Steven R. Cummings

Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures

BACKGROUND Previous studies have shown that alendronate can increase bone mineral density (BMD) and prevent radiographically defined (morphometric) vertebral fractures. The Fracture Intervention Trial aimed to investigate the effect of alendronate on the risk of morphometric as well as clinically evident fractures in postmenopausal women with low bone mass. METHODS Women aged 55-81 with low femoral-neck BMD were enrolled in two study groups based on presence or absence of an existing vertebral fracture. Results for women with at least one vertebral fracture at baseline are reported here. 2027 women were randomly assigned placebo (1005) or alendronate (1022) and followed up for 36 months. The dose of alendronate (initially 5 mg daily) was increased (to 10 mg daily) at 24 months, with maintenance of the double blind. Lateral spine radiography was done at baseline and at 24 and 36 months. New vertebral fractures, the primary endpoint, were defined by morphometry as a decrease of 20% (and at least 4 mm) in at least one vertebral height between the baseline and latest follow-up radiograph. Non-spine clinical fractures were confirmed by radiographic reports. New symptomatic vertebral fractures were based on self-report and confirmed by radiography. FINDINGS Follow-up radiographs were obtained for 1946 women (98% of surviving participants). 78 (8.0%) of women in the alendronate group had one or more new morphometric vertebral fractures compared with 145 (15.0%) in the placebo group (relative risk 0.53 [95% Cl 0.41-0.68]). For clinically apparent vertebral fractures, the corresponding numbers were 23 (2.3%) alendronate and 50 (5.0%) placebo (relative hazard 0.45 [0.27-0.72]). The risk of any clinical fracture, the main secondary endpoint, was lower in the alendronate than in the placebo group (139 [13.6%] vs 183 [18.2%]; relative hazard 0.72 [0.58-0.90]). The relative hazards for hip fracture and wrist fracture for alendronate versus placebo were 0.49 (0.23-0.99) and 0.52 (0.31-0.87). There was no significant difference between the groups in numbers of adverse experiences, including upper-gastrointestinal disorders. INTERPRETATION We conclude that among women with low bone mass and existing vertebral fractures, alendronate is well tolerated and substantially reduces the frequency of morphometric and clinical vertebral fractures, as well as other clinical fractures.

Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group.

BACKGROUND Many risk factors for hip fractures have been suggested but have not been evaluated in a comprehensive prospective study. METHODS We assessed potential risk factors, including bone mass, in 9516 white women 65 years of age or older who had had no previous hip fracture. We then followed these women at 4-month intervals for an average of 4.1 years to determine the frequency of hip fracture. All reports of hip fractures were validated by review of x-ray films. RESULTS During the follow-up period, 192 women had first hip fractures not due to motor vehicle accidents. In multivariable age-adjusted analyses, a maternal history of hip fracture doubled the risk of hip fracture (relative risk, 2.0; 95 percent confidence interval, 1.4 to 2.9), and the increase in risk remained significant after adjustment for bone density. Women who had gained weight since the age of 25 had a lower risk. The risk was higher among women who had previous fractures of any type after the age of 50, were tall at the age of 25, rated their own health as fair or poor, had previous hyperthyroidism, had been treated with long-acting benzodiazepines or anticonvulsant drugs, ingested greater amounts of caffeine, or spent four hours a day or less on their feet. Examination findings associated with an increased risk included the inability to rise from a chair without using ones arms, poor depth perception, poor contrast sensitivity, and tachycardia at rest. Low calcaneal bone density was also an independent risk factor. The incidence of hip fracture ranged from 1.1 (95 percent confidence interval, 0.5 to 1.6) per 1,000 woman-years among women with no more than two risk factors and normal calcaneal bone density for their age to 27 (95 percent confidence interval, 20 to 34) per 1,000 woman-years among those with five or more risk factors and bone density in the lowest third for their age. CONCLUSIONS Women with multiple risk factors and low bone density have an especially high risk of hip fracture. Maintaining body weight, walking for exercise, avoiding long-acting benzodiazepines, minimizing caffeine intake, and treating impaired visual function are among the steps that may decrease the risk.

Epidemiology and outcomes of osteoporotic fractures.

Bone mass declines and the risk of fractures increases as people age, especially as women pass through the menopause. Hip fractures, the most serious outcome of osteoporosis, are becoming more frequent than before because the worlds population is ageing and because the frequency of hip fractures is increasing by 1-3% per year in most areas of the world. Rates of hip fracture vary more widely from region to region than does the prevalence of vertebral fractures. Low bone density and previous fractures are risk factors for almost all types of fracture, but each type of fracture also has its own unique risk factors. Prevention of fractures with drugs could potentially be as expensive as medical treatment of fractures. Therefore, epidemiological research should be done and used to identify individuals at high-risk of disabling fractures, thereby allowing careful allocation of expensive treatments to individuals most in need.

Hormone Therapy To Prevent Disease and Prolong Life in Postmenopausal Women

Abstract ▪Purpose:To critically review the risks and benefits of hormone therapy for asymptomatic postmenopausal women who are considering long-term hormone therapy to prevent disease or to prolong...

BONE DENSITY AT VARIOUS SITES FOR PREDICTION OF HIP FRACTURES

Women with low bone density in the radius or calcaneus are at increased risk of hip fracture. To see whether bone density of the hip measured by dual X-ray absorptiometry is a better predictor of hip fracture than measurements of other bones, we assessed bone density at several sites in 8134 women aged 65 years or more. 65 women had hip fractures during a mean follow-up of 1.8 years. Each SD decrease in femoral neck bone density increased the age-adjusted risk of hip fracture 2.6 times (95% CL 1.9, 3.6). Women with bone density in the lowest quartile had an 8.5-fold greater risk of hip fracture than those in the highest quartile. Bone density of the femoral neck was a better predictor than measurements of the spine (p < 0.0001), radius (p < 0.002), and moderately better than the calcaneus (p = 0.10). Low hip bone density is a stronger predictor of hip fracture than bone density at other sites. Efforts to prevent hip fractures should focus on women with low hip bone density.

SeriesEpidemiology and outcomes of osteoporotic fractures

Bone mass declines and the risk of fractures increases as people age, especially as women pass through the menopause. Hip fractures, the most serious outcome of osteoporosis, are becoming more frequent than before because the worlds population is ageing and because the frequency of hip fractures is increasing by 1-3% per year in most areas of the world. Rates of hip fracture vary more widely from region to region than does the prevalence of vertebral fractures. Low bone density and previous fractures are risk factors for almost all types of fracture, but each type of fracture also has its own unique risk factors. Prevention of fractures with drugs could potentially be as expensive as medical treatment of fractures. Therefore, epidemiological research should be done and used to identify individuals at high-risk of disabling fractures, thereby allowing careful allocation of expensive treatments to individuals most in need.

Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis

BACKGROUND Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. Given its unique actions, denosumab may be useful in the treatment of osteoporosis. METHODS We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than -2.5 but not less than -4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures. RESULTS As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P<0.001)--a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P=0.04)--a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01)--a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab. CONCLUSIONS Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791.)

Estrogen Replacement Therapy and Fractures in Older Women

Estrogen replacement therapy is the cornerstone of preventive therapy for osteoporosis and fractures. Current users of estrogen have a statistically significant decreased risk for hip [1-10], wrist [1, 5, 6, 8, 11], and spine fractures [8, 11, 12]. A recent meta-analysis [13] suggested a 25% decrease in the risk for hip fracture in women who reported using estrogen. The International Consensus Development Conference on Osteoporosis [14] concluded that estrogen therapy is the only well-established preventive measure that could significantly decrease the number of osteoporotic fractures. Nevertheless, several important issues remain unresolved. Most research has examined the effect of estrogen on specific fractures associated with osteoporosis (hip, wrist, spine). The effect on all fractures has not been established. The decrease in fracture risk associated with estrogen use is greatest among current or recent users, and the decreased risk tends to diminish with time after stopping estrogen [1, 4, 9]. It is unknown whether previous use, even if initiated around menopause and continued for a substantial length of time, confers any benefit. Most studies [1-9, 12] have examined the relation between unopposed estrogen and fractures. One cohort study [10] with about 30% of participants reporting use of estrogen plus progestin showed similar protective effects on the risk for hip fracture. This study did not, however, compare the relative risks separately for unopposed estrogen and combination therapy (estrogen plus progestin). The effectiveness of estrogen in preventing fractures in elderly women is also uncertain. Estrogen has been shown to be effective in preserving bone mass in elderly women [15, 16], but recent data [17] from Framingham showed little protective effect of an average of 10 years of estrogen therapy on bone density among women 75 years of age and older. In other prospective [9, 10] and casecontrol studies [3], the protective effects of estrogen on fracture were greater in younger women and weaker [3, 9] or nonexistent [10] in older women. In the Study of Osteoporotic Fractures, our prospective study of 9704 women who were 65 years of age or older, we assessed estrogen use and bone mass at baseline and ascertained incident fractures every 4 months to examine the association between estrogen use and fracture in elderly women. Methods Participants From September 1986 through October 1988, women who were at least 65 years of age were recruited for the Study of Osteoporotic Fractures in Portland, Oregon; Minneapolis, Minnesota; Baltimore County, Maryland; and the Monongahela Valley near Pittsburgh, Pennsylvania. Age-eligible women were recruited from population-based lists of women (voter registration, drivers license, and Health Maintenance Organizations membership lists) [18]. The response to these mass mailings varied from 8% in Pittsburgh (voter registration lists) to 19% in Portland (Kaiser Health Plan membership lists). We excluded black women because of their lower incidence of fractures, women who were unable to walk without the assistance of another person, and women who had had bilateral hip replacements. Estrogen Use Detailed information on use of estrogen and progestin was collected at the baseline interview. Information on use of estrogen was missing in 136 women; these women were excluded from all analyses. Participants were asked to bring all medications to the clinic for verification of use, preparation, and dosage. In addition, pictures of tablets were presented to participants to assist them in the recollection of previously prescribed hormone preparations. Information was collected about oral and parenteral estrogens (skin patches, injections, vaginal creams, and suppositories) and oral progestins. Our analyses were confined to oral preparations. Data were also collected on age at initiation of use of hormone preparations and on whether a participant had used such preparations for the entire time period since initiation and, if not, when she had stopped. Initiation of estrogen use with respect to menopause was determined by comparing the age at last menstrual period with the age at initiation of estrogen. To estimate duration of use, women were asked to check all ages, from 40 to 100 years of age, at which they had used estrogen. Duration of use was calculated by adding the total number of years that a woman had used estrogen. Because we were interested in examining the effect of initiation of estrogen and the effect of duration of use with respect to menopause, we excluded from the initiation and duration analyses 889 women for whom age at menopause could not be determined and 231 women who had started estrogen therapy more than 5 years before menopause. Measurement of Bone Mass Bone mineral density (g/cm2) was measured using single-photon absorptiometry (OsteoAnalyzer, Siemens-Osteon, Wahiawa, Hawaii). Details of these methods have been reported elsewhere [18]. We scanned three sites, including the distal radius, the proximal radius, and the calcaneus. The distal radius is composed of about 60% cortical and 40% trabecular bone, the proximal radius is about 99% cortical bone [19], and the calcaneus is about 97% trabecular bone [20]. Other Measurements Reported health status, type of menopause, alcohol consumption, physical activity, and cigarette smoking were assessed by a questionnaire that was reviewed with the participant by a trained interviewer. Women were considered to have had surgical menopause if they reported bilateral oophorectomy at the age they stopped menstruating. The measure of alcohol consumption was drinks per week adjusted for atypical drinking, especially heavy drinking during the previous 30 days. Dietary calcium intake was assessed by a food frequency questionnaire and by interview using standardized food models to estimate portion sizes [21]. Total calcium intake included dietary and supplemental calcium. Women were asked if they walked for exercise and if they had fallen in the previous 12 months. A modified Paffenbarger questionnaire was used to assess sports and recreation for the previous year, expressed in kcal/wk [22]. History of osteoporosis was ascertained by asking women if a physician had ever told them whether or not they had osteoporosis or a spine fracture. Women were also asked whether they had ever taken the following medications: thiazide diuretics, thyroid hormones, sedatives, anxiolytics, and Tums or calcium supplements. Cognitive function was assessed using the Modified Mini-Mental Status examination [23]. During the clinic examination, body weight was measured (after removal of shoes and heavy outer clothing) using a balance beam scale. Height was measured (after removal of shoes) using a Harpenden stadiometer (Holtain Ltd., Dyved, United Kingdom). Height and weight were used to calculate the body mass index (kg/m2). Ascertainment of Incident Fractures Details of our method for identifying new fractures during follow-up have been published [24]. Briefly, we contacted participants every 4 months by postcard or telephone to ask whether they had sustained a fracture or fall. More than 99.5% of these follow-up contacts were completed. We interviewed participants about the way in which the fracture occurred. To confirm fractures, we obtained a copy of the radiographic report, which had to specifically mention the occurrence of an acute fracture. Hip fractures were also confirmed by radiologic review of copies of radiographs. We excluded fractures that occurred because of major trauma such as motor vehicle accidents. Most vertebral fractures do not come to medical attention; these fractures must be discovered by systematically obtaining radiographs from all participants and by comparing them with previous radiographs. Hence, self-reported vertebral fractures were not included. Duration of fracture follow-up was calculated as the time to first occurrence of a fracture. Follow-up for fractures ranged from 0.02 years to 6.5 years. All nonspinal fractures that occurred before 1 April 1993 were included. For women who died during the follow-up period, date of death was used as the end of follow-up when fracture follow-up was not appropriate. The category all nonspinal fractures included hip and wrist fractures. Fractures of the distal radius or ulna were considered wrist fractures. Hip fractures were defined as those of the proximal femur. Statistical Analysis Estrogen use was classified as never, previous, or current. Chi-square tests of homogeneity and analyses of variance and covariance were used to compare baseline characteristics by estrogen use. Proportional hazard regression models were used to assess the relation between estrogen use and fracture. Women who had never used any type of estrogen formed the reference group for all analyses. Separate models were done for current and previous users. To test the hypothesis that the protective effect of estrogen use may be underestimated if a history of osteoporosis is not taken into account, we stratified by history of osteoporosis or spine fracture (or both). We also stratified patients by estrogen regimen (unopposed estrogen compared with estrogen and progestin) and by age ( 75 years or >75 years). Stratification by estrogen regimen was confined to those with wrist and all nonspinal fractures because combination therapy was not used frequently in our cohort and because few participants in this group had hip fractures. The multivariate model included age, body mass index, total calcium intake (supplemental and dietary), physical activity (kcal/wk), surgical menopause (yes or no), history of smoking (yes or no), history of thyroid medication use, current use of thiazide diuretics, history of osteoporosis or spine fracture or both (yes or no), current use of sedatives or anxiolytics, alcohol consumption (drinks/wk), cognitive function (Mini-Mental Status examination 23), and falls in the previous year

BMD at multiple sites and risk of fracture of multiple types: long-term results from the Study of Osteoporotic Fractures.

In a large cohort of U.S. women aged 65 and older, we report the relationships of BMD measured at several sites, and subsequent fracture risk at multiple sites over >8 years of follow‐up. Although we found almost all fracture types to be related to low BMD, the overall proportion of fractures attributable to low BMD is modest.

Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs

PURPOSE To estimate how much the improvement in bone mass accounts for the reduction in risk of vertebral fracture that has been observed in randomized trials of antiresorptive treatments for osteoporosis. METHODS After a systematic search, we conducted a meta-analysis of 12 trials to describe the relation between improvement in spine bone mineral density and reduction in risk of vertebral fracture in postmenopausal women. We also used logistic models to estimate the proportion of the reduction in risk of vertebral fracture observed with alendronate in the Fracture Intervention Trial that was due to improvement in bone mineral density. RESULTS Across the 12 trials, a 1% improvement in spine bone mineral density was associated with a 0.03 decrease (95% confidence interval [CI]: 0.02 to 0.05) in the relative risk (RR) of vertebral fracture. The reductions in risk were greater than predicted from improvement in bone mineral density; for example, the model estimated that treatments predicted to reduce fracture risk by 20% (RR = 0.80), based on improvement in bone mineral density, actually reduce the risk of fracture by about 45% (RR = 0.55). In the Fracture Intervention Trial, improvement in spine bone mineral density explained 16% (95% CI: 11% to 27%) of the reduction in the risk of vertebral fracture with alendronate. CONCLUSION Improvement in spine bone mineral density during treatment with antiresorptive drugs accounts for a predictable but small part of the observed reduction in the risk of vertebral fracture.