Pii: s0749-0690(02)00022-8

aSection of Geriatric Medicine, A91 Cleveland Clinic Foundation, 9500 Euclid Avenue, bCenter for Osteoporosis and Metabolic Bone Disease, Cleveland Clinic Foundation, A50, 9500 Euclid Avenue, Cleveland, OH 44195, USA Osteoporosis is a common disease of older adults and is a major public health problem worldwide. As the population ages, the incidence of osteoporosis andresulting osteoporotic fractures is increasing. Although osteoporosis is more com-mon in women than in men, the incidence in men is increasing. The disability,mortality, and cost of hip and vertebral fractures are substantial in the rapidlygrowing, aging population so that prevention and treatment of osteoporosis is amajor public health concern. This article reviews the impact of osteoporosis andprovides an evidence-based approach toward preventing and treating osteoporosisand its complications.
The Consensus Development Conference statement in 1993 defined osteo- porosis as ‘‘a disease characterized by low bone mass and microarchitecturaldeterioration of bone tissue, leading to enhanced bone fragility and a consequentincrease in fracture risk’’ [1]. In 1994, the World Health Organization (WHO)established bone mineral density (BMD) measurement criteria allowing thediagnosis of osteoporosis before incident fractures [2] (Table 1). This practicaldefinition is based on its major (known) risk factor: reduced bone strength ordensity and includes those individuals who are at a high risk but withoutfractures. Despite the use of a ‘‘bone mass’’ definition, it is important to realizethat bone density is a single risk factor, measured at a single point of time. Other * Corresponding author.
E-mail address: cdeal@ccf.org (C. Deal) 0749-0690/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved.
PII: S 0 7 4 9 - 0 6 9 0 ( 0 2 ) 0 0 0 2 2 - 8 M. Srivastava, C. Deal / Clin Geriatr Med 18 (2002) 529–555 Table 1Diagnostic categories for osteoporosis in postmenopausal women based on World Health OrganizationCriteria A value for BMD that is not more than 1 SD below the youngadult mean value.
A value for BMD that lies between 1 and 2.5 SD below theyoung adult mean value.
A value for BMD that is more than 2.5 SD below the youngadult mean value.
A value for BMD more than 2.5 SD or below the young adultmean in the presence of one or more fragility fractures.
Abbreviations: BMD, bone mineral density; SD, standard deviation.
Data from Kanis JA, Melton LJ, Christiansen C, Johnson CC, Khaltaev N. The diagnosis ofosteoporosis. J Bone Miner Res 1994;9:1137 – 41.
risk factors including age, life expectancy, bone loss, and bone turnover are otherimportant considerations.
Few premenopausal women have osteoporosis; however, the prevalence in- creases with age because of the progressive loss of bone. In the United States, ithas been estimated that up to 54% (16.8 million) of postmenopausal whitewomen have low bone mass (T score of -2.0) and another 20% to 30%(6.9 million) have osteoporosis [3]. In the United States, the prevalence of osteo-porosis increases from 15% in 50- to 59-year-old women to 70% in womenaged 80 years. Epidemiologic studies in other countries have reported similarfindings [4,119].
A fracture is considered to be osteoporotic (fragility fracture) if it is caused by relatively low trauma, such as a fall from standing height or less; a force which ina young healthy adult would not be expected to cause a fracture. Overwhelmingevidence has shown that the incidence of fracture in specific settings is closelylinked to the prevalence of osteoporosis or low bone mass. In a prospective studyof 8134 women older than 65 years in age, Cummings et al showed that thewomen with BMD of the femoral neck in the lowest quartile have 8.5-fold greaterrisk of sustaining a hip fracture than those in the highest quartile [5]. Each 1standard deviation decrease in femoral neck BMD increases the age adjusted riskof having a hip fracture 2.6-fold. Thus, a strong correlation exists between BMDand fracture risk.
The incidence of hip fractures increases dramatically with age and typically peaks after 85 years of age. In the United States, in 1991, there were 300,000 hipfractures. Most of these fractures (94%) occurred in people age 50 and older, and M. Srivastava, C. Deal / Clin Geriatr Med 18 (2002) 529–555 most (55%) occurred in people age 80 and over [6]. According to a large USpopulation-based study of hip fractures among older persons, the age-adjustedrate of hip fractures was highest among white women (8.07 per 1000), followedby white men (4.28 per 1000), black women (3.06 per 1000) and black men(2.38 per 1000) [7].
With increasing life expectancy worldwide, the incidence of hip fractures will rise exponentially with age, unless preventive efforts are undertaken [8]. In 1990,an estimated 1.65 million hip fractures occurred (1.2 million in women and450,000 in men) worldwide [9,10], which is projected to increase to 6.3 millionby the year 2050; of which 70% are expected to come from Asia, Latin America,the Middle East, and Africa. In the United States alone, hip fractures could total840,000 in the year 2040 [11 – 13].
Although vertebral fractures are the most common osteoporotic fractures, less is known about their epidemiology because approximately two thirds are asymp-tomatic and go undetected and because of the lack of a standardized morpho-metric definition [14]. Most studies have shown that there is an exponential risein the number of fractures with aging. In the European Vertebral OsteoporosisStudy, the prevalence of vertebral deformity was 10% in men age 50 to 54 years,rising to 18% at age 75 to 79 years. In women age 50 to 54 years, the prevalencewas only 5%; however, this rose to 24% at age 74 to 79 years [15]. Similar resultswere reported from other studies [14].
Distal forearm fractures almost always result from a fall on the outstretched arm. The incidence in women becomes evident at an earlier age than vertebralfactures, rising rapidly soon after menopause. In men, the incidence remainsrelatively constant between the ages of 20 and 80 years [12,13,16,17]. Fracturesof the proximal humerus and shaft and distal femur have an occurrence patternthat resembles that of hip fractures: substantial age-related increases in ratesamong white women late in life and lower risks in men and blacks of eithersex [16,18]. Pelvic fractures also increase exponentially with age. Most of thesefractures (ie, 70% to 80%) appear to result from minimal trauma, suggestingunderlying osteoporosis.
Bone densitometry is an established method for assessing osteoporosis. A variety of different methods have been developed over the past 25 years. The twomost commonly used methods are dual energy x-ray absorptiometry (DEXA) and M. Srivastava, C. Deal / Clin Geriatr Med 18 (2002) 529–555 quantitative ultrasound. DEXA is recommended and FDA approved for BMDmeasurement; it is precise, noninvasive, has low radiation exposure, and takes10 minutes to administer. Because annual losses of bone mass normally seen withaging range from 1% per year, the precision error of current instruments(approximately 1% to 2% with DEXA) cannot provide reliable information atintervals shorter than 2 years. Therefore, if follow-up studies are desired, aminimum interval of 2 years is recommended. Exceptions to this include high-dose steroid therapy that can result in rapid bone loss in a shorter interval (6 to12 months) The National Osteoporosis Foundation has published recommen-dations for BMD screening using DEXA [19] (Table 2). The cost of DEXA(approximately $150 to $250) is covered by Medicare.
Despite the lack of definitive guidelines concerning biochemical markers, they have the potential to provide independent or adjunctive information on decisionmaking [20,120]. Serum markers of bone formation include bone-specificalkaline phosphatase and osteocalcin. Markers of bone resorption are the collagencross-links: deoxypyridinoline, N-telopeptide (NTx), and C-telopeptide (CTx).
Although the resorption markers are measured in the urine, blood measurementshave recently become available [21,22]. Women who have borderline low BMDand elevated markers are at increased risk of losing bone in the near future andmay be candidates for pharmacologic intervention. The resorption markers arealso independent risk factors for fracture.
Risk factors for osteoporosis and osteoporotic fractures have been determined and are used to identify the need for further evaluation. Risk factors can becategorized as modifiable and nonmodifiable as represented in Table 3.
Table 2National Osteoporosis Foundation recommendations for bone mineral density testing Postmenopausal women (age 50 – 65) with risk factors for osteoporosis (besides menopause) Family history of osteoporosisPersonal history of low trauma fracture at age > 45 yrCurrent smokingLow body weight (< 127 lb) Women age 65 years and older regardless of additional risk factorsPostmenopausal women who present with fracturesWomen considering therapy for osteoporosis if BMD testing would facilitate such a decisionWomen who have been on HRT for prolonged periods Abbreviations: BMD, bone mineral density; HRT, hormone replacement therapy.
Data from National Osteoporosis Foundation. Osteoporosis: review of the evidence for prevention,diagnosis, and treatment and cost-effective analysis. Introduction. National Osteoporosis Foundation:Osteoporosis Int Suppl. 1998;S7 – S80.
M. Srivastava, C. Deal / Clin Geriatr Med 18 (2002) 529–555 GlucocorticoidsBenzodiazepinesAnticonvulsantsThyroid hormones Although low BMD has been established as an important predictor of future facture risks, several studies have shown that other risk factors also contribute tothe fracture risk. In the Study of Osteoporotic Fracture (SOF) [23], clinical riskfactors predictive of fracture were identified and were related to historical factors,such as previous fracture in the individual or her mother, self-rated poor health,use of long-acting benzodiazepines, and sedentary lifestyle; BMD; and physicalexamination findings, such as inability to rise from a chair; poor visualperformance, and resting tachycardia. The presence of five or more of thesefactors increased the rate of hip fractures for women in the highest tertile of BMDfrom 1.1 per 1000 women-years to 9.9 per 1000 women-years, whereas forwomen in the lowest tertile, hip fractures increased from 2.6 per 1000 woman-years to 27.3 per 1000 woman-years. The Framingham Osteoporosis Study eval-uated risk factors for bone loss in elderly men and women [24]. Data from thisstudy suggested that for women, lower baseline weight, weight loss in theinterim, and greater alcohol use were associated with BMD loss, while currentestrogen users had less bone loss than nonusers. For men, lower baseline weight,loss of weight and smoking cigarettes were associated with BMD loss.
Osteoporosis can have a significant impact on the daily life of patients.
Persons in whom osteoporosis is asymptomatic or has resulted in a single fracturecan function well and usually do not experience substantial problems. Whensubsequent fractures occur, however, the functional outlook changes. Most ofthe persistent functional limitations result from fractures of the proximal femuror vertebrae.
Hip fracture mortality is higher for men than for women, increases with age, and is greater for those with coexisting illnesses and poor prefracture functional M. Srivastava, C. Deal / Clin Geriatr Med 18 (2002) 529–555 status [6,25]. There are approximately 31,000 excess deaths within 6 months ofthe approximately 300,000 hip fractures that occur annually in the United States[6]. The mortality is higher in the elderly population—approximately 8% of menand 3% of women age 50 and older die while they are hospitalized for theirfractures. At 1 year after hip fracture, mortality is 36% for men and 21% forwomen and is much higher in older men. Mortality rate returns to normal for thehip fracture population within 1 to 2 years; however, higher rates persist for theelderly [6,26].
Substantial long-term morbidity is associated with hip fractures. The propor- tion of US hip fracture patients who were discharged from hospital to nursinghomes in 1990 varied from 14% for the youngest group (50 to 55 years) to 55%for those older than 90 years. One year after hip fracture, 40% of people were stillunable to walk independently, 60% required assistance with one basic activity ofdaily living, and 80% were unable to perform at least one instrumental activity ofdaily living that they performed before fracture [6]. About one quarter of formerlyindependent people become at least partially dependent, half of those whoalready required assisted living were admitted to nursing homes, and thosealready in nursing homes remained there [6]. A French study of clinical outcomesafter hip fractures also concluded that 20% of previously independent peoplerequired some form of assisted living arrangement after the hip fracture [27].
Multiple cross-sectional and observational studies have found a positive correlation between vertebral fractures and back pain [28 – 30]. Vertebral deform-ity leads to loss of spinal mobility, and patients with osteoporosis have reportedproblems with standing, bending, rising from a chair, walking, carrying items,dressing, fixing hair, washing, bathing, moving in the bed, using the toilet, andgetting to the floor [31 – 34]. Compared with women without existing vertebraldeformities, those women with prevalent deformities have generally higher cruderates of mortality and hospitalization [35,36].
The pain and functional limitations that accompany vertebral fractures often cause a high level of anxiety early in the disease leading to inactivity and asedentary lifestyle, thereby increasing the risks for falls and fractures and for fearsof these events. As disease-related problems in the forms of additional vertebralfractures, pain, and limited mobility continue to appear, anxiety may transforminto depression [31,32,37]. Both women and men living with progressiveosteoporosis have decreased self-image and self-esteem because of feelings ofworthlessness stemming from their inability to work outside the home, to enjoyhobbies, or to do chores around the house. Osteoporosis robs older women ofmany of their social roles. Inability to fulfill the roles such as cooking,housekeeping, working, and sexual intimacy can be devastating, leading tofrustration and embarrassment [37]. Interpersonal relationships can be profoundlyaffected by effects of osteoporosis and can strain familial ties and destroynonfamily relationships, leading to social isolation. Therefore, treatment options M. Srivastava, C. Deal / Clin Geriatr Med 18 (2002) 529–555 for the affected individuals must focus not only on bone remodeling but also onways in which adverse outcomes, such as pain, depression, and loss of self-esteem, can be improved.
Reduction of the potentially modifiable risk factors along with exercise and calcium and vitamin D supplementation form an important adjunct to pharmaco-logic management of osteoporosis.
Physical activity may have a twofold contribution to reducing fracture risk: (1) it may enhance bone strength by optimizing BMD and improving bonequality and (2) it has the potential to reduce the risk of falling. Much of the datasuggesting a relationship between bone strength (measured as BMD) andphysical activity is cross-sectional, however, and cannot prove a cause andeffect relationship.
Resistance training increases bone mass and prevents age-related declines in BMD [38 – 40]. A recent meta-analysis of the role of exercise showed that bothimpact and nonimpact exercise had a positive effect on lumbar spine bone densityin postmenopausal women, whereas only impact exercise probably had a positiveeffect at the femoral neck [41].
The emphasis of physical exercise programs in elderly patients with osteo- porosis should be on improving muscle strength and balance. Older patientsshould be encouraged to participate safely in any activity in a frequent, regular,and sustained manner. The exercise should be weight bearing and easy tocomplete and should fit into their daily routine. A program of walking, sitting,and standing exercises, or water aerobics, can be recommended to start with andgradually increased to more rigorous activity. For patients who have already hadan osteoporotic fracture, physical exercise program can help reduce pain andincrease functional capacity. The program should increase the patient’s ability toperform routine daily activities while minimizing the risk of further fractures. Forpatients with vertebral fractures, back flexion exercises have been found to beharmful and to increase the risk of new vertebral fractures. These patients willbenefit from resistance exercises that strengthen back extensor muscles [42].
Deficiency of calcium and vitamin D contributes to alterations of bone remodeling and bone integrity. Low calcium intake and vitamin D deficiencyhave been repeatedly observed in the elderly population. In elderly women, lowfractional calcium absorption in the setting of low calcium intake increases therisk for hip fracture [43]. Although vitamin D and calcium alone have little effect M. Srivastava, C. Deal / Clin Geriatr Med 18 (2002) 529–555 on bone mass in the early menopausal years [44,45], they can have substantialeffects on bone mass and fragility fractures in the elderly population.
In a 4-year randomized, double-blind, placebo-controlled trial of calcium citrate (1600 mg/d) or placebo in postmenopausal women (mean age, 66.3 years),patients in the calcium group lost significantly less bone at the lumbar spine ( P =0.003 at year one) and proximal femur ( P = 0.02 at year one) as compared withthe placebo [46]. In another randomized, double-blind, placebo-controlled trial ofwomen older than 60 years of age with calcium intake of less than 1 g/d,supplementation with calcium carbonate 1.2 g/d decreased the rate of spinalfractures compared with placebo ( P = 0.023) and halted measurable bone loss[47]. To evaluate whether calcium supplementation can correct seasonal (winter-time) bone loss, 60 elderly women were supplemented with four glasses of milkeach day, calcium carbonate (1000 mg/d), or a placebo [48]. After 2 years, thecalcium group had no loss at the greater trochanter and had significant gains atthe spine and femoral neck, whereas the placebo group had significant bone lossat the greater trochanter ( P < 0.03).
Few studies have evaluated the effects of vitamin D alone on bone mass and fractures. In a population of elderly Finnish men and women (mean age,82.8 years), Heikinheimo et al [49] injected subjects with 150,000 or 300,000 IUvitamin D2 once a year for 4 years. Fewer upper extremity and rib fractures werefound in the group supplemented with vitamin D; however, no difference wasnoted in hip fractures. To evaluate the role of vitamin D in seasonal bone loss,women received a daily placebo or 400 IU vitamin D along with 377 mg/d calciumcitrate [50]. Spinal bone loss in winter was less in the vitamin D-treated group thanin the placebo group ( P = 0.032).
Two placebo-controlled trials have shown a significant protective effect against hip and other nonvertebral fractures by a combined supplement ofcalcium and vitamin D (Table 4). In a nursing home population, Chapuy et al[51] found that in the supplemented group, the parathyroid hormone (PTH) levelsdecreased by 44% from baseline, and serum 25-OH vitamin D levels increased by162% over baseline. A 2.7% increase in BMD was noted in the proximal femur inthe treatment group versus a 4.6% decrease in the placebo group ( P < 0.001) at18 months. The supplemented group had 43% fewer hip fractures ( P = 0.043)and 32% fewer vertebral fractures ( P = 0.015) than the placebo group. In the trialinvolving ambulatory patients, Dawson-Hughes et al [52] found that dietarysupplementation with calcium and vitamin D moderately reduced bone lossmeasured in the femoral neck, spine, and total body over the 3-year study period.
Twenty-six patients in the placebo group and 11 patients in the calcium-vitaminD group had nonvertebral fractures ( P = 0.02).
Thus, calcium and vitamin D are useful adjunctive therapies in preventing and treating osteoporosis in the elderly even though it remains unproved that theyprevent hip fractures in the ambulatory elderly population. Nevertheless, calciumand vitamin D supplementation should be recommended for all elderly individ-uals to preserve bone health with advancing age. The optimal effective dose ofvitamin D is 400 to 1000 IU/d. The recommended dose of calcium for elderly M. Srivastava, C. Deal / Clin Geriatr Med 18 (2002) 529–555 women and men is 1500 mg/d; women on hormone replacement therapy (HRT)need 1000 mg/d. The preferred source of calcium is dietary. Because therecommended dose of calcium and vitamin D usually is not obtained throughdiet alone, calcium and vitamin D supplementation is recommended.
The primary goal of an intervention is to reduce the risk of fracture. The evidence-based approach requires proof of efficacy from adequately poweredrandomized controlled trials in which fracture is the primary endpoint. Adequatelypowered randomized controlled trials with fracture as the primary endpoint existfor alendronate, raloxifene, risedronate, and calcitonin. For HRT, the evidence forantifracture efficacy is based mainly on observational data. Table 5 summarizesthe medications available in the United States to manage osteoporosis.
Bisphosphonates are compounds that bind avidly to hydroxyapatite crystals on bone surfaces and are potent inhibitors of bone resorption. The two bisphospho-nates approved by the FDA are alendronate and risedronate.
Alendronate was the first bisphosphonate approved by the FDA (1995) to treat osteoporosis. In the phase III trial, almost 1000 postmenopausal women (meanage, 64 years) were randomized to alendronate or placebo for 3 years. Alendronateresulted in an increase in BMD of 8.8% in the lumbar spine and of 5.9% in thefemoral neck as compared with placebo ( P < 0.001) [53]. Similar results were seenfrom two other trials [54].
The Fracture Intervention Trial (FIT) (Table 4) examined the effect of alendronate on postmenopausal women with low bone density at the hip andeither with vertebral fracture at baseline (FIT I) or without vertebral fracture atbaseline (FIT II). In the FIT I [55] trial, the rate of new radiographic vertebralfractures was decreased by 47% in the alendronate group compared with theplacebo group ( P < 0.001). A similar reduction was also observed in the risk ofhip and wrist fractures in women receiving alendronate: 51% reduction in hipfractures (95% CI 0.23 to 0.99) and 48% reduction in wrist fractures (95% CI0.31 to 0.87).
In FIT II [56], alendronate did not reduce the risk of clinical fractures (RR = 0.86 [95% CI .73 to -1.01] P = 0.07) in the entire cohort. In posthoc analysis,however, in women whose initial femoral neck T score was -2.5 or less,alendronate significantly reduced the risk of clinical fractures by 36%. (RR =0.64 [95% CI 0.50 to 0.82]) and hip fractures by 56% (RR = 0.44 [95% CI 0.18to 0.97]). The pooled analysis of the FIT [57] concluded that the magnitude of thefracture reductions with alendronate are similar both in women who meet the Table 4Selected clinical trials of drug treatment in management of osteoporosis fractures (95%CI 0.23 – 0.99)48% reduction in wristfracture (95%CI 0.31 – 0.87) fracturesT score > - 2.5: nosignificant decrease inrisk for fractures vertebral fracture ( P = 0.03)100, 400 IU: no significantreduction in risk of newvertebral fracture Hormone replacement therapyLindsay et al [78] 1980 estrogen users RR 0.39(95%CI 0.16 – 0.95) [based onnumber of fractures] Nonspinal fracture — RR 0.69(95% CI 0.57 – 0.83)Wrist fracture — RR 0.46(95% CI 0.29 – 0.72)Hip fracture — RR 0.80(95% CI 0.51 – 1.26)Past estrogen users: Nobenefit for nonspinal, wrist, orhip fractures in BMD: spine 3.5% – 5%;at hip 1.7%Placebo group — lost BMD atspine À 1.8%; at hip À 1.7% LS spine — 4.3% vs 0.4%( P < 0.001)Hip — 1.7% vs À 0.1%( P = 0.02) Nonvertebral fracturesNo significant decrease; RR 0.22 – 0.55)53% decrease in nonvertebralfractures (95% CI 0.25 – 0.88) Abbreviations: I, intervention; P, placebo or control; BMD, bone mineral density; RR, relative risk; HRT, hormone replacement therapy.
M. Srivastava, C. Deal / Clin Geriatr Med 18 (2002) 529–555 Table 5Medications approved in the United States for osteoporosis 1 mg daily  3 days, followed by1 mg/0.09 mg daily  3 days, repeated Estradiol/norethindrone acetate (Activella; Conjugated equine estrogen/medroxyprogesterone(Prempro; 0.625 mg PO daily days 1 – 14, then0.625 mg/5 mg PO daily days 15 – 28 10 mg/d or 70 mg/wk (treatment)5 mg/d or 35 mg/wk (prevention) WHO BMD criterion for osteoporosis without vertebral fracture (FIT II, T score< -2.5) and in those who have existing vertebral fracture but who do not meet theWHO BMD criterion for osteoporosis (FIT I).
Treatment with alendronate also had significant effects on the physical disability resulting from osteoporotic fractures. In the FIT trial, for womenwith preexisting vertebral fractures who took alendronate therapy for 3 years,the number of bed-rest days was reduced by 63% (from 5.1 to 1.9 days), andthe mean number of limited-activity days was reduced by 16% (from 73.2 to61.8 days) [58].
The efficacy of once weekly versus daily dose of alendronate has been compared in a randomized controlled trial with 889postmenopausal women (range, 42 to 95 years of age) with osteoporosis [59]with similar increases in lumbar spine BMD in both groups. The incidence ofclinical and laboratory adverse effects, including gastrointestinal (GI) intol-erance, was also similar although there was a suggestion that serious GI adverseevents (ie, perforation, ulcers, and bleeds) might be less in the 70-mg group.
Although the study was not powered to show fracture reduction, it can beassumed that the new 70 mg once-weekly dosing regimen is a more convenientand therapeutically equivalent alternative to daily regimen and has beenapproved by the FDA for treatment of osteoporosis.
M. Srivastava, C. Deal / Clin Geriatr Med 18 (2002) 529–555 Elderly women with osteoporosis who participated in a 24-month dose-ranging study with alendronate 1, 2.5, or 5 mg versus placebo[60] were continued on 10 mg of alendronate in an open label extension study[61]. The 12-month extension was conducted to evaluate the safety and confirmthe efficacy of 10 mg alendronate in elderly women. A total of 246 women, withages ranging from 62 to 87 years (68% older than 70 years, 41% older than75 years, and 12% older than 80 years) enrolled in the open label treatment. Theoverall number of adverse GI experiences decreased in each group during theextension and only 1% of the subjects withdrew from the study because of anadverse GI effect. They tolerated alendronate therapy well, similar to the youngerwomen, and had significant gains in BMD at lumbar spine and trochanter.
In a randomized, double-blind, placebo-controlled trial [62], risedronate (5 mg/d) increased the lumbar spine BMD from baseline by 4% at 24 monthsin contrast to no-change in the placebo group ( P < 0.001) and BMD at fem-oral neck and trochanter increased by 1% and 3%, respectively, comparedwith placebo.
The Vertebral Efficacy With Risedronate Therapy study had two arms: North American and multinational (Table 4). In the North American arm [63], rise-dronate decreased the cumulative new vertebral fracture incidence and non-vertebral fractures by 41% ( P = 0.003) and 39% ( P = 0.02), respectively. In themultinational arm, risedronate reduced the risk of new vertebral fractures by 49%( P < 0.001) and nonvertebral fractures by 33% ( P = 0.06) compared withplacebo [64].
The Hip Intervention Program (HIP) study enrolled 5445 women (range, 70 to 79 years old) with osteoporosis and 3886 women older than 80 years old withnon-skeletal risk factors for osteoporosis (and not low bone mass). All womenwere randomly assigned to receive treatment with oral risedronate, 2.5 mg or5 mg, or placebo for 3 years [65]. The BMD at the femoral neck and trochanterwas higher in the risedronate group as compared with the placebo group at6 months and at all time points thereafter. These changes in BMD were similar inboth the younger and older group. The incidence of hip fracture in the group ofwomen 70 to 79 years old was 1.9% among those assigned to risedronate and3.2% among those assigned to placebo (41% reduction, P = 0.009). In the groupof women 80 years of age and older who were recruited on the basis of clinicalrisk factors, however, risedronate had no significant reduction in fracture rates. Itcan be concluded that even at age 80 years, measurement of BMD is important inidentifying patients who will benefit from a bisphosphonate.
Bisphosphonates are generally well tolerated. GI side effects may occur, and a small number of patients with erosive esophagitis have been reported with M. Srivastava, C. Deal / Clin Geriatr Med 18 (2002) 529–555 alendronate [66,67]. Because of this potential problem, patients must take themedication in the morning with a full glass of water (6 to 8 ounces), 30 minutesbefore first food or drink of the day and remain upright (sitting or standing) for atleast 30 minutes after the dose. Esophageal stricture or motility dysfunction is acontraindication to use of bisphosphonates. Numerous endoscopic studies havecompared alendronate and risedronate for adverse effects on the esophagus,stomach, and duodenum with conflicting results [66,68]. These are short studies(2 weeks), and it is unknown whether these endoscopic lesions will result inclinically significant outcomes.
It is not yet clear how long bisphosphonate therapy should be given. One major determinant of that answer is what happens when therapy is discontinued.
Women receiving alendronate have been followed for 7 years [54]. The lumbarspine BMD continued to show a linear increase in women who continued toreceive alendronate over that period. Women who discontinued alendronate at theend of 5 years continued to have stable BMD for up to 2 years after discontinuingalendronate. The bone turnover increased, but not to the elevated values seen inuntreated osteoporosis women. The optimal duration of treatment, however, iscurrently unknown.
In addition to its efficacy in treating osteoporosis in postmenopausal women, studies have evaluated the use of alendronate for preventing osteoporosis [69 – 71].
These studies have been done, however, in young postmenopausal women, and nodata are available for elderly patients.
The beneficial effects of hormone replacement on BMD at a variety of skeletal sites have been documented in several randomized, controlled trials in both earlyand late postmenopausal women [72 – 75]. In a recent study of older women,estrogen and medroxyprogesterone acetate produced a 1.4% to 3.9% greaterdifference in BMD at skeletal sites as compared with placebo [76].
One randomized controlled clinical trial showed the effectiveness of HRT in reducing vertebral fractures in women with established osteoporosis; however,the study has been criticized for using number of fractures rather than number ofpatients with fractures as endpoint [77]. Two other trials have shown vertebralfracture reduction (or a presumed surrogate) in postmenopausal women treatedwith HRT [78,79]. All these studies were very small, however, and had fewelderly subjects.
For hip fractures, the evidence of antifracture efficacy is based primarily on observational data (Table 4). In the Study of Osteoporotic Fractures [23], currentestrogen use was associated with a decrease in the risk of wrist fracture (RR = 0.39; M. Srivastava, C. Deal / Clin Geriatr Med 18 (2002) 529–555 95% CI, 0.24 to 0.64) and for all nonspinal fractures (RR = 0.66; 95% CI, 0.54 to0.80) when compared with nonestrogen users. The RR for hip fractures was alsodecreased but not statistically significant. In both the Mediterranean OsteoporosisStudy [80] and the Swedish Hip Fracture Study Group [81], current estrogen userswere significantly protected against hip fractures, whereas no significant differencewas observed for former users.
There are no HRT trials that are both primarily designed and adequately powered to support the observational evidence of fracture risk reduction byHRT. Recently, the presumed skeletal and nonskeletal benefits of HRT havebeen challenged. The Heart and Estrogen/Progestin Replacement Study—adouble-blind, placebo-controlled, randomized trial—was primarily designed toevaluate the effect of HRT on secondary prevention of heart disease, withassessment of fractures being only a secondary endpoint [82]. The authors foundno difference between estrogen and placebo users for hip fracture (RR = 1.10;95% CI, 0.49 to 2.50) or any fracture (RR = 0.95; 95% CI, 0.75 to 1.21).
Patients were not enrolled, however, based on low bone mass, and the study wasnot powered to show fracture reduction. More data on the effect of estrogen onfracture incidence are likely to be available in the coming years as the Women’sHealth Initiative program in the United States and the Women’s InternationalStudy of Long Duration Oestrogen after Menopause trial in the United Kingdomare completed.
An area of concern involves the timing of initiation and duration of HRT.
Recent data suggest that women should be started on estrogen within 2 to 7 yearsof menopause [23,81,83]. In a recent meta-analysis, HRT was found to preventnonvertebral, hip, and wrist fractures when women commenced treatment beforeage 60 years; however, there was insufficient evidence that fracture risk wasreduced when begun after age 60 [84]. Evidence from other controlled trialsshowed, however, that estrogen had positive effect on BMD even when started20 years or more after menopause [77]. Estrogen begun and continued over age60 years maintained BMD [85], and women older than age 65 years withestablished osteopenia treated with estrogen [86] had increases in absolute BMDcomparable to that observed in younger women. There is growing evidence,however, for an attenuation of the beneficial skeletal effects of HRT after thewithdrawal of treatment. This evidence was shown in the Framingham Study[87], in which women treated for 7 years had lost most of the gain in BMD whenremeasured 7 years later. Similar findings were also reported from the SwedishHip Fracture Study [88]. Hence, the duration of therapy necessary to protectwomen against fragility fractures may well be indefinite.
Compliance with HRT, however, is typically poor because of common side effects and concerns over an increased incidence of breast or endometrial cancer.
One major reason to discontinue therapy is irregular uterine bleeding; the amountof which may be less in women on low dose HRT [74]. Thus, low-dose estrogen M. Srivastava, C. Deal / Clin Geriatr Med 18 (2002) 529–555 in elderly women may prevent bone loss and minimize the side effects seen withhigher dose of estrogen.
Selective estrogen receptor modulators (SERMs) are compounds that can bind to and activate estrogen receptors but can cause differential estrogenic orantiestrogenic responses in different tissues. Raloxifene was the first SERMapproved for osteoporosis.
Early studies showed that raloxifene increases lumbar spine and total hip and femur BMD [89,90]. In the Multiple Outcomes of Raloxifene Evaluation study(MORE) [91] (Table 4) for women with low BMD and no prevalent vertebralfracture, the incidence of new vertebral fracture was reduced by 55% (95% CI,0.29 to 0.71) whereas among the women with prevalent vertebral fractures, theincidence of new vertebral fracture was reduced by 30% (95% CI, 0.56 to 0.86)with use of raloxifene 60 mg/d. The MORE study did not have statistical powerto detect a reduction in risk for total nonvertebral fractures or for individualnonvertebral sites. For the pooled raloxifene groups, the RR for total nonvertebralfractures was 0.94 (95% CI, 0.79 to 1.12) as compared with placebo. Similarresults were found at the end of 4 years of the trial. Women receiving raloxifenehad increased risk of venous thromboembolism ( $ 3/1000); a risk similar toestrogen in several series. Hot flashes occur with increased frequency especiallyin early menopausal women. In contrast to estrogen, raloxifene did not causevaginal bleeding or breast pain and was associated with a significant lowerincidence of breast cancer.
Calcitonin is an endogenous hormone secreted by the parafollicular C cells of the thyroid gland, which helps maintain normal calcium homeostasis. Calcitoninacts directly on osteoclasts, with inhibitory effects on bone resorption. In 1994, theFDA approved a new nasal spray preparation formulation of salmon calcitonin.
Previous studies have found calcitonin to be helpful in postmenopausal women with established osteoporosis [92 – 95]. In a recent 5-year, double-blind,randomized controlled study of intranasal calcitonin on vertebral fracture rate inwomen with postmenopausal osteoporosis (Prevent Recurrence of OsteoporoticFractures [PROOF] study) [96] (Table 4), 200 IU salmon calcitonin nasal sprayper day significantly reduced the risk of new vertebral fractures by 33% to 36% inwomen with prevalent vertebral fractures.No significant fracture reduction wasseen, however, in those receiving 100 or 400 IU/d. The PROOF study was notpowered to detect nonvertebral fracture reduction. A nonsignificant reduction wasnoted in the risk of nonvertebral fractures in this study compared with placebo.
There are two major limitations of the PROOF study, however. First, there was a59% discontinuation rate for the 5 years of the study, which was higher than M. Srivastava, C. Deal / Clin Geriatr Med 18 (2002) 529–555 expected. Second, a dose – response curve of nasal calcitonin for fracturereduction was not seen [97]. Adverse effects with intranasal calcitonin are rare.
In the PROOF study, a significant increase was noted in only rhinitis [96].
Alternative therapies are now being studied for their effect on BMD. Among these are phytoestrogens, which are a diverse group of compounds found in a widevariety of plant foods that are believed to have estrogen-like activity and morerecently have been thought to have both estrogenic and antiestrogenic activity[98]. Some preliminary studies had shown a possible role of phytoestrogens inpreventing osteoporosis. The Ipriflavone Multicenter European Fracture Study, aprospective, randomized, double-blind, placebo controlled trial (475 postmeno-pausal women with low BMD), concluded, however, that ipriflavone did notprevent bone loss or affect biochemical markers of bone metabolism [99].
In contrast to the current available drugs that slow bone turnover and thereby allow bone formation to exceed bone resorption, anabolic agents, such as PTH,actually stimulate remodeling, preferentially increasing formation over resorption.
Data for effect of PTH on BMD are available from three recent randomized clinical trials [100 – 102]. In the largest trial, 1637 postmenopausal women wereadministered 20 or 40 mg human PTH (I-34) or placebo and followed for21 months [102]. The RR for vertebral fractures in women receiving 20 mgwas 0.35 (95% CI, 0.22 to 0.55); for 40 mg, 0.31 (95% CI, 0.19 to 0.50). Newnonvertebral fragility fractures occurred in 6% of women in the placebo groupand in 3% of those in each PTH group (RR, 0.47 and 0.46, respectively [95% CI,0.25 to 0.88 and 0.25 to 0.86]). New or worsening back pain was reported by23% of the women in the placebo group but by only 17% and 16% of those in the20 and 40 mg PTH groups, respectively ( P = 0.007). Nausea and headache werethe most common side effects, and these occurred infrequently and in a dose-dependent manner. In July 2001, PTH injection (20 mg subcutaneous once a day)received FDA advisory committee approval for postmenopausal osteoporosis.
Estrogen and bisphosphonates together produce greater gains in BMD than either agent used alone [103,104]. The addition of 10 mg alendronate daily towomen receiving estrogen significantly increased spine and hip trochanter BMDover 12 months as compared with estrogen alone [105]. None of these studies arelarge enough, however, to determine if there is a decrease in the fracture risk withcombination therapy.
Combination therapy using anabolic agents (eg, PTH) and antiresorptive agents are being launched. Recent clinical trials of PTH in combination withestablished estrogen [106,107] have shown a significant increase in both spine M. Srivastava, C. Deal / Clin Geriatr Med 18 (2002) 529–555 and femoral neck BMD with PTH plus estrogen compared with estrogen alone.
Also, the combination decreased vertebral fracture occurrence by 75% to 100%,compared with HRT alone [107]. Thus, PTH and estrogen have a greater effect onbone mass at both spine and femur than either alone.
PTH and bisphosphonates has been evaluated in one open label study after the 1 year, multicenter PTH trial [101]. Women who received either PTH or placebowere given 10 mg alendronate for another year. Women who received alendronateshowed a 14.3% increase in spine BMD compared with a 7% increase in thosereceiving placebo. The response was thus additive. The role of combinationtherapy in osteoporosis management is not clearly defined at present.
Although the incidence of osteoporosis in men is lower than in women, one third of all hip fractures worldwide occur in men. The risk factors for osteopo-rosis in men age 60 years and older are low femoral neck BMD, quadricepsweakness, low body weight, falls in the preceding year, and a history of fracturesin last 5 years [108,121]. The Framingham Osteoporosis Study [24] identifiedlow baseline weight, weight loss, and smoking cigarettes as risk factors forosteoporosis. In a large population-based study of elderly men from the RanchoBernardo Study [109], low estradiol level was shown to be associated withvertebral fractures, whereas men with low testosterone level consistent withhypogonadism had no significant increased odds for fracture. Although age-related decline in testosterone level has been thought to play a role in decreasedbone formation in elderly men, studies involving otherwise healthy older menhave been unable to show an association between testosterone levels and bonedensity [110 – 114].
Currently, no validated guideline is available for preventing or treating osteoporosis in men; however, there are recent reviews on the management ofosteoporosis in men [115,118,122]. Men with history of previous fractures andmen with known risk factors for low bone density should be targeted forprevention of osteoporosis and can be offered BMD measurement. The BMDthreshold at which therapy should be started is unclear.
Lifestyle modifications, including increasing physical activity, cessation of smoking, and alcohol, should be offered to all men. Calcium and vitamin Dsupplementation should be recommended for older men even though its evidencefor decreasing fractures in older men is limited and conflicting. A large multi-center, randomized controlled trial of alendronate was completed in 241 men withT-score less than 2 at the femoral neck or with osteoporotic fracture [116]. After2 years, the BMD at lumbar spine increased by 7.1% in those receivingalendronate as compared with 1.8% with placebo ( P < 0.001), along with sig-nificant improvement in BMD at the femoral neck and trochanter. A trend towardfracture reduction was noted in the treated group; however, it did not reachstatistical significance.
M. Srivastava, C. Deal / Clin Geriatr Med 18 (2002) 529–555 The use of testosterone therapy in eugonadal men is controversial and present data do not support any benefit associated with routine testosterone replacementin older men [117]. Testosterone replacement is appropriate only in the setting ofproven hypogonadism in men with markedly low total testosterone levels.
Currently, the role of PTH, growth hormone, and raloxifene are being evaluatedfor use in men.
Osteoporosis is a major clinical problem in older women and men. Almost any bone can fracture as a result of the increased bone fragility of osteoporosis. Thesefractures are associated with higher health care costs, physical disability, impairedquality of life, and increased mortality. Because the incidence of osteoporoticfracture increases with advancing age, measures to diagnose and preventosteoporosis and its complications assume a major public health concern.
BMD is a valuable tool to identify patients at risk for fracture, to maketherapeutic decisions, and to monitor therapy. Several other modifiable andnonmodifiable risk factors for osteoporosis have also been identified.
Treatment of potentially modifiable risk factors along with exercise and calcium and vitamin D supplementation forms an important adjunct to pharma-cologic management of osteoporosis. Improved household safety can reduce therisk of falls. Hip protectors have been found to be effective in nursing homepopulation. The pharmacologic options include bisphosphonates, HRT, SERMsand calcitonin. PTH had received FDA advisory committee approval. Alendro-nate has been approved for treatment of osteoporosis in men, and other treatmentsfor men are under evaluation.
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