

parathyroid hormone (70).

Selective estrogen receptor modulators

There are two classes of selective estrogen receptor

modulators: triphenylethylenes and benzothioph-

enes. Tamoxifen is a triphenylethylene known to have

estrogen antagonist activity in the breast and has

demonstrated activity consistent with estrogen ag-

onism in bone. Other triphenylethylene selective

estrogen receptor modulators are clomiphene (used

to induce ovulation) and toremifene (used for breast

cancer treatment). The benzothiophene selective

estrogen receptor modulator in clinical use is ra-

loxifene. It was developed specifically to avoid the

uterotrophic effects of the other selective estrogen

receptor modulators and has been approved for the

treatment and prevention of postmenopausal osteo-

porosis (142). It has been studied extensively and acts

as an antiresorptive agent, preserving both bone

mineral density and bone strength in a manner

identical to that of ethinyl estradiol (160), while

reducing the incidence of breast cancer in a targeted

population of women (67, 178). It has the following

effects on bone physiology: decreased bone forma-

tion and resorption, and fracture risk reduction re-

lated to decreased biochemical markers of turnover,

but no changes in bone density, no significant

change in bone volume, slight increase in minerali-

zation density and no evidence of osteomalacia or

bone toxicity (131). Note that selective estrogen

receptor modulators have not shown effectiveness in

reducing the vasomotor problems (i.e. hot flushes)

that are associated with menopause. Droloxifine,

idoxifene and toremifene are similar selective estro-

gen receptor modulator agents, but are still consid-

ered experimental (209).

Calcitonin

Calcitonin is a naturally occurring 32-amino-acid

polypeptide hormone produced by the C cells of the

thyroid. It is involved in calcium and phosphate

metabolism by decreasing calcium absorption by the

intestines, decreasing osteoclastic activity in bones

and decreasing calcium and phosphate reabsorption

by the kidney tubules. Osteoclasts have calcitonin

receptors, and calcitonin inhibits osteoclastic activ-

ity. Calcitonin is also associated with vitamin D reg-

ulation and enhanced bone mineral metabolism.

Studies evaluated bone loss in women after meno-

pause and found that calcitonin stopped bone loss,

normalized bone turnover without subjective or

objective side effects (42, 174, 188), reduced sub-

sequent vertebral fractures in patients with estab-

lished postmenopausal osteoporosis (40) and its

mechanism of action appears to be related to the

inhibition of bone resorption and preservation of

microarchitecture without a significant increase in

118

Otomo-Corgel

bone mineral density (41, 106). Calcitonin results in

reduced vertebral fracture risk, but has not been

demonstrated to reduce nonvertebral or hip fracture

risk. Calcitonin is unique for its analgesic effect on

vertebral fracture as a result of salmon calcitonin-

binding sites in the central nervous system (215).

Currently, research is underway to evaluate an oral

type of calcitonin, as well as a form of rectal sup-

pository. Further studies are needed to evaluate the

effects of intermittent administration (1 month on

and 1 month off) of calcitonin vs. daily doses, as well

as the possibilities of combination therapy with other

antiresorptive medications. Calcitonin-salmon is a

US Food and Drug Administration-approved daily

metered dose (200 IU) administered via intranasal

spray or an intramuscular or subcutaneous injection.

Estrogen ⁄ hormone replacement therapy

Estrogen, progesterone and androgen receptors are

present in all bone cell types. Both estrogen

replacement therapy and hormone replacement

therapy have been shown to reduce the risk of hip

and spine fractures and to reduce bone loss in

postmenopausal women. For women who require

drug therapy to reduce the risk for osteoporosis,

including women at high risk of fracture during

the next 5–10 years, estrogen replacement therapy ⁄hormone replacement therapy can be considered

an option (29). Owing to the results of the Women�sHealth Initiative, many women elected to treat

osteoporosis with alternative methods (241). Recent

data concluded that the incidence of fractures

among perimenopausal women and postmeno-

pausal women increased significantly in the 3 years

after publication of the Women�s Health Initiative

and Heart and Estrogen ⁄ Progestin Replacement

Study II, following a decline in the use of hormone

therapy, concurrent with an increase in the use of

other bone-modifying agents (94). The findings

using conjugated equine estrogens and progesterone

indicated an increase in the risk of venous throm-

boembolism, ischemic stroke, cardiovascular com-

plications and breast cancer when receiving estrogen

replacement therapy and ⁄ or hormone replacement

therapy. Note that these findings are contrary to

decades of previous clinical and observational trials

and clinical experience that validated the rationale

for hormone therapy. Current recommendations are

for short-term use and the early prevention of

osteoporosis. Wulf Utian, Director of the North

American Menopausal Society, noted that although

the North American Menopausal Society was the

first professional body to recommend stopping the

estrogen replacement therapy ⁄ hormone replace-

ment therapy group of the Women�s Health Initia-

tive, there are benefits of hormone replacement

therapy (241). For example, the hormone replace-

ment therapy group showed a significant reduction

in colon cancer (127). The beneficial effect was more

marked in women who began therapy within 5 years

after menopause (39). The net clinical effect of

estrogen is that it is primarily an antiresorptive

agent and therapeutically prevents osteoporosis by

inhibiting bone resorption and bone turnover. It has

been shown that estrogen deficiency led to fragility

of the trabecular structure of molar alveolar bone

that was inversely correlated with lumbar bone

mineral density in ovariectomized monkeys (14).

Currently, low-dose estrogen therapy for prevention

of bone loss in postmenopausal women as a

monotherapy is seen as a viable option in clinical

medical practice (194). Note that treatment with

androgens stimulates new bone formation and

results in higher bone mineral density than estrogen

therapy alone (166).

Alternative estrogens need further research. The

effect of phytoestrogen on bone and menopausal

vasomotor symptoms has yet to be confirmed (196).

The risk ⁄ benefit ratio of hormone replacement

therapy needs to be assessed with greater knowledge

of the effects of other treatments that exist for men-

opausal symptoms.

Denosumab

Denosumab is a human monoclonal antibody that

binds RANKL. It therefore blocks interaction with the

RANK receptor on osteoclasts and osteoclast pre-

cursors. Data also indicate that it is similarly effective

in various stages of renal function impairment: it

does not impair fracture healing processes or con-

tribute to atherosclerosis progression in patients with

high cardiovascular risks (72). The result is inhibition

of osteoclast-mediated bone resorption. Clinical tri-

als indicate that subcutaneous administration of

60 mg of denosumab every 6 months for 36 months

reduces bone turnover and increases bone mineral

density significantly more than alendronate at the

lumbar spine and hip in osteoporotic female patients

(46). Clinical data also indicate that it inhibits

structural damage in patients with rheumatoid

arthritis when added to methotrexate (124). Near-

maximal reductions in the mean levels of serum

C-telopeptide from baseline were evident 3 days after

administration of denosumab, and suppression of

119

Osteoporosis and osteopenia: implications for periodontal and implant therapy

bone turnover appeared to be dose-dependent (141).

This is a promising new treatment for osteoporosis

and rheumatoid arthritis that reduced bone resorp-

tion by a median of 86% at 1 month, which is greater

than that seen when using other antiresorptive drugs

(45). Note that Aghaloo et al. (4) have reported ONJ

associated with denosumab.

Strontium ranelate

Strontium ranelate is a new oral drug that reduced

the risk of all nonvertebral fractures and, in a high-

risk subgroup, of hip fractures over a 3-year period

(189). It is well tolerated and is a possible alternative

to current bisphosphonates. It acts by dissociating

bone remodeling by increasing bone formation and

decreasing bone resorption and in a Phase 3 trial led

to early and sustained reductions in the risk of

vertebral fractures (149, 189).

Periodontal implications

The evidence supporting the relationship between

osteoporosis and periodontitis is increasing. How-

ever, confounding factors play a significant role as

a result of the chronicity of both problems. Studies

on tooth loss, alveolar crestal height and clinical

attachment loss have been performed; however,

problems in extrapolation and application of data

arise owing to small sample sizes, study design vari-

ations and inadequately controlled confounding

factors, which have limited our understanding of the

relationship between the two diseases.

There are data which relate bone mineral density of

the spine, trochanter and other skeletal bones with

that of the maxilla and mandible. The preponderance

of evidence shows an association between systemic

measures of osteoporosis (such as dual-energy X-ray

absorptiometry) and oral bone mineral density (98).

Animal models indicated fragility of the trabecular

structure of molar alveolar bone (222), as well as

increased vertical loss of mandibular alveolar bone

(168, 224). In one study, the fragility of the monkey

alveolar bone trabecular structure inversely

correlated with lumbar bone mineral density when

ovariectomized (14). In a 28-month longitudinal

study of postmenopausal women, mandibular bone

loss, assessed by dual-energy X-ray absorptiometry,

was much higher than in other skeletal sites (56).

Also, Inagaki et al. (92) found that periodontitis and

tooth loss may be a useful indicator of metacarpal

bone mineral density loss in Japanese women. It has

been suggested that radiographic examination of the

facial skeleton may lead to early detection of osteo-

porosis (115). Although there are no current standard

methodologies to evaluate maxillary and mandibular

bone mineral density, research with newer technol-

ogies may permit dental practitioners to assess oral

bone quality.

Evaluation of dental panoramic radiographs for

identification of osteoporotic changes has yielded

mixed results. In an evaluation of mandibular pano-

ramic radiographs, it was found that osteoporotic

patients were more likely to have altered inferior cor-

tex morphology, but no statistically significant differ-

ences in cortical width, degree of alveolar crest

resorption, fractal dimension or number of mandib-

ular teeth were identified compared with nonosteo-

porotic patients. The authors recommended training

practitioners to use specific evaluation techniques to

detect significant radiographic changes, especially at

the inferior mandibular cortex, to help identify post-

menopausal women with currently undetected low

bone mineral density, as well as undetected spinal

fractures (220). Dental panoramic radiographs may be

useful for identifying women under the age of 65 with

osteoporosis by observation of a thin cortical width

and ⁄ or a severely eroded cortex (66, 221). Panoramic

studies indicate that the relative bone density of the

mandible is statistically significantly lower in patients

with osteoporosis (32, 170). However, when pano-

ramic-based indices were used to correlate bone

mineral density of the mandible and hip, it was found

that they were not able to distinguish normal from

osteopenic ⁄ osteoporotic mandibles (58).

Four different dental radiographic techniques were

compared for detecting osteoporosis: fractal dimen-

sion (measuring loss of trabecular continuity and

dimensions of space); microdensitometry (light

transmission through a selected area on a radio-

graph); pixel intensity (blackness or whiteness); and

panoramic analysis (cortical bone thickness at the

gonial angle). They were compared with standard

bone density measurement techniques used to

diagnose osteoporosis in bones other than the jaws:

quantitative computed tomography, and single- and

dual-photon absorptiometry. Pixel intensity was the

most effective dental method, and only panoramic

analysis was ineffective (119). Digitized bitewings

may be a more reliable method of monitoring chan-

ges in bone density. Jonasson et al. (100) found that

subjects with sparse mandibular trabeculation on

digitized radiographs had an increased risk of frac-

ture. Therefore, high-risk subjects may be identifiable

prior to fracture.

120

Otomo-Corgel

A study using a novel computed tomography ⁄micro-computed tomography-based hard-normal-

soft classification system proposed a formula to

convert ordinary computed tomography values,

expressed in Hounsfield units, into bone volume

percentages for objective measurements of bone

density (184). Computed tomography scanners can

determine the percentage of calcification in localized

sites, and this could be used in treatment planning

and may predict periodontal disease progression

before clinical attachment loss. This determination

would also enhance dental implant therapy.

Standardization of radiographic methods would be

needed to permit chairside determination of bone

mineral density, and although there is potential for

dentists to identify signs of osteoporosis in dental

radiographs, clear methodologies and criteria for

assessing bone have not yet been defined.

Tooth loss and alveolar crestal loss

Studies show the greatest associations between tooth

loss ⁄ alveolar ridge atrophy and osteoporosis (47, 57,

66, 85, 154, 246). There is also less risk of tooth loss

when postmenopausal women are placed on hor-

mone replacement therapy (84, 219). Krall et al. (114)

found that the odds of being edentulous were re-

duced by 6% for each 1-year increase in duration of

hormone replacement therapy use. It is also apparent

that there is increased alveolar ridge resorption in

edentulous patients with osteoporosis (54), and

greater alveolar crestal height loss is noted with

osteoporosis and osteopenia (155, 228, 236).

Periodontal disease

Current knowledge regarding the effects of osteopo-

rosis ⁄ osteopenia on periodontal diseases and alveolar

bone loss is inconclusive. The association of osteo-

porosis in postmenopausal women with periodontitis,

attachment loss and gingival recession has been re-

ported (33, 80, 93, 112, 228, 237). Several studies have

indicated that reduced bone mineral density was

associated with increased clinical attachment loss

(156, 201, 245). Others have found weak or no signifi-

cant associations between systemic bone mineral

density and clinical attachment loss (68, 180, 239).

However, recent studies provide stronger evidence of

an association between osteoporosis and clinical

attachment loss in humans (6, 135, 214, 218, 219, 221).

The relationship between periodontal disease and

plasma cytokines, vitamin D and bone mineral density

in postmenopausal women, with and without osteo-

porosis, has been investigated, and it was found that

periodontal disease was more common in women with

osteoporosis and was associated with lower vitamin D

and higher concentrations of RANKL and osteoprote-

gerin (95). Sub-antimicrobial doses of doxycycline in

postmenopausal women have shown a possible benefit

in reducing the progression of attachment loss with an

effect on serum biomarkers of bone loss (79, 177, 192).

Most studies indicate improved periodontal status in

women on hormone replacement therapy ⁄ estrogen

replacement therapy (43, 193, 219), characterized by

increased alveolar bone mass and improved alveolar

crest height, reduced clinical attachment loss and re-

duced periodontal inflammation. Also, estrogen

receptor-alpha gene polymorphism was shown to be a

possible indicator for bone mineral density variation of

lumbar spine L2–L4 and Ward�s triangle in both pre-

menopausal and postmenopausal Chinese women

with periodontitis (248). The lipoxygenase gene Alox 15

is shown to be a negative regulator of peak bone mineral

density in mice (111) suggesting future therapeutic

approaches to reduce periodontal disease may impact

osteoporosis. A recent study found that hypergonado-

tropic hypogonadism in men contributed to the pro-

gression of periodontal disease (229). The effect of daily

administration of teriparatide vs. placebo was studied

in conjunction with periodontal regeneration in pa-

tients with severe periodontal disease. Radiographic

linear resolution of osseous defects was significantly

greater after teriparatide therapy than after placebo at

6 months, with a mean linear gain in bone of 29% at

1 year vs. 3% in those receiving placebo (P < 0.001)

(21). A recent review suggested that reduced bone

mineral density is a shared risk factor for periodontitis

rather than a causal factor, but more prospective

studies are required to fully determine what, if any,

relationship truly exists between periodontal disease

and reduced bone mineral density (144).

Bisphosphonates: patientmanagement and their effect onthe periodontium

Thus far, animal studies have shown resistance-

conferring benefits of oral bisphosphonates in

experimentally induced periodontitis models (7, 8, 9,

35, 173, 187, 212, 238, 243). Topical (25, 81, 148, 243)

and systemic (108) alendronate applied during peri-

odontal flap elevation reduced alveolar bone loss in

rats. In contrast, a recent study, in which aggressive

periodontal disease was induced in conjunction with

potent bisphosphonate therapy (zoledronic acid),

121

Osteoporosis and osteopenia: implications for periodontal and implant therapy

induced osteonecrosis of the jaws in rats (5). Recent

studies on rats suggest that alendronate and ⁄ or doxy-

cycline may inhibit the expression of matrix metallo-

proteinase-8, increase the levels of tissue inhibitors of

matrix metalloproteinases in gingiva (37), increase ser-

um osteocalcin and provide slight inhibition of lipo-

polysaccharide-induced alveolar bone resorption (36).

A 2003 systematic review stated that preliminary

data on patients taking bisphosphonates reported

impacts on periodontitis management (186). Human

studies also showed a positive effect of bisphospho-

nates on the progression of periodontal disease (222,

223). Lane et al. (117), in a randomized, double-

masked, placebo-controlled 12-month study, and

Rocha et al. (199), in a controlled, double-masked,

prospective 6-month study, showed that bisphosph-

onate treatment improved the clinical outcome of

nonsurgical periodontal therapy and may be an

appropriate adjunctive treatment to preserve peri-

odontal bone mass. Jeffcoat et al. (97) also showed a

significant gain, over 2 years, in baseline alveolar

bone height in a group with low mandibular bone

mineral density treated weekly with alendronate rel-

ative to a placebo group receiving nonsurgical ther-

apy. Other investigators also showed positive gains

on alveolar bone density and height with weekly

alendronate therapy; however, these gains did not

last for longer than 6 months (65, 198, 200).

Given the potential for bisphosphonate-induced

osteonecrosis of the jaw, the use of bisphosphonates

as an adjunctive treatment for periodontal disease is

not indicated.

Further research on comparisons of long-term

bisphosphonates and the possible effect on the

periodontium and periodontal therapies are war-

ranted. There are no studies evaluating bisphos-

phonate therapy to improve surgical outcomes. In

clinical practice, the therapist should:

• Identify patients at risk for osteoporosis if not

diagnosed.

• Review medications, including length of time on

the medication(s), compliance, method of delivery

and dosages if the patient has been diagnosed with

osteoporosis.

• Evaluate lifestyle (i.e. exercise and diet).

• Explain to the patient the possible impact of

bisphosphonates on periodontal and implant

therapies.

• Institute a comprehensive oral hygiene program.

• Eliminate periodontal ⁄ dental inflammation.

• Consult with the physician if there is a question

regarding recommended periodontal ⁄ implant

treatment and bisphosphonates.

Figure 3 presents an algorithm to help dental

clinicians make the right decisions about how to

manage their patients who are taking bisphospho-

nates, and to provide advice on when to consult with

medical colleagues.

Bisphosphonates: dental implantimplications

There is currently an assumption that osteoporosis

will affect successful integration of dental implants

in the maxilla or mandible, and it is not clear

whether successful implant therapy can be ex-

pected in patients with osteoporosis. There are no

reliable data showing that systemic bone dual-

energy X-ray absorptiometry scans accurately

reflect the bone mineral density of the maxilla or

mandible (96, 235). Becker et al. (22) found no

association between peripheral dual-energy X-ray

absorptiometry scores and the risk of implant

failure. This exploratory study suggested that a

simple visual assessment of bone quality at the site

of implant placement may be more informative

regarding implant failure than peripheral bone

mineral density dual-energy X-ray absorptiometry

(22). In a review by Mombelli et al. (157), data from

17 papers showed low evidence for an association

between osteoporosis and implant failure. Most

published studies are case reports or cross-

sectional, have biased sampling, or used varying

criteria for measuring osteoporosis. However, most

show implant success despite skeletal osteoporosis

(24, 48, 51, 62, 73–76, 82, 132).

Animal studies provide mixed results in this re-

gard. The compact layer of bone in the rabbit tibia

was 28% thicker in controls than in animals in

which osteoporosis had been induced, and this

could potentially affect implant placement (132).

Ovariectomized rats had significant osteoporosis

around implants, but no difference in the extent of

implant–bone contact (175). In rabbits with steroid-

induced osteoporosis, significant correlations were

demonstrated between the bone density of the fe-

mur and the torque required to remove implants

placed in the tibia. However, there was no signifi-

cant difference in the torque required to remove

the implants placed in the mandible, suggesting

that steroid administration, which results in lower

bone mineral density, could have less effect on the

osseointegration of titanium implants in the

mandible than in skeletal bone (77). Most data,

however, do not suggest increased risk of implant

122

Otomo-Corgel

failure as a result of decreased bone mineral

density, although the long-term biomechanical sta-

bility of implants under masticatory forces is as yet

unknown (109).

Only a few studies have evaluated the effect of

hormone replacement therapy or oral bisphospho-

nates on implant success in humans, but most of

these noted minimal complications. Qi et al. (182)

found that estrogen therapy may promote bone

healing around titanium implants. Minsk et al. (153)

showed that hormone therapy did not improve out-

comes of implant therapy, while Moy et al. (159)

indicated that women on hormone replacement

therapy had an increased relative risk for implant

failure of 2.55. August et al. (15) found that post-

menopausal estrogen status could have an impact on

implant healing in the maxilla, but not in the

mandible. A recent animal study showed that

alendronate may prevent the negative influence of

estrogen deficiency on bone healing around titanium

implants (59). Jeffcoat (97) also showed 3-year results

of a single-blind controlled study with oral alendro-

nate or risedronate on implant placement. Implants

were >99% successful in both groups and no

occurrences of osteonecrosis of the jaw were noted. A

recent study showed that estrogen replacement

therapy and alendronate were effective in preventing

bone mass loss around integrated implants in ovari-

ectomized rats (78). Studies with adjunctive systemic

alendronate have also shown reduced vertical bone

resorption postextraction and suppression of free

bone graft resorption in Wistar rats (7–9) and in hu-

man wisdom teeth extraction sites (83).

Currently, many patients may have taken oral bis-

phosphonates for approximately 3 years and hence

may have experienced significant impacts on the

quality of oral and alveolar bone. The clinician must

evaluate the length of the time the patient has been

Intravenous bisphosphonates Oral bisphosphonatesIntravenous bisphosphonate for multiple myeloma, metastatic cancer and/or severe osteoporosis (once a month pamidronate or zoledronic acid)

Thorough oral examination, and consultation with prescribing physician

Prior to initiation of bisphosphonate

�Comprehensive periodontal examination and treatment toachieve optimal periodontal health

�Periodontal therapy needed to enhance control of disease

�Extraction of poor tohopeless teeth with reductionof irregular osseous contours

� Bisphosphonate therapy (ifsystemic conditions permit)should be delayed 14–21 days

� Assess restorative needs: �Removable appliances

should be stable with no rough areas that could traumatize mucosa�Caries control� Complete all invasive dental

procedures�Frequent periodontal/dental

maintenance visits andmonitoring

Bisphosphonate therapy already initiated

Intravenouszoledronic acid 5

mg once a year for up to 2 years

Follow guidelines for oral route

No ONJ

>65 year old woman>2–3 years on oral bisphosphonate History of steroid therapy Other medical risks*

�Non-surgical periodontal therapy�Close periodontal

maintenance�Antimicrobial

mouthrinse and antibiotics as needed�Prevent osseous injury�No extractions�No dental implants�Nonrestorable teeth

require endodontictherapy of theremaining roots�Good oral hygiene

practices

*Medical risksCancerSmokerDialysis

Low hemoglobinDiabetesObesity

Chemotherapeutic agentsHead/neck radiation therapy

>65 year old woman

No steroid therapyNo medical risks*

<65 year old woman<2–3 years on oral bisphosphonate No steroid therapyNo medical risks*

�Consult with prescribing physicianregarding proposed treatment, drug holiday, antibiotic regimen

�Antibiotic therapy � Pain reduction as needed�Antimicrobial mouthrinses�Gentle debridement of loose or

sharp bone segments�Follow Box 2 AAOMS

�Comprehensive periodontal examination � Clear treatment

plan with the physician, if extensive �Initiate treatment in

a single site or sextant to assesshealing potential�Close periodontal

maintenance�Sound oral hygiene

Consultation with prescribing physicianAdvise patients of risks of ONJ

�Comprehensive periodontal examination�Currently, no contraindications to

periodontal or implant therapy�Close periodontal maintenance�Sound oral hygiene practices

ONJ

Follow guidelines in Box 2 (AAOMS Staging and Treatment Strategies for ONJ)

Collaborate with prescribing physician

Close periodontal maintenance with gentle debridement

�Treat periodontal disease/periapical pathoses as soon aspossible�Treat in sextants if

assessing bone healing –nonsurgically if possible�Discuss options to avoid

extractions�Extractions should be

conservative with primary closure �Systemic antibiotics to

avoid risk of infections�Antimicrobial rinses�Sound oral hygiene �Close periodontal

monitoring

NB No validated diagnostictechnique to currently assess increased riskfor developing ONJ

NB Discontinuingbisphosphonates (time-outs) should bethrough the prescribingphysician

ONJ

>2–3 years on oral bisphosphonate

Fig. 3. Decision tree for managing patients who are taking

bisphosphonates. According to the medical and medi-

cation history, the dental clinical treatment can follow

pathways for the dental and periodontal treatment of pa-

tients who are taking bisphosphonates, including the

management requirements if bisphosphonate-induced

osteonecrosis of the jaws is identified. All patients pre-

scribed bisphosphonates should be informed of the risks

and possible effects of the bisphosphonate on oral bone

and treatment outcomes. Discussions should be docu-

mented, the options reviewed and consent obtained for

the elected course of treatment. Please note that this

algorithm does not apply to all patients in all situations.

The clinician must base decisions on their best clinical

judgment for individual patients at the time of treatment.

AAOMS, American Association of Oral & Maxillofacial

Surgeons; ONJ, Osteonecrosis of the jaw.

123

Osteoporosis and osteopenia: implications for periodontal and implant therapy

on an oral bisphosphonate, together with assessment

of case complexity, the patient�s overall systemic

health and risk factors (231). Currently, the American

Association of Oral and Maxillofacial Surgeons rec-

ommends that patients should be informed of the

small risk of compromised bone healing following

implant placement after oral bisphosphonate ther-

apy, especially if the implant is placed within 3 years

of bisphosphonate therapy. The American Associa-

tion of Oral and Maxillofacial Surgeons recommen-

dations for implant placement are (3):

• If the patient has been taking an oral bis-

phosphonate for less than 3 years without any

other clinical risk factors (e.g. steroids, chemo-

therapy, thalidomides, or genetic perturbations)

then no alteration or delay in the planned

implant surgery is necessary. It is important to

note that:

s Informed consent should be provided regarding

possible future implant failure and possible

osteonecrosis of the jaws if the patient continues

taking oral bisphosphonates and

s The prescriber of the oral bisphosphonates

should be contacted to suggest monitoring,

alternate dosing of the bisphosphonates, drug

holidays, or an alternative to the bisphosphonate

therapy.

• If the patient has been taking an oral bisphos-

phonate for less than 3 years and is also taking

concomitant corticosteroids then the prescriber

should be contacted and asked to consider dis-

continuing the oral bisphosphonates for at least

3 months prior to implant placement (or oral ⁄periodontal surgery). If systemic conditions permit,

bisphosphonates should not be restarted until

osseous healing has occurred.

• If the patient has been taking oral bisphosphonates

for more than 3 years, with or without concomitant

corticosteroids, the prescriber should be contacted

to discontinue the bisphosphonates for 3 months

prior to the oral surgery, if systemic conditions

permit. The oral bisphosphonate should not be

restarted until osseous healing is complete.

Note that dental implants are contraindicated in

patients taking monthly intravenous bisphospho-

nates for multiple myeloma, metastatic breast or

prostatic cancer of the bone, severe osteoporosis or

Paget�s disease.

There are many questions yet to be answered with

respect to osteoporosis and dental implants. Cur-

rently, there are no convincing data to contraindicate

dental implant placement in the osteoporotic patient.

However, limited case reports have shown osteone-

crosis of the jaws after implant therapy (23). One

study compared a control group of female patients

with dental implants taking no oral bisphosphonates

with a test group who were taking a bisphosphonate.

The bisphosphonate group had an 86% success rate

vs. a 95% success rate in the group not taking the

medication (105). In contrast, a recent animal study

showed that single-dose zoledronic acid improved

osseointegration in estrogen-deficient rabbits (244). A

second animal study showed that strontium ranelate

increased mechanical fixation of the implant in rats

(134).

Controlled studies are required to assess implant

outcomes in varying bone densities, in people taking

different bisphosphonates, in atrophic alveolar rid-

ges, in two-stage vs. early-loading vs. immediate-

loading situations, and in different implant systems

and implant surfaces. It has been noted that in-

creased function of the mandible 2 years after im-

plant overdentures were placed seemed to cause a

load-related bone formation that minimized, or in

some cases counteracted, the physiologic age-related

bone mineral density loss leading to osteoporosis

(234).

Osteonecrosis of the jaw

Bisphosphonate-induced osteonecrosis of the jaw

(Osteonecrosis of the jaw [ONJ], Bisphosphonate

osteonecrosis [BON], Bisphosphonate-related osteo-

necrosis of the jaw [BRONJ], Antiresorptive osteo-

necrosis of the jaw [ARONJ]) was described by Marx

in 1983 (136). It may, however, be the same disease

that was described in 1899 as an industrial disease

seen in phosphate miners and match factory work-

ers and referred to as phossy jaw (49, 50, 89). This

condition refers to exposure of bone in the mandible

or maxilla persisting for more than 8 weeks in a

patient who has previously, or is currently receiving,

treatment with a bisphosphonate and who has no

history of radiation therapy to the jaws (152).

Osteonecrosis of the jaw originates in the alveolar

bone, but may spread to the basal bone. Early

radiographic findings include sclerosis or loss of the

lamina dura, and ⁄ or widening of the periodontal

ligament space (136).

Osteonecrosis of the jaw is frequently observed in

the jaw as a result of the rapid rate of bone

remodeling. The alveolar crest remodels at 10 times

the rate of the tibia, at five times the rate of the

mandible at the level of the mandibular canal and at

3.5 times the rate of the mandible at the inferior

124

Otomo-Corgel

border (55). Thus, there is a higher uptake and

concentration of bisphosphonates in the alveolar

bone compared with other sites. It appears that

alveolar bone depends more on osteoclastic bone

resorption-remodeling and renewal than any other

bone in the adult skeleton. Sedghizadeh et al. (210)

also see the unique nature of the oral biofilm as a

potential source of osteonecrosis of the jaw. Histo-

pathologic and scanning electron microscopy

examination of osteonecrosis of the jaw vs. osteo-

myelitis specimens revealed that subjects with

osteonecrosis of the jaw had a greater diversity of

bacteria, in addition to fungal organisms not seen in

osteomyelitis of the jaws (210).

Bisphosphonates are used to prevent and reduce

the bone resorption that occurs in metabolic bone

diseases, such as osteoporosis, osteitis deformans

(Paget�s disease), metastatic bone diseases (i.e. mul-

tiple myeloma, metastatic breast cancer, metastatic

prostatic cancer and other metastatic cancers), or

other diseases that can reduce bone mineral density

secondarily (hyperthyroidism and diabetes mellitus).

It has become apparent that the intravenous nitrog-

enous bisphosphonates are implicated in osteone-

crosis of the jaw. Their potent anti-osteoclastic and ⁄or antiresorptive effects occur via inhibition or cell

death of the osteoclast, which resorbs bone and in-

gests the bisphosphonates. They become bound to

the mineral crystals on bone surfaces and, with in-

creased doses, accumulate in the bone matrix. When

bone resorption is inhibited, old bone is not removed

and new osteoid is not formed. The osteocyte that acts

as a mechanoreceptor to maintain the mineral matrix

of the bone outlives normal bone remodeling (44).

The result is hypermineralization or a hypodynamic

bone that has a reduced biomechanical competency.

Some authors warn that prolonged oral bisphospho-

nate use needs to be weighed against such long-term

suppression of bone metabolism (126, 171, 172).

Others say that long-term use may retard fracture

healing, but not affect bone mineralization or bone

mechanics (126). According to Marx, repeated bis-

phosphonate dosing is a �biologic catch-22�, in that

the drug accumulates in bone matrix and can be re-

moved only by osteoclast-mediated resorption as part

of the bone turnover cycle. The problem is that

bisphosphonates are toxic to osteoclasts and prevent

bone turnover. Bisphosphonates are also anti-

angiogenic (150), may be comorbid medications in

immunocompromised patients and may indirectly

modulate the osteoblast–osteoclast balance (122, 205).

Numerous reports in recent years have raised

concern about the serious nature of osteonecrosis of

the jaw (17, 18, 60, 86, 99, 101, 137, 145, 146, 181, 206,

207, 247). A systematic review reported on 368 cases

of osteonecrosis of the jaw. The primary medical

diagnoses were multiple myeloma (162 cases), met-

astatic breast cancer (134 cases) and metastatic

prostatic cancer (23 cases), which together consti-

tuted 91.5% of the reported cases. Over 94% of pa-

tients were taking intravenous zoledronic acid,

pamidronate, or both (240). Sixty per cent of patients

with osteonecrosis of the jaw had received dentoal-

veolar surgery, but 40% of the cases of osteonecrosis

of the jaw appeared spontaneously, often in denture

wearers, in which 39% were associated with exosto-

ses. Osteonecrosis of the jaw was more frequently

located in the mandible (65%) than in the maxilla

(26%) or both the mandible and maxilla (9%). Mul-

tifocal or bilateral involvement was more common in

the maxilla than in the mandible (31% vs. 23%,

respectively). There were 17 cases reported in pa-

tients using oral bisphosphonates. Of those, 15 were

taking alendronate (4.2%), one was taking rise-

dronate (0.3%) and one was taking ibandronate

(0.3%). The most important predisposing factor for

development of osteonecrosis of the jaw was the type

and dose of the bisphosphonates, followed by a his-

tory of trauma, dental surgery or dental infection.

Badros et al. (16) retrospectively reviewed 90 mul-

tiple myeloma patients with osteonecrosis of the jaw

and found it to be time-dependent, with a higher risk

in older multiple myeloma patients after long-term

use of bisphosphonates, often after dental extrac-

tions. Bamias et al. (18) found that the duration of

exposure to bisphosphonates was strongly related to

development of osteonecrosis of the jaw. Those who

developed osteonecrosis of the jaw received a median

of 35 (range, 13–68) infusions of bisphosphonates vs.

15 (range, 6–74) infusions for patients without

osteonecrosis of the jaw. Also the median time for

exposure to bisphosphonates was 39.3 (range, 11–86)

months for patients with osteonecrosis of the jaw

compared with 19 (range, 4–84.7) months for patients

without osteonecrosis of the jaw (18). Note that bis-

phosphonate doses for oncologic purposes are often

12 times higher than doses for treating osteoporosis

(191). It is becoming increasingly evident that the

cumulative dose of the bisphosphonate, its potency,

the stereochemistry of the nitrogen side chain

(monthly intravenous zolendronate and pamidro-

nate), patient�s age, medical status, history of dental

trauma, pre-existing dental disease and other phar-

macologic agents (corticosteroids, cytotoxic drugs

and multimodal antiretroviral therapies) all increase

the risk for osteonecrosis of the jaw.

125

Osteoporosis and osteopenia: implications for periodontal and implant therapy

Clinically, osteonecrosis of the jaw may present as

exposed alveolar bone occurring spontaneously or

after dental surgery. The sites usually are painful,

have soft tissue swelling or ulceration, mobile teeth

and induration with drainage (Fig. 4). Radiographi-

cally, if teeth are present, there may be sclerosis of

the alveolar lamina dura, loss of the alveolar lamina

dura and ⁄ or widening of the periodontal ligament

space, particularly at molars (138).

Intravenous bisphosphonates andosteonecrosis of the jaw:prevention and therapy

Before placing patients on intravenous bisphospho-

nates, the oncologist and dental team need to develop

management protocols similar to those developed by

the radiation therapist ⁄ oncologist before initiation of

full-course irradiation therapy to the head and ⁄ or

neck. Although osteochemonecrosis and osteoradi-

onecrosis are different, because of a lack of blood

supply in the latter, pre-oncologic therapy should be

aggressive in order to prevent postcancer therapy

sequelae. However, once intravenous bisphospho-

nates have been given to the patient, it is imperative

that meticulous monitoring and home care are

implemented and that periodontal maintenance is

provided at frequent intervals. Surgical therapy

should be avoided if possible. Even extractions should

ideally not be performed unless teeth are extremely

mobile (12) or there is spreading infection that cannot

be controlled by conservative therapy. However,

Adornato et al. (2) have reported successful treatment

of osteonecrosis of the jaw with bone resection and

autologous platelet-derived growth factors. A recent

review states that laser application at low intensity

may improve the reparative osteonecrosis of the jaw

process and can be used for conservative surgery,

whereby necrotic bone is vaporized until healthy

bone is reached (232). Ozone therapy was also

discussed for treatment of osteonecrosis of the jaw

during and after oral surgery to stimulate cell prolif-

eration and soft tissue healing. Marx et al. (138) rec-

ommends the treatments in Box 1 for therapy with

intravenous bisphosphonates specific to the stage of

osteonecrosis, in which effective control to a pain-free

state without resolution of the exposed bone was

90.1%. The American Association of Oral and Maxil-

lofacial Surgeons has revised their �Staging and

Treatment Strategies� for osteonecrosis of the jaw, as

shown in Box 2 (12).

Medical researchers have been actively engaged in

trying to identify ways to manage the sequelae of

osteonecrosis of the jaw (69, 91, 102, 110, 197). A re-

cent consensus statement recommended that intra-

venous bisphosphonates should be discontinued after

2 years of therapy for multiple myeloma patients who

achieve a complete response and ⁄ or plateau. If their

disease is still active, they have not achieved a re-

sponse, or have threatening bone disease beyond

2 years of therapy, the frequency of treatment can be

decreased to every 3 months. The consensus state-

ment recommended dental evaluation, good dental

hygiene, attention to reducing periodontal and peri-

apical infections, extracting teeth as necessary, but

withholding bisphosphonate treatment for at least

1 month before the procedure, and resuming treat-

ment when the patient has fully recovered and the

wound fully healed (116). It was recently noted that

surgery is more successful in patients with osteopo-

rosis or multiple myeloma than in those with solid

tumors, and that discontinuation of bisphosphonate

therapy favored the surgical outcome (242).

A B C

Fig. 4. Bisphosphonate-induced osteonecrosis of the jaw

in a 73-year-old woman with multiple myeloma, type II

diabetes, myocardial infarction and total hip replace-

ment. The patient had been taking intravenous zolendr-

onate for 1 year, and there was a history of extraction

1 year before this clinical presentation of bisphospho-

nate-induced osteonecrosis of the jaw. (A) Clinical

appearance. (B) Radiographic appearance. (C) Surgical

exposure to reveal the extensive necrosis and alveolar

bone defect.

126

Otomo-Corgel

Oral bisphosphonates andosteonecrosis of the jaw:prevention and therapy

Most osteoporotic patients who present in dental

practice are taking oral bisphosphonates, such as

alendronate, risedronate or ibandronate (as opposed to

an intravenous infusion of zolendronate or pamidro-

nate). Recently, intravenous zoledronate, 5 mg once a

year for 2 years, has increased in use as a result of ease

of compliance. It is now 18 years since alendronate

(Fosamax�) was approved by the US Food and Drug

Administration, 8 years since risedronate (Actonel�)

was approved and just 3 years since ibandronate

(Boniva�) was approved. Currently, alendronate poses

a higher risk for osteonecrosis of the jaw than risedr-

onate as a result of the numbers of patients who have

been prescribed alendronate over the years, whereas

ibandronate has been available only for a short period

of time. Some alternatives to bisphosphonates may not

be a safe option in light of new reports of osteonecrosis

of the jaw in patients taking denosumab (4).

Patients with, or at high risk of, osteopenia should

be counseled regarding the importance of weight-

bearing exercise, dietary vitamin D, calcium and

Box 1. Recommendations fordental treatment of patientsreceiving intravenousbisphosphonates (monthly),specific to the stage ofosteonecrosis

Stage 0 – Patients at risk (osteoclast

hypocellularity, apoptosis with a reduction in

endosteal osteoblasts and their osteoid

production) (12)

• Eliminate existing inflammatory dental

pathologies

• Withhold intravenous bisphosphonate ther-

apy for 2–3 months, if systemic conditions

permit, to allow dental providers to obtain

optimum dental health:

s Remove abscessed, nonrestorable or peri-

odontally unsalvageable teeth

s Perform caries control, restorative, root canal

and periodontal therapy (including peri-

odontal surgery)

s Provide fixed or removable partial dentures

s Leave impacted teeth undisturbed unless they

have oral communication

s Leave small single tori undisturbed; remove

large, multilobular lingual tori and large

midline palatal tori

s Prophylactic antibiotic coverage is recom-

mended for invasive dental procedures in

cancer patients

Stages 1a and 1b (Stage 1a, bone exposure

<1 cm and painless; Stage 1b, largest area of

exposure is >1 cm and painless)

Asymptomatic exposed bone requires either

no treatment or maintenance with a 0.12%

chlorhexidine oral rinse three times daily

Stages 2a, 2b and 3a (Stage 2a, a single ex-

posed area of bone measures <2 cm and is

accompanied by pain and ⁄ or clinical infection;

Stage 2b, exposure area is >2 cm; and Stage 3a,

exposed bone >3 cm in area or showing sig-

nificant osteolysis or an orocutaneous fistula)

These scenarios require an antibiotic regimen

and 0.12% chlorhexidine rinses administered

through one of three regimens:

• Rinse three times daily, plus penicillin VK

500 mg four times per day ongoing

• Rinse three times daily, plus penicillin VK

500 mg four times per day until pain is con-

trolled (for those concerned about long-term

penicillin problems)

• Rinse three times daily plus an alternative to

penicillin because of allergy or nonrespon-

siveness: doxycycline 100 mg once daily,

levofloxacin 500 mg once daily or erythro-

mycin ethylsuccinate 400 mg three times

daily

Note: metronidazole 500 mg three times daily

in addition to penicillin, doxycycline or levo-

floxacin has been shown to control pain and

infection in cases refractory to any of the anti-

biotics alone, but is recommended for only

10 days on an intermittent basis because of

toxicity

Stage 3b (Stage 3a plus a pathologic fracture)

The clinician may duplicate Stage 3a, but to

choose a more interventional approach: alveo-

lar resection or a continuity resection may be

performed. Titanium reconstruction plates

should not be placed immediately and deferred

until 3 months or when infection is resolved

127

Osteoporosis and osteopenia: implications for periodontal and implant therapy

magnesium, and therapies to improve the balance of

the body, before taking oral bisphosphonates. The

medical histories taken by clinicians should include

questions on lactose intolerance, hormone replace-

ment therapy, hysterectomy (date of), menstrual

history, menopause (at what age and if hormone

replacement therapy was prescribed), medications

that alter the calcium balance (especially corticos-

teroids or chemotherapy), diet and exercise ⁄ balance

histories. If a patient is taking oral bisphosphonates,

they need to be questioned regarding the type of

bisphosphonate, length of time they have been taking

it, compliance and side effects. There are many new

therapies available that may be better alternatives to

fit the individual patient to their individual needs at

that particular time, but current data do support oral

bisphosphonates as being effective in preventing hip

and spine fractures.

The risks for osteonecrosis of the jaw when the

patient is taking oral bisphosphonates have been

reported to be as low as 0.7 ⁄ 100,000 (202) and as

high as 4% (211). However, a new study by Barasch

et al. (19) found that oral bisphosphonates were a

potent risk factor for osteonecrosis of the jaw with

an odds ratio of 12.2 (95% CI: 4.3–35.0).

Currently, there are no clear guidelines to

determine precisely which patients on oral

bisphosphonates are at risk for osteonecrosis (a

variety of guidance documents and Web resources

are indicated in Box 3). There are recommendations

indicating increased risk of osteonecrosis of the jaw

in patients treated with oral bisphosphonates for

Box 2 American Association of Oral and Maxillofacial Surgeons staging and treatment strategies for manage-ment of osteonecrosis of the jaw

BRONJ* Staging Treatment strategies�

At-risk category: No apparent necrotic bone in patients

who have been treated with either oral or intravenous

bisphosphonates

• No treatment indicated

• Patient education

Stage 0: No clinical evidence of necrotic bone, but

nonspecific clinical findings and symptoms

• Systemic management, including the use of pain

medication and antibiotics

Stage 1: Exposed and necrotic bone in patients who are

asymptomatic and have no evidence of infection• Antibacterial mouth rinse

• Clinical follow-up on a quarterly basis

• Patient education and review of indications for

continued bisphosphonate therapy

Stage 2: Exposed and necrotic bone associated with infection

as evidenced by pain and erythema in the region of the ex-

posed bone with or without purulent drainage

• Symptomatic treatment with oral antibiotics

• Oral antibacterial mouth rinse

• Pain control

• Superficial debridement to relieve soft tissue irrita-

tion

Stage 3: Exposed and necrotic bone in patients with pain,

infection and one or more of the following: exposed and

necrotic bone extending beyond the region of alveolar bone

(i.e. inferior border and ramus in the mandible, maxillary

sinus and zygoma in the maxilla) resulting in pathologic

fracture, extra-oral fistula, oral antral ⁄ oral nasal communi-

cation, or osteolysis extending to the inferior border of the

mandible or sinus floor

• Antibacterial mouth rinse

• Antibiotic therapy and pain control

• Surgical debridement ⁄ resection for longer term

palliation of infection and pain

*Exposed bone in the maxillofacial region without resolution in 8–12 weeks in persons treated with a bisphosphonate who have not received radiationtherapy to the jaws.�Regardless of the disease stage, mobile segments of bony sequestrum should be removed without exposing uninvolved bone. The extraction of symp-tomatic teeth within exposed, necrotic bone should be considered because it is unlikely that the extraction will exacerbate the established necrotic process.Discontinuation of the intravenous bisphosphonates shows no short-term benefit. However, if systemic conditions permit, long-term discontinuation maybe beneficial in stabilizing established sites of bisphosphonate-related osteonecrosis of the jaw, reducing the risk of new site development and reducingclinical symptoms. The risks and benefits of continuing bisphosphonate therapy should be made only by the treating oncologist in consultation with theOral Maxillofacial surgeon and the patient. Discontinuation of oral bisphosphonate therapy in patients with bisphosphonate-related osteonecrosis of thejaw has been associated with gradual improvement in clinical disease. Discontinuation of oral bisphosphonates for 6–12 months may result in eitherspontaneous sequestration or resolution following debridement surgery. If systemic conditions permit, modification or cessation of oral bisphosphonatetherapy should be performed in consultation with the treating physician and the patient.

128

Otomo-Corgel

2–3 years or longer with concomitant use of steroids

(138). In one study, patients on oral bisphosphonates

had increased complications and incidence if they

were taking them for longer than 3 years (139). A

recent study indicated risk within 2 years of bis-

phosphonate initiation that increased four-fold after

2 years (19). This study also found that suppuration,

dental extractions, steroid use and head ⁄ neck radi-

ation significantly increased the risk for osteonecrosis

of the jaw. Patients with periodontal disease and

dental abscesses are also at higher risk. Migliorati�sstudy indicated that 84% of patients with osteone-

crosis of the jaw also had periodontal disease

(151). Marx proposed the potential of an indicator of

bone turnover, C-terminal cross-linking telopeptide,

to measure higher risk after 3 years on oral

bisphosphonates; however, the American Dental

Association Report of the Council on Scientific Affairs

concluded �the current screening and diagnostic tests

are unreliable for predicting a patient�s risk of

developing osteonecrosis of the jaw� (63).

Owing to the aforementioned risk factors, the

clinician should work closely with their medical

colleagues before prescribing oral bisphosphonates.

Ideally, optimal periodontal ⁄ dental health state

should be established before the patient com-

mences bisphosphonate therapy. This involves clo-

sely evaluating radiographs, extracting teeth with a

hopeless prognosis, removal of multilocular tori,

appropriate periodontal therapy, root canal therapy

and provision of necessary restorative treatment.

Also, the patient should be informed of the risks

associated with 2–3 years or longer of continuous

oral bisphosphonate therapy. Finally, the treating

physician should be updated regarding the patient�soral status.

If the patient has already been on an oral bis-

phosphonate, there is minimal risk of osteonecrosis

of the jaw if they have been taking the medication

for less than 2–3 years, there are no medical risk

factors and they have no dental problems. One

source has stated that it is safe to proceed with

periodontal and oral surgical procedures as needed

(138). The latter did not, however, differentiate be-

tween length of time of treatment with the oral

bisphosphonates. It has also been recommended

that patients with active periodontitis should receive

�appropriate forms of non-surgical therapy which

should be combined with a prolonged phase of

initial therapy for observation… if the disease does

not resolve, surgical treatment should be aimed

primarily at obtaining access to root surfaces with

modest bone recontouring being considered and

necessary� (63). There are no data on the risk of

osteonecrosis of the jaw with periodontal regenera-

tive therapy. With regard to implants, there is con-

sensus that the recommendations are to obtain

documented consent from the patient after review-

ing the risks, benefits and treatment alternatives.

There are no clear data to guide the clinician

Box 3. Guidance documents andweb resources for clinicians toseek information relating tomanagement of dental patientswho are taking bisphosphonates

• American Academy of Endodontists Position

Statement �Endodontic Implications of

Bisphosphonate-Associated Osteonecrosis of

the Jaws� 2006 http://www.aae.org/dentalpro/

guidelines.htm (10)

• Ruggiero et al. (206), Practical Guidelines for the

Prevention, Diagnosis, and Treatment of

Osteonecrosis of the Jaw in Patients with

Cancer, 2006.

• American Society of Clinical Oncologists (13).

Updated Recommendations for the Prevention,

Diagnosis, and Treatment of Osteonecrosis of

the Jaw in Cancer Patients, 2006.

• Migliorati et al. (151), Managing the care of pa-

tients with bisphosphonate-associated osteone-

crosis. An Academy of Oral Medicine position

paper, 2005.

• American Academy of Periodontology State-

ment on Bisphosphonates http://www.perio.

org/resources-products/bisphosphonates.htm

(11)

• American Dental Association Report of the

Council on Scientific Affairs – Expert Panel

Recommendations: Dental Management of Pa-

tients on Oral Bisphosphonate Therapy, 2008

(63)

• American Association of Oral and Maxillofacial

Surgeons – Position Paper on Bisphosphonate-

Related Osteonecrosis of the Jaws – 2009 Update

(12)

• Canadian Consensus Practice Guidelines for

Bisphosphonate Associated Necrosis of the Jaw,

2008 (102).

• National Institutes of Health Consensus Devel-

opment Panel on Osteoporosis Prevention,

Diagnosis, and Therapy, 2001 (165).

129

Osteoporosis and osteopenia: implications for periodontal and implant therapy

regarding the impact of oral bisphosphonate therapy

on implant placement and occurrence of osteone-

crosis of the jaw. Two recent studies found that oral

bisphosphonate therapy did not alter implant out-

comes and there were no reported cases of osteo-

necrosis of the jaw (82, 133). The American Dental

Association states that the risk for osteonecrosis of

the jaw increases when augmentation of atrophic

ridges or extensive implant placements are per-

formed (63). Patients with implants and receiving

therapy with oral bisphosphonates should be mon-

itored and maintained closely.

If the patient has been taking oral bisphosphonates

for longer than 3 years, the treating physician should

be contacted. The physician needs to be informed of

the patient�s periodontal ⁄ dental status and of the

dental treatment plan. If a surgical procedure is war-

ranted, current American Association of Oral and

Maxillofacial Surgeons recommendations are that the

patient discontinues the oral bisphosphonates for

3 months before the procedure. However, this is

controversial and the American Dental Association,

states �discontinuing bisphosphonate therapy may

not eliminate any risk for developing osteonecrosis of

the jaw� (63). �Drug holidays� have been recommended

following a 10-year alendronate study, indicating that

stopping the medication after 3 years diminished

bone mineral density minimally, had no increase in

fractures, and improved bone remodeling (30). Bio-

chemical markers of bone turnover may be used to

complement measurement of bone mineral density;

however, their clinical utility is limited. Current

markers of bone resorption include serum collagen

type 1 cross-linked telopeptide, cross-linked N-

telopeptides of type I collagen, and pyridinoline

cross-linked carboxy-terminal telopeptide of type I

collagen. There are also biochemical markers of bone

formation, such as specific-alkaline phosphatase,

osteocalcin and procollagen type I N- and C-pro-

peptides (227). Urinary cross-linked N-telopeptides of

type I collagen and serum pyridinoline cross-linked

carboxy-terminal telopeptide of type I collagen cor-

relate with risk for skeletal complications, disease

progression and overall survival. Rosen et al. identi-

fied serum CTX as a marker of bone resorption that

was useful specifically to assess the efficacy of anti-

resorptive treatments (203). Marx recommended that

a test for collagen type 1 cross-linked telopeptide

should be performed at the initial consultation and

immediately before performing a procedure (138).

Therefore, serum collagen type 1 cross-linked

telopeptide might provide the clinician with infor-

mation regarding bone suppression and risk of

osteonecrosis of the jaw (Table 7). His recommenda-

tion is therefore:

• Take a baseline initial serum measurement of

collagen type 1 cross-linked telopeptide.

If it is less than 150 pg ⁄ ml, consult with the

medical doctor.

Recommend to discontinue the oral bisphospho-

nate for 3 months with the consent of the pre-

scribing physician.

If the patient has severe osteoporosis, the physician

may elect to prescribe an alternative drug (see

Table 4).

• Repeat the measurement of serum collagen type 1

cross-linked telopeptide in 3 months.

If the level of serum collagen type 1 cross-linked

telopeptide is ‡150 pg ⁄ ml, it is permissible to

proceed with dental procedures.

• Restart the oral bisphosphonate 3 months after the

procedures.

For each month in which the patient is not taking the

oral bisphosphonate, the collagen type 1 cross-linked

telopeptide value will increase by approximately

25 pg ⁄ ml.

The American Dental Association and others,

however, indicate that the collagen type 1 cross-

linked telopeptide may be of questionable value and

is not based on strong clinical evidence (63, 113).

If a patient has established oral bisphosphonate-

induced osteonecrosis of the jaw, the treating physi-

cian should be contacted. The medication should be

discontinued and it is recommended that the pre-

scribing physician should provide an alternative

medication. There is also an opinion that discon-

tinuing the bisphosphonate should not be recom-

mended once necrosis of the jaws has occurred (122);

however, this was based on four case reports. If the

physician elects to not prescribe a substitute drug,

stringent periodontal maintenance and monitoring is

necessary. Oral bisphosphonate-induced osteone-

crosis of the jaw has been reported to be less exten-

sive and more responsive to discontinuation of the

medication without debridement. Marx states that

Table 7. Laboratory risk assessment for patients takingoral bisphosphonates

Telopeptide CTX

(pg ⁄ ml)

Risk for osteonecrosis

of the jaw

300–600 None

150–299 None or minimal

101–149 Moderate

<100 High

130

Otomo-Corgel

approximately 60% of patients will have recovering

osteoclasts that will resorb bone around the necrotic

area in order to sequestrate it from adjacent viable

bone within 6 months to 1 year. The 40% that do

not sequestrate will require surgical debridement,

including extraction of teeth in necrotic sites with

alveolar resection and primary closure (138). He also

states that the remaining bone should be viable and

restored with nonimplant-supported appliances;

however, if an alternative osteoporosis drug is pre-

scribed, bone augmentation and implants are viable.

It is imperative that dental clinicians treat these

patients in partnership with medical professionals.

Patients need to be aware of the risks vs. benefits of

the procedures. Recently, case reports indicate heal-

ing of osteonecrosis of the jaw after therapy with

teriparatide after other treatments have failed (118,

162). Clinical trials are urgently needed to evaluate

the most effective treatment protocols for patients

with different stages of osteonecrosis of the jaw.

Cases of oral bisphosphonate-induced osteonecro-

sis of the jaw are seldom reported, so it may appear to

be a rare occurrence. A randomized clinical trial may

not have adequate numbers of cases of osteonecrosis

of the jaw or the drug may have been taken for too short

a duration to present adverse effects. A database

should be developed for clinicians to easily report

cases, citing the type of bisphosphonate, duration of

use, compliance, medical history and nature of the

reported osteonecrosis of the jaw. Currently, it is

imperative that clinicians report cases of osteonecrosis

of the jaw to the US Food and Drug Administration at

http://www.fda.gov/MedwWatch/report.htm.

Conclusion

Clinical periodontal and implant therapy in the

osteoporotic ⁄ osteopenic patient provide new chal-

lenges. The numbers of patients with low bone

mineral density and the numbers of patients who are

taking bisphosphonates for long periods of time are

rising dramatically. As the treatment of osteoporosis

evolves, we need to present options to our patients

and to recognize the impact of osteoporosis ⁄ oste-

openia on our clinical therapy. Decisions regarding

periodontal treatment and implant placement in

patients taking bisphosphonates depend on a host of

variables: length of time on the drug, patient age, type

of drug, dosage, dosing (continuous or intermittent),

compliance, oral vs. intravenous delivery, dental ⁄periodontal status and overall systemic health. With

the development of alternative medications to oral

bisphosphonates, we must monitor other potential

oral side effects. We must stay current with medical

technologies that enhance earlier diagnostics to

prevent or treat complications. The clinician needs to

understand the mechanisms of actions of the various

therapies. Periodontal therapy, augmentation and

placement of dental implants are still viable options

for the clinician predicated on best clinical judg-

ment for that individual patient. Preventive care,

especially oral hygiene reinforcement, monitoring

and periodontal maintenance therapy, is of para-

mount importance.

Periodontal professionals can potentially play a

pivotal role in the early detection of osteoporosis via

diagnostic tests (e.g. radiographs), clinical monitor-

ing and continual updating of patient risk. With the

advent of genomic, experimental, mechanistic and

clinical trials we must continually interpret the data

in the context of the healthcare needs of our patients

at a given time. There is no single therapy that is safe

and effective for all people and therefore it is vital

that data from population-based studies do not get

�lost in translation� when applied to individuals (121).

Because osteoporotic patients are at higher risk for

periodontal disease and patients with periodontitis

are at higher risk for osteonecrosis of the jaw, peri-

odontal intervention and disease prevention are

imperative. Close periodontal maintenance, meticu-

lous monitoring, understanding of periodontal and

implant therapy for the individual patient at a given

time and collaboration with medical professionals

will provide patients with the highest level of care.

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