Publication
Article
The American Journal of Managed Care
Medical Management of Osteoporosis
Author(s):
Osteoporosis is a cause of considerable morbidity and mortalityin men and women. Medical intervention can reduce the progressionof osteoporosis and decrease the fracture risk associatedwith low bone mineral density. In this article, we review the evidencefor medical therapies for osteoporosis, including estrogen,calcitonin, bisphosphonates, selective estrogen receptor modulators,and the newest approved agent, recombinant human parathyroidhormone (1-34). We also discuss several controversial areas inosteoporosis treatment, including the management of men withosteoporosis, approach to monitoring the effects of osteoporosistherapy, and need for cost-effective strategies for osteoporosistreatment.
(Am J Manag Care. 2004;10:445-455)
Osteoporosis is a common skeletal disorder withcostly complications. It is characterized by aprogressive decline in bone mass and density,resulting in fragile bones and increased risk of fracture.Ten million Americans have osteoporosis, and an additional18 million have ostopenia.1 Eighty percent ofaffected individuals are postmenopausal women, but 8to 15 million men older than 50 years have osteoporosisor low bone density.2 While women experience aphase of rapid bone loss at menopause, men experiencean exponential increase in the incidence of osteoporosisapproximately 5 to 10 years later.3 The disorder typicallyremains silent until a fracture occurs, most frequentlyat the spine, hip, or distal radius.
Approximately 1.3 million osteoporotic fracturesoccur each year, and this figure is expected to rise withincreasing life expectancy.4 Vertebral fractures are themost common. They can result in pain, reduced mobility,thoracic deformity, and impaired pulmonary function.Among persons who reach 90 years of age, 33% ofwomen and 17% of men will suffer a hip fracture.5 Deathoccurs in 1 of 5 persons within 1 year of hip fracture,and of those who survive, one half will lose the ability tofunction independently and one third will become permanentnursing home residents.1 For unknown reasons,mortality following hip fracture is higher among menthan women, even after adjustment for comorbiditiesrelated to aging.3 The direct expenditures for treatingosteoporotic fractures are estimated at $10 to $15 billionannually.1,3 The true costs of osteoporosis, whichinclude pharmacotherapy to prevent fractures and theindirect expense from lost wages and productivity, arehigher.
The most widely used method for diagnosing osteoporosisis bone mineral density (BMD) measurement.Dual-energy x-ray absorptiometry scanning is the mostappropriate technique for measuring bone density, as ityields precise measurements at clinically importantsites (spine and hip) with minimal radiation exposure.6Peripheral techniques to measure BMD, such as heelultrasound, are useful screening tests to identifypatients at risk for low BMD, but do not replace centraldual-energy x-ray absorptiometry for diagnosis.7
The World Health Organization (WHO) definesosteoporosis as a BMD of at least 2.5 SDs below themean for young adults of the same race and sex (Tscore), and osteopenia as a T score of 1.0 to 2.5 SDsbelow the mean. These diagnostic criteria were determinedfrom the relationship between BMD and fracturerisk in postmenopausal white women.6 The relationshipbetween BMD and fracture risk in men and nonwhitewomen is not well-known. Several organizationshave published guidelines for BMD testing in women(Table 1),7-9 and the WHO and the International Societyfor Clinical Densitometry have made recommendationsfor BMD testing in men (Table 2).10,11 The cost effectivenessof screening increases with age and the numberof clinical risk factors for osteoporosis.12
Once a diagnosis of osteoporosis has been made,remediable secondary causes should be addressedbefore initiating osteoporosis-specific therapies.Secondary causes account for 10% to 30% of cases ofosteoporosis in postmenopausal women (Table 3)7,13and up to two thirds of cases in men. An exhaustivesearch is neither practical nor cost effective, but themost common diseases can be ruled out with reasonablecertainty with a few simple laboratory tests (Table 4).One cross-sectional study14 found that testing for 24-hour urine calcium, serum calcium, and serum parathyroid hormone (PTH) in all women and serum thyrotropinin women receiving thyroid hormone therapy woulddetect most secondary causes of osteoporosis, at anacceptable cost ($75) per patient screened. A moreextensive search should be pursued in patients who areyoung or premenopausal and in patients whose historyor examination indicates an underlying disorder. The Zscore, a reflection of BMD relative to age-matched controls,may be another useful indicator for pursuing secondarycauses of osteoporosis if it is low (less than−2.0 or −3.0).6 If no secondary cause isfound or if low BMD persists, despitetreatment of secondary factors, a diagnosisof primary osteoporosis is made.
Who should be offered treatmentfor osteoporosis? As with BMD testing,several organizations have proposedguidelines (Table 5) about who maybenefit from pharmacologic intervention.8-10 Formal guidelines for men arenot available. Treatment is recommendedfor all women with vertebralfractures or a T score less than 2.5 SDsbelow the mean, because they are atsignificant risk for future fractures.6Because there is a continuous increasein fracture risk with declining BMD, nosingle T score is considered thethreshold for initiating therapy.Instead, recommendations for therapyshould be based on BMD and otherrisk factors for fracture, such as lowbody weight, tobacco use, or familyhistory of fracture.
This article will discuss theapproach to managing patients withprimary osteoporosis. A review ofosteoporosis therapy is timely becauseof the declining use of hormone therapy (HT) and theintroduction of several new pharmacologic treatments.
NONPHARMACOLOGIC THERAPY
Nondrug therapy for osteoporosis consists of calciumand vitamin D, exercise, and smoking cessation. Thesecomponents have been examined primarily as preventivemeasures for BMD loss and fracture occurrence.Several randomized controlled trials (RCTs) suggest apositive effect of calcium and vitamin D on BMD andfracture risk, and adequate intake of both should beemphasized as cornerstones of effective osteoporosistherapy.15-19
Recommendations for adults older than 50 years areto consume at least 1200 mg/d of calcium, ideallythrough calcium-rich foods.7,20 Calcium supplementsshould be prescribed if needed to achieve recommendeddaily levels. The least expensive preparation is calciumcarbonate. Adverse effects, such as intestinal gas andconstipation, are minimized by taking calcium withfood. Calcium citrate causes less frequent gastrointestinaladverse effects and may be better absorbed.7 VitaminD is less widely available in the diet than calcium, andsupplements may be necessary to provide the recommended level of 400 to 600 IU/d for all adults older than50 years. Those at high risk for vitamin D deficiency,such as older persons, the chronically ill, or those whoare housebound, should receive 800 IU/d through foodor supplements.7,20 A simple method for calculating thecalcium and vitamin D content of foods is availableonline through the National Osteoporosis Foundation.20Adequate protein intake may also be important for bonehealth, based on a study21 of 82 older women withrecent hip fracture assigned to a protein supplement orplacebo. All women received calcium and vitamin D,but the protein supplement group had less BMD loss at12 months (−2.3% vs −4.7%) and shorter rehabilitationstays (33 vs 54 days).
Weight-bearing exercise has been associated withan improvement in BMD and a reduction in hip fracturerisk in postmenopausal women.22,23 A prospectivecohort study24 of more than 61 000 postmenopausalwomen found a 41% lower risk of hip fracture in womenwho walked at least 4 h/wk compared with those whowalked 1 h/wk or less. The increase in BMD in thisstudy was small, and some of the decline in fractureincidence may have resulted from improved musclestrength and fewer falls. High-intensity exercise has notbeen shown to yield greater benefits than low-intensityexercise25; therefore, postmenopausal women areencouraged to engage in regular weight-bearing exercise(such as walking or jogging) for 1 hour at least 4times a week.7,20
Smoking accelerates bone loss, in part due toincreased metabolism of estrogen. Moreover, cigarettesmokers tend to be thinner and undergo earlier menopause.7 A cross-sectional study26 of female twins whowere discordant for tobacco use found that smoking 1pack of cigarettes per day throughout adulthood wasassociated with a 5% to 10% lower BMD. Other studies27,28have demonstrated an association between cigarettesmoking and a decreased BMD response to HTin postmenopausal women. Consequently, smokingcessation is recommended to protect and maintainbone health.
PHARMACOLOGIC THERAPY
Most available drugs for treatment of osteoporosis areantiresorptive. They alter the balance of bone remodelingby inhibiting bone breakdown to a greater extentthan bone formation, thereby preventing a decline inBMD and decreasing fracture risk. Recently, a syntheticform of PTH became the first anabolic, or bone formation,agent to be approved for osteoporosis treatment.This section will discuss agents approved by the Foodand Drug Administration (FDA) for the treatment ofosteoporosis and the role of phytoestrogens and investigationalagents.
Estrogen
Estrogen reduces bone turnover by inhibiting osteoclastrecruitment and activity. Hormone therapy withestrogen has been on the market since 1942 for thetreatment of menopausal symptoms. It was approvedfor the prevention of postmenopausal osteoporosismore than 50 years later based on large observationalstudies29,30 that found an association between postmenopausalestrogen use, increased BMD, anddecreased nonvertebral fracture rates. A subsequentsmall RCT of transdermal estrogen in postmenopausalwomen demonstrated a reduced risk of vertebral fractures(relative risk, 0.39; 95% confidence interval,0.16-0.95).31 The prospective Postmenopausal Estrogen/Progestin Interventions (PEPI)32 trial establishedthat the addition of progesterone to HT did not alter theBMD effects of estrogen.
The Women's Health Initiative (WHI) was the firstlarge RCT to confirm the positive effect of HT on bonehealth. In 2002, data were reported from the first WHIstudy,33 a primary prevention trial of 16 608 postmenopausalwomen randomized to placebo vs estrogenplus progestin therapy. The primary outcome was coronaryheart disease, with fractures as a secondary outcome.Hormone therapy was found to reduce the risk ofvertebral, hip, and other osteoporotic fractures by 33%,33%, and 23%, respectively. However, the trial wasstopped 3.3 years early because of an increased risk inbreast cancer (hazard ratio, 1.26) and an excess incidenceof coronary disease (hazard ratio, 1.29) in theestrogen and progestin group. These adverse outcomeshad been demonstrated previously in a secondary preventiontrial of postmenopausal women with establishedcoronary disease treated with estrogen and progestin.34A parallel WHI trial, investigating the effect of estrogenalone in postmenopausal women, was concluded inMarch 2004, and the final results are pending.33
The adverse outcomes in the WHI prompted FDArequirements to relabel all estrogen-containing productsfor postmenopausal women with new safety information.While HT is effective in preventing osteoporosis andreducing fracture risk, it can no longer be recommendedas a first-line therapy. Hormone therapy should be limitedto women with persistent menopausal symptoms orwomen who are intolerant of other agents for osteoporosistreatment.
Calcitonin
Calcitonin is produced by the C cells of the thyroidgland, and it slows bone loss by inhibiting osteoclastformation and attachment. Injectable salmon calcitoninwas approved for therapy of osteoporosis in 1984,but was not widely used because of discomfort of subcutaneousinjections, high cost, and limited tolerance.35 In 1995, the FDA approved salmon calcitoninnasal spray based on data showing consistent modestincreases in BMD and several small studies showingfracture reduction at the spine and hip.36-38
The 5-year, multicenter Prevent Recurrence ofOsteoporotic Fractures39 study was the first large-scaleRCT to demonstrate reduced risk of new fractures withcalcitonin nasal spray in postmenopausal women withosteoporosis. A 33% risk reduction in vertebral fractureswas noted with 200 IU/d of calcitonin compared withplacebo. However, several aspects of the study have beencriticized, including the fact that investigators were notblinded to BMD results, 26% of participants did not meetentry criteria in retrospect, and 59% of women droppedout. These limitations have led some to question thefracture reduction results.39,40 Large-scale studies toassess the effect of intranasal calcitonin on hip fracturesor other nonvertebral fractures have not been conducted.
A possible benefit of nasal calcitonin is an analgesiceffect in acute vertebral fractures. In one study,41 56osteoporotic women with atraumatic vertebral fractureswere randomized to 100 IU/d of intramuscular salmoncalcitonin or placebo for 2 weeks. The mean pain scoresand analgesic consumption in the calcitonin group weresignificantly lower than in the placebo group by thefourth day. Similar analgesic effects were found in smalltrials using intranasal calcitonin and calcitonin suppositories.42,43 Adverse effects of calcitonin are greater withparenteral preparations, which cause flushing and nauseain up to 20% of subjects. Gastrointestinal adverseeffects are rarely seen with nasal spray, but nasal discomfort,rhinitis, and epistaxis can occur.7
Because of calcitonin's frequent adverse effects, highcost (≥$50/d),35 and inconclusive fracture data, it is nota first-line treatment of osteoporosis. It is an attractiveoption for patients with back pain associated withacute vertebral fracture, and its main use is in this clinicalsetting.
Bisphosphonates
Bisphosphonates inhibit osteoclast activity and promoteosteoclast death, thereby reducing bone resorption.44 Alendronate sodium was approved for treatmentof postmenopausal osteoporosis in 1995 based on datademonstrating a positive effect on BMD and a reductionin fracture risk.45 Risedronate sodium was approved forosteoporosis treatment in 2000.
Three major placebo-controlled trials have investigatedthe effects of alendronate on BMD and fracture risk.Liberman et al45 noted increased BMD in alendronatetreatedpatients at 1 year (4.9% at the spine and 2.4% atthe hip) and at 3 years (6.2%-8.8% at the spine and 4.1%-5.9% at the hip) compared with placebo. New vertebralfractures were decreased by 45% to 48% at 3 years. TheFracture Intervention Trial,46 which enrolled 2027 postmenopausalwomen with osteoporosis and baseline vertebralfractures, found a 55% reduction in clinicalvertebral fractures, 51% reduction in hip fractures, and28% reduction in any clinical fracture at 3 years comparedwith placebo. Another arm of the FractureIntervention Trial,47 which studied 4432 postmenopausalwomen with low BMD but no preexisting vertebral fractures,showed a 44% reduction in radiographic vertebralfractures at 4 years. Women with femoral neck T scoresof −2.5 or less had a 56% reduction in hip fractures and a36% reduction in all clinical fractures. A third study48assessed the efficacy of alendronate vs placebo on BMD in1908 postmenopausal women with low BMD of the lumbarspine. A 4.9 % increase in lumbar spine BMD and a3% increase in total hip BMD were noted at 1 year.Clinical nonvertebral fractures, captured as adverseevents, were reduced by 47% in the alendronate group.
Risedronate has been studied in 2 large RCTs, eachspanning 3 years. The Vertebral Efficacy With RisedronateTherapy49 trial enrolled 2458 postmenopausalwomen from 2 sites with baseline vertebral fractures.With risedronate, investigators found a 61% to 65% reductionin new vertebral fractures at 1 year and a 41% to 49%reduction at 3 years, compared with placebo. Nonvertebralfractures, a secondary outcome, were reducedby 39% at 3 years. McClung et al50 subsequently investigatedthe effect of risedronate on hip fracture reductionin a randomized trial of more than 9000 postmenopausalwomen. They showed a 30% risk reduction in hip fractureswith risedronate, and a 40% to 60% risk reduction insubsets of women with osteoporosis or osteoporosis plusvertebral fractures. No reduction was demonstrated inolder women with risk factors alone. Taken together, the2 trials demonstrate that risedronate decreases the risk ofvertebral and hip fractures in postmenopausal womenwith confirmed osteoporosis or previous fractures, butnot in women with risk factors for fracture alone.
The main adverse effects of the oral bisphosphonatesare gastrointestinal, specifically esophageal irritation.Tolerability is affected by adherence to dosing instructions(ie, taking the medicine on an empty stomachwith a large glass of water and remaining upright for 30minutes after the dose). Alendronate and risedronateare likely to be well tolerated if taken according to theseguidelines.51 The regimen can be challenging forpatients on a daily basis; therefore, once-weekly therapyis now recommended.
Schnitzer et al52 compared the efficacy and safety ofonce-weekly (70 mg), twice-weekly (35 mg), and daily(10 mg) alendronate in 1258 women with postmenopausalosteoporosis. The primary end point, anincrease in spine BMD, did not differ among the 3groups (5.1%, 5.2%, and 5.4%, respectively). Secondaryend points of hip BMD and bone turnover, as assessedby biochemical markers, also were similar for each regimen.Fewer serious upper gastrointestinal adverseevents occurred with once-weekly dosing, and a trendtoward fewer esophageal events was noted. The FDAsubsequently approved once-weekly alendronate forprevention (35 mg/wk) and treatment (70 mg/wk) ofosteoporosis.35 In 2002, weekly risedronate (35 mg/wk)was approved for the treatment of osteoporosis based ondata supporting its efficacy.53,54
For patients who cannot tolerate oral bisphosphonates,intravenous preparations are available, including zoledronicacid and pamidronate disodium. Use of these medicationsfor postmenopausal osteoporosis is off-label, as theyare FDA-approved for use in hypercalcemia of malignancyand bone metastases.55 In a recent study,56 zoledronicacid infusions given to postmenopausal women with lowBMD at intervals of up to 1 year increased BMD at thespine and hip, and the magnitude of change was similarto that seen in trials of oral bisphosphonates. The shortduration of the study did not allow fracture incidence tobe examined as a primary or secondary outcome. Giventhe minor, infrequent adverse effects (myalgia andpyrexia) in this study,56 zoledronic acid could be anattractive option if fracture efficacy is confirmed.
Bisphosphonates have been extensively studied forthe treatment of postmenopausal osteoporosis. The 2FDA-approved agents, alendronate and risedronate,increase BMD and decrease the risk of vertebral andnonvertebral fractures in large RCTs. No trial has directlycompared the efficacy of alendronate and risedronate,but data indicate that they are comparable with regardto fracture reduction.44 Because of their proven efficacyin reducing fractures at multiple sites and their safetyprofile, alendronate and risedronate should be consideredfirst-line agents for treatment of osteoporosis.
Selective Estrogen Receptor Modulators
Raloxifene hydrochloride is a mixed estrogen receptoragonist-antagonist and the first selective estrogenreceptor modulator to be approved for treatment of post-menopausal osteoporosis. It acts as an agonist in bone,reducing turnover by inhibiting osteoclast recruitmentand activity, and as an antagonist in the breast anduterus. It was approved in 1997 for the prevention ofosteoporosis in recently menopausal women, and in1999 for the treatment of postmenopausal osteoporosis.
A meta-analysis57 of 7 trials of raloxifene vs placeboconcluded that raloxifene increased BMD and decreasedvertebral fractures in postmenopausal women. The positiveeffects on BMD, which occurred at the spine andhip, increased during 2 years. The Multiple Outcomes ofRaloxifene Evaluation58 trial was the largest of the raloxifenetrials. It studied the effects of placebo vs 60 mg or120 mg of raloxifene given daily to 7705 postmenopausalwomen with osteoporosis. At 3 years,both dosages of raloxifene increased spine and hipBMD by 2% to 3% and decreased the risk of new vertebralfractures by 30% to 50%, compared with placebo.There was no difference in nonvertebral fractures.Adverse effects of raloxifene include exacerbation ofhot flushes and a 3-fold increase in the risk of venousthromboembolism.57
There are limited data comparing raloxifene withother treatments for postmenopausal osteoporosis. Twostudies59,60 have shown that estrogen and alendronateproduce a greater increase in BMD compared withraloxifene. No studies have evaluated fracture riskreduction with raloxifene vs other antiresorptive agents.
Because raloxifene increases BMD and reduces therisk of vertebral fractures, although to a lesser degreethan the bisphosphonates, it is a valuable second-lineagent for the treatment of postmenopausal osteoporosis.In addition, raloxifene has been associated with favorablechanges in lipids and with a potential decrease inthe risk of cardiovascular events and breast cancer.61Large trials are under way to investigate these possibleextraskeletal effects.62,63
Parathyroid Hormone
Produced by the parathyroid glands, PTH normallyhelps control calcium exchange between the bones andthe bloodstream. Although continuous exposure to highlevels of PTH elicits a catabolic response and a decreasein BMD, as seen in primary hyperparathyroidism, intermittentlow-dose synthetic human PTH causes an anabolicresponse, increasing the number and action ofosteoblasts.64 A synthetic form of PTH containing itsbiologically active portion (recombinant human PTH[rhPTH] 1-34) was approved in 2002 for the treatmentof osteoporosis in postmenopausal women and men athigh risk for fracture.
In the first large RCT of rhPTH (1-34), Neer et al65enrolled 1637 postmenopausal women with prior vertebralfractures and randomized them to once daily injectionsof 20 μg, 40 μg, or placebo. Compared with placebo,the treatment groups had greater increases in spineand femoral neck BMD at 2 years, and they had a significantreduction in the risk of vertebral (65%-69%) andnonvertebral (53%-54%) fracture.
P
A subsequent study66 of 146 postmenopausal womenwith osteoporosis compared 40 μg/d of rhPTH (1-34)with 10 mg/d of alendronate and showed a greaterincrease in spine and hip BMD in the PTH-treatedgroup. Nonvertebral fractures, a secondary end point,occurred in 4.1% of PTH-treated patients and in 13.7%of alendronate-treated patients ( = .042).
Adverse effects of rhPTH include nausea, headache,and leg cramps. Transient mild asymptomatic hypercalcemiaoccurred following rhPTH injections in both studies.65,66 A more serious concern is the potentialincreased risk of osteosarcoma with rhPTH. Although nocases have occurred in humans, several cases havedeveloped in rats treated with high, nearly lifetime dosesof rhPTH.65 Based on this finding, a "black-box" warningis included in the package insert of teriparatide, thecommercially available form of rhPTH (1-34). Teriparatideis contraindicated in patients at high risk of osteosarcoma,namely pediatric populations, young adultswith open epiphysis, and patients with Paget disease. Itshould not be administered to individuals with bonemetastases, metabolic bone diseases besides osteoporosis,hypercalcemia, or a history of skeletal malignancy.67
In summary, rhPTH produces an impressive increasein BMD and decline in fracture incidence. However, itrequires a daily injection, is expensive (estimated at$20/d), and may be associated with bone malignancy. Itis indicated for postmenopausal women and men withosteoporosis who are at high risk for fracture, such asindividuals with prior osteoporotic fractures.
Phytoestrogens
Phytoestrogens are plant compounds with propertiessimilar to those of estrogens. They are available in theUnited States as dietary supplements and have beenpromoted by manufacturers for climacteric complaints,primarily hot flushes.68 A positive effect on bone healthhas been postulated based on the lower incidence ofosteoporosis-related fractures in Asian countries, wherephytoestrogens are routinely consumed.69 In a review ofavailable prospective trials, Tham et al70 concluded thatipriflavone, an isoflavone-derived phytoestrogen, preventedbone loss. However, an RCT of the same agentdid not confirm this finding in 474 postmenopausalwomen.71 Concerns also exist about uterine and mammarycell hyperproliferation.68 Given the absence offracture data, conflicting BMD data, and questionablesafety of phytoestrogens, they should not be recommendedfor treatment of postmenopausal osteoporosis.
Investigational Agents
Investigational agents for the treatment of osteoporosisinclude androgens, growth factors, and 3-hydroxy-3-methylglutaryl coenzyme A reductaseinhibitors (statins). Androgens have been proposed forwomen with osteoporosis based on the fact that menattain higher BMD at skeletal maturity than women.However, trials of combined androgen and estrogentherapy vs estrogen alone have yielded conflicting BMDresults.72,73 The benefits of androgen therapy requiresubstantiation, and the adverse effects of androgens onlipids may outweigh any benefits.
Growth hormone (GH) and insulin-like growth factorI have been studied as treatments for osteoporosis.Growth hormone increases BMD in GH-deficient individuals,74 but trials of GH administration to osteoporoticwomen with normal GH levels have yieldedconflicting results.75-77 Similarly, low insulin-likegrowth factor I levels were associated with low BMD in425 older women in the Framingham Heart Study,78but administration of insulin-like growth factor I topostmenopausal women for 1 year failed to increaseBMD.79 Growth factors are appropriate only for replacementin deficient individuals.
Several observational studies80-82 suggest that statinsincrease BMD and decrease fracture risk. Small trialshave reported reductions in fracture incidence of up to60% with statin use. These positive findings, if confirmedin large prospective studies, would be notable,given statins' moderate cost, ease of administration,infrequent adverse effects, and powerful effect on cardiovascularhealth.
OSTEOPOROSIS IN MEN
The diagnosis of osteoporosis in men is challenging.The WHO definition for osteoporosis (2.5 SDs belowthe mean for young adults of the same race and sex) isbased on data in postmenopausal women, in whom therelationship between T score and fracture risk is continuousand exponential. This T score threshold identifies30% of postmenopausal women as osteoporotic. Inmen, however, a T score of −2.5 or less may not be asmeaningful, because fracture risk in men is not well-known.83 While some studies have found a similar relationshipbetween fracture risk and BMD in men andwomen, other studies have found that men fracture ata higher absolute BMD than women.84-87 Therefore, theuse of a male or female database to derive T scores inmen remains controversial. Current practice in theUnited States is to use a male database to derive Tscores, ie, comparing with average young men.3
Men diagnosed with osteoporosis should undergo anexpanded investigation for secondary causes, becauseup to two thirds of cases will be associated with apotentially treatable condition. Hypogonadism, corticosteroiduse, and alcoholism are common in men withlow BMD.3 Recommendations for pharmacologic therapyfor men with osteoporosis are less straightforwardthan for women, as men have been studied in fewerclinical trials, with smaller sample sizes, and data onfracture reduction are sparse.
General recommendations for calcium and vitamin Dintake in all adults (see the "NonpharmacologicTherapy" section) should be followed. Vitamin D supplementationfor men is supported by epidemiologic surveys,which indicate a 5% prevalence of vitamin Ddeficiency in men older than 50 years and lower vitaminD levels in men hospitalized for fractures.88-90 Studies20,91of men in nursing homes and community-dwelling oldermen have demonstrated that vitamin D supplementsincrease BMD and decrease appendicular fractures.
Alendronate and rhPTH (1-34) are approved to treatmen with osteoporosis. Randomized clinical trials ofbisphosphonate therapy in osteoporotic men havedemonstrated increased spine and hip BMD andreduced vertebral fracture incidence.92,93 Daily rhPTHinjections have increased spine BMD, and to a lesserextent hip BMD, in men with osteoporosis.94,95Although fracture efficacy data are not available,extrapolation to studies of postmenopausal women suggeststhat rhPTH is a potent anabolic modality in menand women.
While hypogonadal men with osteoporosis experiencesignificant and consistent increases in spineBMD with androgen replacement,96 eugonadal menwith primary osteoporosis have not been proven tobenefit from androgen therapy. Studies97-99 of eugonadalmen have been small and at best have demonstrateda modest effect on spine BMD and markers ofbone turnover. The absence of supportive data, togetherwith the potential adverse effects of androgenson cardiovascular and prostate health, arguesagainst their use in male osteoporosis except instates of androgen deficiency, in which physiologicdoses of testosterone or a synthetic anabolic steroidshould be given.
MONITORING THERAPY
Changes in BMD typically are used to determine apatient's response to therapy. Because increases inBMD correlate with a reduction in fracture risk in mosttrials of antiresorptive agents, follow-up in patients withBMD is appropriate.100 Several caveats must be kept inmind, however.
First, not all studies support this correlation, and ameta-analysis of 12 trials concluded that increases inBMD account for only a small, albeit predictable, partof the fracture risk.101 Second, because mean measurementprecision errors are 1% at the spine and 1.5% atthe hip, BMD changes must exceed 3% in the spine or4.5% in the hip to be significant. This degree of changerequires at least 12 months, the minimum time thatshould elapse between measurements to detect a meaningfulchange in BMD.100 The National OsteoporosisFoundation20 recommends repeat dual-energy x-rayabsorptiometry scans for monitoring the response totherapy every 1 or 2 years. Two years is consistent withguidelines from the Centers for Medicare & MedicaidServices. Third, the loss of BMD or the absence of gainin BMD at 1 site may not be indicative of treatment failure.Bone mineral density might have declined furtherwithout treatment; therefore, therapy may decrease apatient's risk of fracture without an apparent increasein BMD.6
Markers of bone turnover, which include urinary andserum by-products of collagen breakdown, have beenused as indicators of antiresorptive effect in some trials.35,55 Some experts have advocated their use inassessing early response to therapy, as they can changeby 40% to 60% after only 3 months, and these changesare predictive of BMD increases at 1 to 2 years.100In this context, bone turnover markers could provideearly feedback about the efficacy of treatment,reassure patients about the effects of therapy, orenhance patient compliance. However, considerablevariability exists in the values of bone turnovermarkers within individuals, with a precision errorgreater than 20%, and large changes are required toindicate a treatment effect. Therefore, while theuse of markers of bone turnover in population studiesis accepted, their role in individual patient monitoringis not well defined.20
FUTURE DIRECTIONS
Many questions face clinicians and healthcareadministrators regarding the treatment of osteoporosis.Once a patient starts a medication forosteoporosis, how long should he or she continueit? Is combination therapy superior tomonotherapy, and if so, which medicationsshould be combined? What are the most cost-effectivestrategies for treating osteoporosis and preventingfractures?
No guidelines exist regarding optimal duration oftherapy. Most RCTs of antiresorptive treatments havefollowed up subjects for up to 3 years, with a few studiesextending follow-up to 5 years. The exception isalendronate, for which 10-year follow-up data exist.Emkey and colleagues102 reported the results of 247postmenopausal women with osteoporosis who wererandomized to alendronate or placebo and studied for 8to 10 years. There was a 10-year increase in spine BMD(9.8%-13.7%) and a decrease in the incidence of nonvertebralfractures in the treatment groups comparedwith placebo. These data support the idea that longeruse of antiresorptives continues to prevent bone lossand fractures, although the persistence and magnitudeof this effect should be reproduced with alendronateand confirmed with other agents.
The use of combination therapy is also controversial.Although studies103-105 have demonstrated greaterincreases in BMD with dual therapy compared withmonotherapy, fracture efficacy has not been studied as aprimary end point. Moreover, most studies of combinationtherapy have included estrogen. Only one prospectivetrial has evaluated a non—estrogen-containingregimen, and it showed a greater increase in spine andhip BMD in patients treated with a combination of alendronateand raloxifene compared with each agent alone,but, again, fracture data were not generated.106 Finally,although no evidence in humans exists, some have worried that combination therapy could reduce boneturnover to levels that adversely affect skeletal mineralization,paradoxically increasing the propensity to fracture.107 Future investigation of other anabolic agents incombination with antiresorptive agents may hold moreappeal than treatment with 2 antiresorptive drugs.35,107
Cost-effective strategies for treating osteoporosis arenot well established. The decision to initiate treatmentis complex, and the ultimate goal must be to preventfractures. Several analyses suggest that the cost oftreating postmenopausal women with low BMD withantiresorptive therapy (compared with no treatment) iswithin accepted thresholds for cost effectiveness, andthe cost effectiveness increases further when high-riskgroups are targeted.12,108-111 However, comparisons ofantiresorptive therapies are needed, specifically of nonestrogenregimens. Factors besides BMD may be moreimportant in predicting the risk of fracture than BMD.For example, conditions that predispose to falls may bemore important in predicting hip fracture than BMD,because more than 90% of hip fractures result from fallsonto the greater trochanter.112 Strategies to identifyand modify non-BMD risk factors for fracture may beappropriate for widespread implementation by organizationsserving diverse populations.
CONCLUSIONS
Primary osteoporosis can be treated with appropriatemanagement. Adequate calcium and vitamin Dintake is fundamental to therapy, and supplementsshould be prescribed if requirements are not metthrough the diet. Weight-bearing exercise and smokingcessation are important lifestyle measures for bonehealth.
The list of drugs approved for the treatment of osteoporosisis growing (Table 6).20 Bisphosphonates shouldbe considered first-line agents, given their efficacy invertebral and hip fracture reduction and low incidenceof adverse effects. Raloxifene is a second-line option, asit has been studied less extensively than the bisphosphonatesand has not been shown to reduce hip fracturerisk. It is effective in reducing the risk of vertebralfractures and is being studied for potential extraskeletalbenefits in women at high risk for breast cancer orheart disease. Recombinant PTH is the first approvedanabolic agent and is a promising drug for men andwomen with prior fractures or disease that has progressed,despite other therapies. Given its cost, inconvenientadministration, and limited safety data, rhPTHshould be reserved for the subgroup of patients at highestrisk for fracture. Calcitonin and estrogen are bestlimited to acute vertebral fractures and severe postmenopausalsymptoms, respectively. Estrogen hasbeen shown to reduce fracture risk in the lowest-riskgroup of women studied to date, so it may preventosteoporosis and reduce fractures in women whochoose to use it.33
Monitoring progress in patients receiving drug therapyfor osteoporosis should include serial BMD measurementsat the hip and spine at intervals of 2 years.Future research may provide a more evidence-basedapproach for monitoring response to treatment, includingthe role of biochemical markers of bone turnover,and elucidate the optimal duration of therapy, use ofmultiple agents, and most cost-effective strategies totreat osteoporosis. The prevalence of osteoporosis andthe attendant morbidity, mortality, and cost compel usto identify men and women with osteoporosis and totreat those at highest risk before a fracture occurs.
From the Department of Medicine (DK) and Division of Endocrinology, Diabetes, andMetabolism (SAF), University of Pennsylvania, Philadelphia.
Address correspondence to: Stephanie A. Fish, MD, Division of Endocrinology,Diabetes, and Metabolism, University of Pennsylvania, One Maloney, 3400 Spruce Street,Philadelphia, PA 19104. E-mail: safish@mail.med.upenn.edu.
JAMA.
1. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis,and Therapy. Osteoporosis prevention, diagnosis, and therapy. 2001;285:785-795.
J Bone Miner Res
2. Looker AC, Orwoll ES, Johnston Jr CC, et al. Prevalence of low femoral bonedensity in older US adults from NHANES III. . 1997;12:1761-1768.
WMJ
3. Binkley N, Krueger D. Osteoporosis in men. . 2002;101:28-32.
J Bone Miner Res
4. Ray NF, Chan JK, Thamer M, et al. Medical expenditures for the treatment ofosteoporotic fractures in the United States in 1995: report from the NationalOsteoporosis Foundation. . 1997;12:24-35.
J Bone Miner Res
5. Melton LJ, Chrischilles EA, Cooper C, et al. Perspective: how many womenhave osteoporosis? . 1992;7:1005-1010.
JAMA.
6. Cummings SR, Bates D, Black DM. Clinical use of bone densitometry: scientificreview. 2002;288:1889-1897.
Endocr Pract
7. Osteoporosis Task Force. American Association of Clinical Endocrinologists2001 medical guidelines for clinical practice for the prevention and managementof postmenopausal osteoporosis. . 2001;7:293-312.
Physician's Guide to Prevention and Treatmentof Osteoporosis
8. National Osteoporosis Foundation. . Washington, DC: National Osteoporosis Foundation; 2003.
Ann Intern Med
9. US Preventive Services Task Force. Screening for osteoporosis in postmenopausalwomen: recommendations and rationale. . 2002;137:526-528.
Osteoporos Int
10. Genant HK, Cooper C, Poor G, et al. Interim report and recommendations ofthe World Health Organization Task-Force for Osteoporosis. .1999;10:259-264.
J Clin Densitom
11. Binkley N, Schemeer P, Wasnich R, et al. What are the criteria by which adensitometric diagnosis of osteoporosis can be made in males and non-Caucasians? . 2002;5(suppl):S19-S27.
Osteoporos Int
12. Ankjaer-Jensen A, Johnell O. Prevention of osteoporosis: cost-effectiveness ofdifferent pharmaceutical treatments. . 1996;6:265-275.
Mayo Clin Proc
13. Fitzpatrick LA. Secondary causes of osteoporosis. . 2002;77:453-468.
J ClinEndocrinol Metab
14. Tannenbaum C, Clark J, Schwartzman K, et al. Yield of laboratory testing toidentify secondary contributors to osteoporosis in otherwise healthy women. . 2002;87:4431-4437.
N Engl J Med.
15. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to preventhip fractures in the elderly women. 1992;327:1637-1642.
BMJ
16. Chapuy MC, Arlot ME, Delmas PD, et al. Effect of calcium and cholecaldiferaltreatment for 3 years on hip fractures in elderly women. . 1994;308:1081-1082.
Am J Med
17. Reid IR, Ames RW, Evans MC, et al. Long-term effects of calcium supplementationon bone loss and fractures in postmenopausal women: a randomized controlledtrial. . 1995;98:331-335.
J Bone Miner Res
18. Recker RR, Hinders S, Davies KM, et al. Correcting calcium nutritional deficiencyprevents spine fractures in elderly women. . 1996;11:1961-1966.
N Engl J Med
19. Dawson-Hughes B, Harris SS, Krall EA, et al. Effect of calcium and vitamin Dsupplementation on bone density in men and women 65 years of age or older.. 1997;337:670-676.
20. National Osteoporosis Foundation. Physician's Guide to Prevention andTreatment of Osteoporosis. Available at: http://www.nof.org/physguide. AccessedAugust 29, 2003.
Ann Intern Med
21. Schurch MA, Rizzoli R, Slosman D, et al. Protein supplements increase seruminsulin-like growth factor–I levels and attenuate proximal femur bone loss inpatients with recent hip fracture: a randomized, double-blind, placebo-controlledtrial. . 1998;128:801-809.
Ann Intern Med
22. Gregg EW, Cauley JA, Seeley DG, et al. Physical activity and osteoporoticfracture risk in older women. . 1998;129:81-88.
Cochrane Database Syst Rev
23. Bonaiuti D, Shea, B, Iovine, R, et al. Exercise for preventing and treating osteoporosisin postmenopausal women. . 2002;3:CD000333.
JAMA.
24. Feskanich D, Willett W, Colditz G. Walking and leisure-time activity and riskof hip fracture in postmenopausal women. 2002;288:2300-2306.
JAMA.
25. Nelson ME, Fiatarone MA, Morganti CM, et al. Effects of high-intensitystrength training on multiple risk factors of osteoporotic fractures. 1994;272:1909-1914.
N Engl J Med.
26. Hopper JL, Seeman E. The bone density of female twins discordant for tobaccouse. 1994;330:387-392.
Ann Intern Med
27. Kiel DP, Baron JA, Anderson JJ, et al. Smoking eliminates the protective effectof oral estrogens on the risk for hip fracture among women. .1992;116:716-721.
Osteoporos Int
28. Komulainen M, Kroger H, Tuppurainen MT, et al. Identification of early postmenopausalwomen with no bone response to HRT: results of a 5-year clinicaltrial. . 2000;11:211-218.
N Engl J Med.
29. Grodstein F, Stampfer MJ, Colditz GA. Postmenopausal hormone therapy andmortality. 1997;336:1769-1775.
AnnIntern Med
30. Cauley JA, Seeley DG, Ensrud K, et al, Study of Osteoporotic FracturesResearch Group. Estrogen replacement therapy and fractures in older women. . 1995;122:9-16.
Ann Intern Med
31. Lufkin EG, Wahner HW, O'Fallon WM, et al. Treatment of postmenopausalosteoporosis with transdermal estrogen. . 1992;117:1-9.
JAMA.
32. Writing Group for the PEPI Trial. Effects of hormone therapy on bone mineraldensity: results from the Postmenopausal Estrogen/Progestin Interventions (PEPI)trial. 1996;276:1389-1396.
JAMA.
33. Rossouw JE, Anderson GL, Prentice RL, Writing Group for the Women'sHealth Initiative Investigators. Risks and benefits of estrogen plus progestin inhealthy postmenopausal women: principal results from the Women's HealthInitiative randomized controlled trial. 2002;288:321-333.
JAMA
34. Hulley S, Grady D, Bush T, et al, Heart and Estrogen/Progestin ReplacementStudy (HERS) Research Group. Randomized trial of estrogen plus progestin for secondaryprevention of coronary heart disease in postmenopausal women. .1998;280:605-613.
Obstet Gynecol Surv
35. Watts NB. Focus on primary care postmenopausal osteoporosis: an update.. 2000;55:S49-S55.
BMJ
36. Overgaard K, Hansen MA, Jensen SB, et al. Effect of salcatonin givenintranasally on bone mass and fracture rates in established osteoporosis: a dose-responsestudy. . 1992;305:556-561.
Eur J Clin Invest
37. Reginster JY, Meurmans L, Deroisy R, et al. A 5-year controlled randomizedstudy of prevention of postmenopausal trabecular bone loss with nasal salmon calcitoninand calcium. . 1994;24:565-569.
Calcif Tissue Int
38. Rico H, Revilla M, Hernandez ER, et al. Total and regional bone mineral contentand fracture rate in postmenopausal osteoporosis treated with salmon calcitonin:a prospective study. . 1995;56:181-185.
Am J Med
39. Chestnut CH III, Silverman S, Andriano K, et al, PROOF Study Group. A randomizedtrial of nasal spray salmon calcitonin in postmenopausal women withestablished osteoporosis: the Prevent Recurrence of Osteoporotic Fractures study.. 2000;109:267-276.
Endocr Rev
40. Marcus R, Wong M, Heath H III, Stock JL. Antiresorptive treatment of postmenopausalosteoporosis: comparison of study designs and outcomes in large clinicaltrials with fracture as an endpoint. . 2002;23:16-37.
Calcif Tissue Int
41. Lyritis GP, Tsakalakos N, Magiasis B, et al. Analgesic effect of salmon calcitoninin osteoporotic vertebral fractures: a double-blind placebo-controlled clinicalstudy. . 1991;49:369-372.
Clin J Pain
42. Lyritis GP, Ioannidis GV, Karachalios T, et al. Analgesic effect of salmon calcitoninsuppositories in patients with acute pain due to recent osteoporotic vertebralcrush fractures: a prospective double-blind, randomized, placebo-controlled clinicalstudy. . 1999;15:284-289.
Calcif Tissue Int
43. Gennari C, Agnusdei D, Camporeale A. Use of calcitonin in the treatment ofbone pain associated with osteoporosis. . 1991;49(suppl 2):S9-S13.
Rheum Dis ClinNorth Am
44. Watts NB. Treatment of osteoporosis with bisphosphonates. . 2001;27:197-214.
N Engl J Med.
45. Liberman UA, Weiss SR, Broll J, et al, Alendronate Phase III OsteoporosisTreatment Study Group. Effect of oral alendronate on bone mineral density andthe incidence of fractures in postmenopausal osteoporosis. 1995;333:1437-1443.
Lancet.
46. Black DM, Cummings SR, Karpf DB, et al, Fracture Intervention TrialResearch Group. Randomised trial of effect of alendronate on risk of fracture inwomen with existing vertebral fractures. 1996;348:1535-1541.
JAMA.
47. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk offracture in women with low bone density but without vertebral fractures: resultsfrom the Fracture Intervention Trial. 1998;280:2077-2082.
Osteoporos Int
48. Pols HA, Felsenberg D, Hanley DA, et al, Fosamax International Trial StudyGroup. Multinational, placebo-controlled, randomized trial of the effects of alendronateon bone density and fracture risk in postmenopausal women with lowbone mass: results of the FOSIT study. . 1999;9:461-468.
JAMA.
49. Harris ST, Watts NB, Genant HK, et al, Vertebral Efficacy With RisedronateTherapy (VERT) Study Group. Effects of risedronate treatment on vertebral andnonvertebral fractures in women with postmenopausal osteoporosis: a randomizedcontrolled trial. 1999;282:1344-1352.
N Engl J Med.
50. McClung M, Geusens P, Miller PD, et al. Effect of risedronate on the risk ofhip fracture in elderly women. 2001;344:333-340.
Mayo Clin Proc
51. Cryer R, Bauer DC. Oral bisphosphonates and upper gastrointestinal tractproblems: what is the evidence? . 2002;77:1031-1043.
Aging
52. Schnitzer T, Bone HG, Crepaldi G, et al, Alendronate Once-Weekly StudyGroup. Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate10 mg daily in the treatment of osteoporosis. . 2000;12:1-12.
J Clin Densitom
53. Delaney MF, Hurwitz S, Shaw J, LeBoff MS. Bone density changes with onceweekly risedronate in postmenopausal women. . 2003;6:45-50.
Endocr Pract
54. Gordon MS, Gordon MB. Response of bone mineral density to once-weeklyadministration of risedronate. . 2002;8:202-207.
N Engl J Med
55. Solomon CG. Bisphosphonates and osteoporosis [comment]. .2002;346:642.
N Engl J Med.
56. Reid IR, Brown JP, Burckhardt P, et al. Intravenous zoledronic acid in postmenopausalwomen with low bone mineral density. 2002;346:653-661.
Endocr Rev
57. Cranney A, Tugwell P, Zytaruk N, et al, Osteoporosis Methodology Groupand Osteoporosis Research Advisory Group. Meta-analyses of therapies for postmenopausalosteoporosis, IV: meta-analysis of raloxifene for the prevention andtreatment of postmenopausal osteoporosis. . 2002;23:524-528.
JAMA.
58. Ettinger B, Black DM, Mitlak BH, et al, Multiple Outcomes of RaloxifeneEvaluation (MORE) Investigators. Reduction of vertebral fracture risk in postmenopausalwomen with osteoporosis treated with raloxifene: results from a 3-yearrandomized clinical trial. 1999;282:637-645.
J Clin EndocrinolMetab
59. Prestwood KM, Gunness M, Muchmore DB, et al. Comparison of the effects ofraloxifene and estrogen on bone in postmenopausal women. . 2000;85:2197-2202.
J Clin Endocrinol Metab
60. Johnell O, Scheele WH, Lu Y, et al. Additive effects of raloxifene and alendronateon bone density and biochemical markers of bone remodeling in postmenopausalwomen with osteoporosis. . 2002;87:985-992.
N Engl J Med.
61. Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bonemineral density, serum cholesterol concentrations, and uterine endometrium inpostmenopausal women. 1997;337:1641-1647.
Breast J
62. Dunn BK, Ford LG. From adjuvant therapy to breast cancer prevention: BCPTand STAR. . 2001;7:144-157.
Am J Cardiol
63. Mosca L, Barrett-Connor E, Wenger NK, et al. Design and methods of theRaloxifene Use for The Heart (RUTH) study. . 2001;88:392-395.
Curr OpinRheumatol
64. Rubin MR, Bilezekian JP. New anabolic therapies in osteoporosis. . 2002;14:433-440.
N Engl J Med.
65. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone(1-34) on fractures and bone mineral density in postmenopausal women withosteoporosis. 2001;344:1434-1441.
J ClinEndocrinol Metab
66. Body JJ, Gaich GA, Scheele WH, et al. A randomized double-blind trial tocompare the efficacy of teriparatide [recombinant human parathyroid hormone(1-34)] with alendronate in postmenopausal women with osteoporosis. . 2002;87:4528-4535.
67. RPhLink.com. Forteo. Available at: http://www.rphlink.com/forteo.html.Accessed August 24, 2003.
Maturitas
68. Wuttke W, Jarry H, Becker T, et al. Phytoestrogens: endocrine disrupters orreplacement for hormone replacement therapy? . 2003;44:S9-S20.
Am J Public Health
69. Ho SC, Bacon WE, Harris T, et al. Hip fracture rates in Hong Kong and theUnited States, 1988-1989. . 1993;83:694-697.
J Clin Endocrinol Metab
70. Tham DM, Gardner CCD, Haskell WL. Clinical Review 97: potential healthbenefits of dietary phytoestrogens: a review of the clinical, epidemiological, andmechanistic evidence. . 1998;83:2223-2225.
J BoneMiner Res
71. Alexanderson P, Toussaint A, Reginster J. Iprioflavone has no effect on bonemetabolism and causes lymphopenia in osteopenic women [abstract]. . 2000;15:S198.
J Bone Miner Res
72. Erdtsieck RJ, Van Kujik C, Birkenhager-Frenkel DH, et al. Course of bonemass during and after hormonal replacement therapy with and without addition ofnandrolone decanoate. . 1994;9:277-283.
Maturitas
73. Castelo-Branco C, Vicente JJ, Figueras F, et al. Comparative effects of estrogensplus androgens and tibolone on bone, lipid pattern and sexuality in postmenopausalwomen. . 2000;34:161-168.
QJM
74. Labram EK, Wilkin TJ. Growth hormone deficiency in adults and its responseto growth hormone replacement. . 1995;88:391-399.
Horm Metab Res
75. Kruse HP, Kuhlencordt F. On an attempt to treat primary and secondary osteoporosiswith human growth hormone. . 1975;7:488-491.
J Clin Endocrinol Metab
76. Aloia JF, Zanzi I, Ellis K, et al. Effects of growth hormone in osteoporosis.. 1976;43:992-999.
J Clin Endocrinol Metab
77. Holloway L, Kohlmeier L, Kent K, et al. Skeletal effects of cyclic recombinantgrowth hormone and salmon calcitonin in osteopenic postmenopausal women.. 1997;82:1111-1117.
J Clin Endocrinol Metab
78. Langlois JA, Rosen CJ, Visser M, et al. Association between insulin-likegrowth factor I and bone mineral density in older women and men: theFramingham Heart Study. . 1998;83:4257-4262.
J Clin Endocrinol Metab
79. Friedlander AL, Butterfield GE, Moynihan S, et al. One year of insulin-likegrowth factor I treatment does not affect bone density, body composition or psychologicalmeasures in postmenopausal women. .2001;86:1496-1503.
Ann Pharmacother
80. Cushenberry LM, de Bittner MR. Potential use of HMG-CoA reductase inhibitorsfor osteoporosis. . 2002;36:671-678.
Arterioscler ThrombVasc Biol
81. Demer LL. Boning up (or down) on statins [comment]. . 2001;21:1565-1566.
Arch Intern Med
82. Pasco JA, Kotowicz MA, Henry MJ, et al. Statin use, bone mineral density, andfracture risk: Geelong Osteoporosis Study. . 2002;162:537-540.
Curr Opin Rheumatol
83. Burgess E, Nanes MS. Osteoporosis in men: pathophysiology, evaluation, andtherapy. . 2002;14:421-428.
J Bone Miner Res
84. Cheng S, Suominen H, Sakari-Rantala R, Laukkanen P, Avikainen V,Heikkinen E. Calcaneal bone mineral density predicts fracture occurrence: a five-yearfollow-up study in elderly people. . 1997;12:1075-1082.
J Bone Miner Res
85. Kanis JA, Johnell O, Oden A, et al. Ten year probabilities of osteoporotic fracturesaccording to BMD and diagnostic thresholds [abstract]. .2001;16:S194.
J Bone Miner Res
86. Orwoll E. Assessing bone density in men. . 2000;15:1867-1870.
Osteoporos Int
87. Selby PL, Davies M, Adams JE. Do men and women fracture bones at similarbone densities? . 2000;11:153-157.
National Health and NutritionExamination Survey III, 1988-1994
88. Centers for Disease Control and Prevention. . Hyattsville, Md: National Center for HealthStatistics, Dept of Health and Human Services. CD-ROM Series 11, No. 2A.
Osteoporos Int
89. Thiebaud D, Burckhardt P, Cosstanza M, et al. Importance of albumin,25(OH)-vitamin D and IGFBP-3 as risk factors in elderly women and men with hipfracture. . 1997;7:457-462.
N Engl J Med.
90. Thomas MK, Lloyd-Jones DM, Thadani RI, et al. Hypovitaminosis D in medicalinpatients. 1998;338:777-783.
Calcif Tissue Int
91. Heikinheimo RJ, Inkovaara JA, Harju EJ, et al. Annual injection of vitamin Dand fractures of aged bones. . 1992;51:105-110.
N Engl J Med.
92. Orwoll E, Ettinger M, Weiss S, et al. Alendronate for the treatment of osteoporosisin men. 2000;343:604-610.
J Clin EndocrinolMetab
93. Ringe JD, Faber H, Dorst A. Alendronate treatment of established primaryosteoporosis in men: results of a 2-year prospective study. . 2001;86:5252-5255.
J Bone Miner Res
94. Slovik DM, Rosenthal DI, Doppelt SH, et al. Restoration of spinal bone inosteoporotic men by treatment with human parathyroid hormone (1-34) and 1,25-dihydroxyvitamin D. . 1986;1:377-381.
J Clin Endocrinol Metab
95. Kurland ES, Cosman F, McMahon DJ, et al. Parathyroid hormone as a therapyfor idiopathic osteoporosis in men: effects on bone mineral density and bonemarkers. . 2000;85:3069-3076.
Calcif Tissue Int
96. Francis RM. Androgen replacement in aging men. . 2001;69:235-238.
Bone
97. Anderson FH, Francis RM, Faulkner K. Androgen supplementation in eugonadalmen with osteoporosis: effects of 6 months of treatment on bone mineraldensity and cardiovascular risk factors. . 1996;18:171-177.
J Bone Miner Res
98. Anderson FH, Francis RM, Peaston RT, et al. Androgen supplementation ineugonadal men with osteoporosis: effects of 6 months' treatment on markers ofbone formation and resorption. . 1997;12:472-478.
J Clin Endocrinol Metab
99. Behre HM, Kliesch S, Leifke E, et al. Long-term effect of testosterone therapyon bone mineral density in hypogonadal men. .1997;82:2386-2390.
JAMA
100. Altkorn D, Vokes T. Treatment of postmenopausal osteoporosis. .2001;285:1415-1418.
Am J Med
101. Cummings SR, Karpf DB, Harris F, et al. Improvement in spine bone densityand reduction in risk of vertebral fractures during treatment with antiresorptivedrugs. . 2002;112:281-289.
J BoneMiner Res
102. Emkey R, Reid I, Mulloy A, et al. Ten-year efficacy and safety of alendronatein the treatment of osteoporosis in postmenopausal women [abstract]. . 2002;17(suppl 1):S139.
Am J Med
103. Wimalawansa SJ. A four-year randomized controlled trial of hormonereplacement and bisphosphonate, alone or in combination, in women with postmenopausalosteoporosis. . 1998;104:219-226.
J Clin Enocrinol Metab
104. Bone HG, Greenspan SL, McKeever C, et al, Alendronate/Estrogen StudyGroup. Alendronate and estrogen effects in postmenopausal women with lowbone mineral density. . 2000;85:720-726.
J Clin Endocrinol Metab
105. Lindsay R, Cosman F, Lobo TA, et al. Addition of alendronate to ongoinghormone replacement therapy in the treatment of osteoporosis: a randomized,controlled clinical trial. . 1999;84:3076-3081.
J Clin Endocrinol Metab
106. Johnell O, Scheele WH, Lu Y, et al. Additive effects of raloxifene and alendronateon bone density and biochemical markers of bone remodeling in postmenopausalwomen with osteoporosis. . 2002;87:985-992.
J Clin Endocrinol Metab
107. Ettinger B, Bilezekian JP. For osteoporosis, are 2 antiresorptive drugs betterthan one? . 2002;87:983-984.
Pharmacoeconomics
108. Johnell O, Jonsson B, Jonsson L, Black D. Cost effectiveness of alendronate(Fosamax) for the treatment of osteoporosis and prevention of fractures.. 2003;21:305-314.
J Rheumatol
109. Cranney A, Coyle D, Welch V, et al. Current controversies in cost effectivenessanalysis of osteoporosis therapies. . 1999;26:2300-2302.
Osteoporos Int
110. Executive Summary. Osteoporosis: review of the evidence for prevention,diagnosis and treatment and cost-effectiveness analysis. . 1998;8(suppl 4):S3-S6.
Curr OpinRheumatol
111. Tella MN, Feinglass J, Chang RW. Cost-effectiveness, cost-utility, and costbenefitstudies in rheumatology: a review of the literature, 2001-2002. . 2003;15:127-131.
JAMA.
112. Greenspan SL, Myers ER, Maitland LA, et al. Fall severity and bone mineraldensity as risk factors for hip fracture in ambulatory elderly. 1994;271:128-133.
