Vitamin D status and falls, frailty, and fractures among postmenopausal Japanese women living in Hawaii.

UNLABELLED: Vitamin D status and its relationship to physical performance, falls, and fractures in 495 postmenopausal women of Japanese ancestry in Hawaii were investigated. The mean 25-hydroxyvitamin D (25-OHD) was 31.94 ng/mL. No significant association of 25-OHD was demonstrated with most outcomes, possibly due to higher 25-OHD levels in this population. INTRODUCTION: In this study, we investigated vitamin D status and its relationship to physical performance, muscle strength, falls, and fractures in postmenopausal Japanese females living in Hawaii. METHODS: Of 510 community-dwelling women who participated in the eighth examination of the Hawaii Osteoporosis Study, 495 were included in these analyses. Multivariate regression models were used to evaluate the relationship of 25-OHD (D(3) and total) to eight performance-based measurements, 12 activities of daily living (ADLs), and muscle strength (grip, triceps, and quadriceps). Logistic regression analyses were performed to evaluate the relationship of 25-OHD to falls, vertebral fractures, and non-vertebral fractures. RESULTS: The mean total 25-OHD was 31.94 +/- 9.46 ng/mL; 44% of subjects had values <30 ng/mL, while none had values <10-12 ng/mL. There was little evidence of seasonal variation. Among performance-based measures, ADLs, and strength tests, only quadriceps strength was significantly associated with total 25-OHD (p = 0.0063) and 25-OHD(3) (p = 0.0001). No significant association of 25-OHD was found with vertebral or non-vertebral fractures, or incidence of one or more falls. CONCLUSIONS: Lack of serum 25-OHD relationship with falls and fractures or most physical performance measures in this study may be related to the low prevalence of very low 25-OHD levels in this population.

Osteoporosis Current practice and future perspectives.

Initiation of estrogens or other drugs as preventive measures for osteoporosis should be based upon objective estimates of actual, future fracture risk. Bone mass measurements, when considered in the context of age, life expectancy, expected bone loss, and other risk factors, enable improved patient risk stratification, and more rational treatment choices.

Vertebral fracture and other predictors of physical impairment and health care utilization.

BACKGROUND: A better understanding of the impact of vertebral fractures on physical functioning would help clinicians gauge the potential benefits of identifying patients at high risk and prevent vertebral fractures due to osteoporosis. METHODS: We explored the associations of vertebral fractures and other potential predictors with physical impairment and health care utilization based on the data collected from 569 postmenopausal Japanese American participants of the Hawaii Osteoporosis Study, aged from 55 to 93 years. A major advantage of this study is the availability of serial spine radiographs for all participants. All vertebral fractures could be identified and the fracture dates estimated. RESULTS: Poor physical functioning was related to increases in number of recent vertebral fractures, age, body mass index, and number of other painful joints. Recent vertebral fractures had a strong impact on bending- and walking-related activities. For each recent vertebral fracture, the odds of impairment increased about 2 times and the odds of a physician visit for back pain increased 3.6 times. The number of recent vertebral fractures was also a significant predictor of poor performance in functional reach and walking speed tests. The effects of vertebral fractures on physical functioning may persist for several years. CONCLUSIONS: Recent vertebral fractures may lead to long-term poor physical functioning. Clinicians should take appropriate measures to identify those at risk, to prevent progression of osteoporosis, and to limit associated disability.

Vertebral fractures and other predictors of back pain among older women.

We examined the prevalence and predictors of back pain (BKP) among 645 postmenopausal Japanese-American women in Hawaii with a mean age of 73.9 years (ranging from 55 to 93 years) and serial spine radiographs during the preceding 12 years. The overall prevalence of BKP was 32.9% and appeared to be constant up to age 80, with an increase thereafter. At most ages, pain in the lower back was the most common, upper BKP was less so, and mid-BKP was the least common. The overall prevalence of BKP among Japanese-American women in Hawaii was about half of that reported for U.S. Caucasians. Vertebral fractures were divided into three categories based on the length of time since the fracture was identified on radiographs. BKP was only associated with recent vertebral fractures (during the previous 4 years, on average) and increased progressively with the number and severity of fractured vertebrae. A history of a single recent fracture was associated with a 2.8-fold increase in the odds of BKP; two recent fractures with a 7.8-fold increase and three recent fractures with a 21.7-fold increase in the odds of BKP. In addition, self-reported disk problems, body mass index, and the number of other painful joints also showed independent associations with BKP. Height, spine bone mineral density (BMD), calcaneus BMD, smoking, and number of live births were not significantly associated with BKP.

Short-term and long-term fracture prediction by bone mass measurements: a prospective study.

Prospective and cross-sectional studies have demonstrated that bone mass predicts fracture risk. However, most prospective studies have been limited to a few years of follow-up. We investigated the long-term associations of bone mass with vertebral fractures using longitudinal data collected from more than 500 postmenopausal Japanese-American women in the Hawaii Osteoporosis Study. New vertebral fractures were identified during an average of 2.7 years between 1992 and 1995. Short-term fracture prediction was evaluated using bone mass (spine, calcaneus, distal radius, and proximal radius) measured at the beginning of follow-up. Long-term prediction was evaluated using bone mass measured before the follow-up period (11 years earlier for nonspine bone mass and 8 years earlier for spine). All four bone mass measurements were significant predictors of vertebral fractures identified during the subsequent 2.7 years (short-term prediction), with odds ratios (ORs) ranging from 1.5 to 1.9. The ORs for long-term prediction were slightly lower in magnitude, but the confidence intervals overlapped the short-term ORs considerably, suggesting that both long-term and short-term associations are similar in magnitude. Furthermore, cross-sectional analyses based on bone mass measurements performed at the end of follow-up (after fractures had occurred) yielded results similar to those based on prospective data (bone mass measured prior to fractures), suggesting that the relatively quick and inexpensive cross-sectional studies are useful for preliminary evaluations of new bone mass measurement techniques. The results suggest that bone mass measurements made up to 11 years earlier can predict vertebral fractures almost as well as measurements made more recently.

Detection of prefracture spinal osteoporosis using bone mineral absorptiometry.

Bone mineral measurements have been criticized for their inability to clearly distinguish fracture and "nonfracture" populations. However, this failure is not unexpected, since some individuals in the "nonfracture" group have low bone mass and are at increased risk but have not yet experienced fractures. Although standard radiographs are not sensitive indicators of vertebral demineralization, they do identify some of the "prefracture" osteoporotic subpopulation within the nonfracture group. Prospective follow-up of 536 Japanese-American women demonstrated that 14 new spine fractures occurred in the prefracture osteoporosis group, whereas none occurred in the nonosteoporotic group (p less than or equal to 0.03). However, bone mineral content (BMC) measurements using photon absorptiometry were much more accurate than radiographs as indicators of spine fracture risk. BMC values were somewhat higher in the prefracture group than in those with existing fractures, but values for both groups were significantly lower than in nonosteoporotic patients even after adjusting for age, height, and weight (p less than 0.0001). The magnitude of the difference was proportional to the trabecular bone content of the measurement site; the differences were greatest for the os calcis and lumbar spine, smaller for the distal radius, and least for the proximal radius. The prevalence of spinal osteoporosis (including both fracture and prefracture cases) was inversely proportional to BMC (p less than 0.0001). Again, the relations were strongest for the os calcis and lumbar spine. These results indicate that BMC measurements are valid indicators of osteoporosis status, particularly when osteoporosis is defined to include both patients with existing fractures and those at increased risk for fractures. However, dual-photon spine BMC was adversely influenced by the presence of aortic calcification, arthritis, and other disease processes (p less than or equal to 0.0001).

Evidence for both generalized and regional low bone mass among elderly women.

The consistency of bone mass measurements across bone sites was examined in a cohort of elderly Japanese-American women. The study included 744 women of mean age 66.6 years (age range 47-82 years) who had bone densitometry measurements at the spine, calcaneus, and distal and proximal radius. The women were classified at the four bone sites as in the lower, middle, or upper bone mass tertile for their age. Slightly more than half (56%) of the women were in the lower tertile at one or more of the bone sites, and such women were usually in the lower category at more than one site. Of the women, 24% were classified in the lower tertile at all four sites. Furthermore, as a group, women classified as in the low bone mass category at any one site had a low average bone mass at all four sites. Prospectively, the number of low bone mass sites predicted the risk of new spine fractures after adjusting for age and the number of spine and nonspine prevalent fractures. The risk increased approximately 1.3-fold for each additional low bone mass site. A subgroup (15%) of the population had marked heterogeneity in bone mass between sites. These women had one or more lower tertile bone mass site(s) and one or more upper tertile bone mass site(s). The results suggest that osteoporosis may occur as either a generalized or as a regional disorder.

Relationship between bone mass and rates of bone change at appendicular measurement sites.

The rate of bone change among postmenopausal women may vary depending upon the initial bone mass. Examining this possibility is difficult, however, because of a negative statistical bias that occurs when change is regressed against the initial value of the same variable. In this article, four statistical methods were applied to measure the association between bone mass and the rate of bone change. The study population was Japanese-American women, who were monitored for approximately 5 years. Bone changes were determined for the calcaneus and the distal and proximal radius. The results were consistent across the bone sites but differed between statistical methods. Three of the four methods indicated that the women with the greater bone mass had the greater loss rates. The fourth method did not support this association. Possible reasons for the discordant results are discussed. Using the "best" estimate of the relationship, a gradual convergence of bone mass was projected over time toward the population mean. The convergence occurred because women with higher bone mass had a somewhat faster loss rate than women with lower bone mass. Overall, however, the variation in bone mass between individuals was large compared to the rate of convergence.

Perspectives: methodologic issues in evaluating risk factors for osteoporotic fractures.

Techniques for measuring bone mineral content (BMC) were developed for the purpose of providing an objective and noninvasive indication of bone strength (or lack thereof) and fracture risk, to the extent that strength relates to bone mass. As such, BMC measurements could help to (1) identify those who are most likely to experience nonviolent fractures in the future and who would therefore benefit most from preventive measures, (2) improve their treatment compliance, and (3) monitor the efficacy of treatments intended to reduce bone loss. All these potential uses require that the measurement provide an indication of fracture risk (probability of fractures). During the past 10-15 years there have been conflicting reports regarding the association of reduced BMC with nonviolent fractures. Some authors have criticized the usefulness of BMC measurements, whereas others have questioned the value of one or more techniques. However, the epidemiology of osteoporosis has only recently been subjected to rigorous study. The use of appropriate statistical methods for relating fracture risk to bone mass may be no more widely practiced in osteoporosis epidemiology today than it was for studying risk factors (e.g., blood pressure) in cardiovascular epidemiology during the 1960s. The intent of this article is to explore three areas that may have contributed to controversy in the study of bone mass and fracture occurrence: (1) perspective of the investigators, (2) study design, and (3) analytic methodology. Although the focus of this paper is on bone mass, these considerations are equally applicable to some investigations of other risk factors for osteoporotic fractures (e.g., bone architecture, bone turnover and loss rate, or biochemical markers of bone loss).

The effects of smoking on bone mass and the rates of bone loss among elderly Japanese-American men.

Bone density and bone loss rates were examined among Japanese-American men categorized as current cigarette smokers, past smokers, and nonsmokers. The design included a retrospective study of smoking and bone density and a prospective study of current smoking and bone loss rates. The mean length of follow-up was 5 years; the setting was the island of Oahu. The subjects included 1303 men in the Hawaii Osteoporosis Study, 51-82 years old at their initial examination. Twenty percent were current smokers, 45% past smokers, and 35% had never smoked. Their bone density was measured at the distal and proximal radius and calcaneus using single photon absorptiometry. Compared with never smokers, current and past smokers had significantly lower bone density, especially in the predominantly cancellous calcaneus (4.8 and 4.3% lower, respectively) and partially trabecular distal radius (1.8 and 3.3% lower, respectively). The magnitude of the smoking effect was linked strongly to the duration of smoking and also to the number of cigarettes smoked. Bone loss rates subsequent to the initial measurement were greater in the current smokers than the never smokers (20.5, 27.2, and 9.7% greater at the calcaneus, distal, and proximal radius, respectively) but the differences did not achieve significance. Smokers of more than one pack per day had 32.0, 77.6, and 30.7% greater loss rates than never smokers in these same sites; the difference achieved significance at the distal radius. The results from the distal radius suggest that these smokers may increase their fracture risk 10-30% per decade of smoking. The adverse effects of smoking appeared to be greater in cancellous than cortical bone.

Contributions of vertebral fractures to stature loss among elderly Japanese-American women in Hawaii.

Loss of stature is a typical feature of osteoporosis and associated vertebral fractures. However, there have been few prospective population-based studies to estimate the magnitude of this association. Further, the separate contributions of different types of vertebral fractures to stature loss have not been evaluated using prospective data. In this study we investigated the extent to which stature loss could be explained by the number of different types of vertebral fractures (wedge, endplate, and crush fractures) after adjusting for other covariates. Longitudinal data on stature loss and vertebral fractures were collected among 504 postmenopausal Japanese-American women living in Hawaii with mean age 73.4 (SD 4.9) years. During an average of 7.7 years of follow-up, women with at least one incident vertebral fracture had an average of 2.1 cm of stature loss while the average stature loss among those without incident fractures was only 0.4 cm. The mean rate of stature loss was very slight (< 1 mm/year) for those without incident vertebral fractures even after age 80. Our analyses suggest that both the number of wedge and the number of crush fractures are strong predictors of stature loss. After adjusting for age and total height loss in the anterior dimension over T3-L5, the estimated stature loss resulting from each wedge and crush fracture was 0.86 and 1.08 cm, respectively. Endplate fractures did not show significant contributions to stature loss.

Blinded reading of radiographs increases the frequency of errors in vertebral fracture detection.

We examined the effect of blinding X-rays to film sequence and patient identity on vertebral fracture detection. A sample of 50 postmenopausal women with low bone density and two sets of spine X-rays 3.6 years apart was selected; based on prior morphometric studies, about half of the women had experienced new fractures after the initial film. New morphometric and semiquantitative radiologist readings were each performed twice: blinded and unblinded. For morphometry, incident fractures were defined as vertebral height decreases of more than 15% compared with the initial film. The incidence was slightly higher when blinded versus unblinded (5.6 vs. 5.3% of all vertebrae for morphometry, and 9.7 vs. 8.7% for the radiologist), but these differences were not significant. The error rate was investigated by examining the frequency of "fracture reversals"-vertebrae identified as fractured on the initial film but not on the later film. Agreement between blinded and unblinded readings was generally greater than 80% for fractures but less than 10% for "fracture reversals," suggesting that reversals are not true events but random errors. The number of reversals was higher when the radiologist was blinded (2.1% of all vertebrae vs. 0.8% when unblinded; p = 0.07). The number of vertebrae with increases greater than 15% in size over time was also greater when morphometry readings were blinded versus unblinded: 0.8 versus 0% (p < 0.05). Although these errors are small, they are similar in magnitude to the annual fracture incidence in many populations. These data show that blinding X-rays to sequence offers no advantages, increases the frequency of errors, and may inflate incidence rates. We conclude that the assessment of X-rays for vertebral fractures in clinical trials should not be performed with the evaluator blinded to the sequence of the X-rays.

Falls among community-dwelling elderly in Japan.

Japanese have a lower incidence of hip fracture than Caucasians despite having lower bone mass. Hip fractures usually occur after a fall, and differing incidence rates of falls might explain the observed differences in hip fracture rates. To explore this hypothesis, we studied falls and related conditions among 1534 (624 men, 910 women) community-dwelling people aged 65 years and over in Japan and compared the prevalence of falls to Japanese-Americans living in Hawaii and to published studies of Caucasians. In Japan, 9% of the men and 19% of the women reported one or more falls during the past year. The prevalence of falls increased with age in both genders and was greater among women compared with men. In logistic regression models, having musculoskeletal disease, physical disability or limited activity increased the risk of falls by two to four times in both genders. Most fallers (92%) reported fear of future falls, and about one third of fallers reported that they went out less often as a result of their falls. Compared with native Japanese, the age-standardized prevalence of falls among Japanese-Americans was similar but about twice as high for Caucasians, which may explain the lower hip fracture risk of Japanese.

Comparison of cross-sectional and longitudinal measurements of age-related changes in bone mineral content.

Age-related, postmenopausal bone loss was examined among a cohort of Japanese-American women living in Hawaii. None of the women were using estrogens or thiazides. Cross-sectional and longitudinal measurements of bone mineral content were compared at the calcaneus, the proximal radius, and the distal radius. Cross-sectional measurements were also available for the lumbar spine. The longitudinal data showed a slowing rate of bone loss with increasing age at the radius sites. By contrast, the cross-sectional data suggested constant rates of bone loss for all ages at both radius sites and the spine. The calcaneus demonstrated a complex pattern of bone loss in both cross-sectional and longitudinal analyses. The loss rates among women in their fifties were greater than for those in their sixties. From the middle sixties onward calcaneal bone loss remained essentially constant. Because of the sustained bone loss, however, women in their seventies were actually losing greater percentages of their calcaneal bone mineral than they had in their sixties.

A new method for vertebral fracture diagnosis.

A number of methods have been proposed for estimating the prevalence of vertebral fractures. Most methods are based on the distribution of normal vertebral dimensions in the population. However, these methods fail to identify a significant proportion (20-30% or more) of fractures documented on serial radiographs. This may occur because vertebral size varies between individuals as a result of differences in body size (and possibly other factors), and a normal range based on population reference data may be too large. In this paper, a new method is described for identifying vertebral fractures that are missed using diagnostic criteria based on vertebral dimension distributions of the population. This new method is based on calculating the average vertebral size, and statistical confidence limits, for the individual. The average vertebral size method was evaluated by testing its ability to identify incident fractures (which were identified from changes in dimensions compared to previous radiographs), using only the final film. The new method correctly identified most (81% of crush and 83% of wedge) incident fractures on the final radiograph. In contrast, criteria based on population distributions correctly identified only 53% of crush and 72% of wedge incident fractures. Using prospective data, prevalent fractures identified using both population-based and individual size-based criteria predicted the risk of incident fractures. Furthermore, incident fractures identified using both methods (population- and individual-based criteria) were associated with increased back pain. These data suggest that both types of prevalent deformities are important indicators of disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Low body mass index is an important risk factor for low bone mass and increased bone loss in early postmenopausal women. Early Postmenopausal Intervention Cohort (EPIC) study group.

Thinness (low percentage of body fat, low body mass index [BMI], or low body weight) was evaluated as a risk factor for low bone mineral density (BMD) or increased bone loss in a randomized trial of alendronate for prevention of osteoporosis in recently postmenopausal women with normal bone mass (n = 1609). The 2-year data from the placebo group were used (n = 417). Percentage of body fat, BMI, and body weight were correlated with baseline BMD (r = -0. 13 to -0.43, p < 0.01) and 2-year bone loss (r = -0.14 to -0.19, p < 0.01). Women in the lowest tertiles of percentage of body fat or BMI had up to 12% lower BMD at baseline and a more than 2-fold higher 2-year bone loss as compared with women in the highest tertiles (p

Antifracture efficacy of antiresorptive agents are related to changes in bone density.

There is a current debate about the extent to which antifracture efficacy of antiresorptive drugs are related to changes in bone mineral density (BMD). In vitro studies show that most of the variability in bone strength is related to BMD, and prospective studies have shown that low BMD is an important predictor of fracture risk. It seems that higher levels of bone turnover are also associated with increased fracture risk. Over the short term, a reduction in activation frequency or resorption depth would lead to fewer (and/or shallower) resorption sites and refilling of existing sites initially. There is also evidence that inhibiting resorption allows bone to respond to mechanical demands, preferentially thickening critical trabeculae, and this may help compensate for reduced connectivity. Each of these mechanisms would increase BMD and would disproportionately improve bone strength. Over the long term, maintaining bone mass and preventing loss of structural elements would result in progressively greater differences in BMD and fracture risk over time, relative to untreated women. The conceptual model predicts that both the short- and long-term antifracture efficacy of antiresorptive drugs will depend on the extent to which treatment can increase and maintain BMD. To examine this issue, we compiled data from clinical trials of antiresorptive agents and plotted the relative risk of vertebral fractures against the average change in BMD for each trial. The confidence intervals are large for individual trials, and there was substantial variability in antifracture efficacy at any given level of change in BMD. Overall, however, trials that reported larger increases in BMD tended to observe greater reductions in vertebral fracture risk. Poisson regression was used to quantify this relationship. The model predicts that treatments that increase spine BMD by 8% would reduce risk by 54%; most of the total effect of treatment was explained by the 8% increase in BMD (41% risk reduction). These findings are consistent with the short-term predictions of the conceptual model and with reports from randomized trials. The small but significant reductions in risk that were not explained by measurable changes in BMD might be related to publication bias, measurement errors, or limitations of current BMD technology.

Monitoring of alendronate treatment and prediction of effect on bone mass by biochemical markers in the early postmenopausal intervention cohort study.

To establish whether biochemical markers could be used to monitor alendronate (ALN) treatment and predict long-term response in bone mass, we used results from an ongoing, randomized trial of ALN treatment for prevention of postmenopausal osteoporosis (n = 1202). In women treated with ALN (5 mg), change from baseline at month 6 in urine N-telopeptide cross-links of type I collagen (NTX) and osteocalcin (OC) correlated with change from baseline at month 24 in spine, hip, and total body bone mineral density (BMD) [r = -0.28 to -0.31 (NTX) and r = -0.16 to -0.25 (OC), P<0.001]. This corresponded to a 4- to 5-fold greater increase at month 24 in BMD in the tertiles, with the greatest decrease at month 6 in NTX or OC. In women treated with ALN (5 mg) who had a change at month 24 in spine BMD of at least 0%, 86% (NTX) and 79% (OC) had a decrease at month 6 of at least 40% (NTX) or 20% (OC) (sensitivity). The corresponding specificities were 48% (NTX) and 53% (OC). In conclusion, change at month 6 in NTX and OC, in groups of women treated with ALN, indicated the numeric long-term response in BMD within these groups. In individual women, a decrease at month 6, in NTX or OC below the cut-point, validly identified women who responded, on ALN treatment, with a stabilization or an increase in bone mass. However, lack of decrease below the cut-point in NTX or OC could not be used to identify women with a bone loss during ALN treatment.

Alendronate in early postmenopausal women: effects on bone mass during long-term treatment and after withdrawal. Alendronate Osteoporosis Prevention Study Group.

We studied the effect on bone mass of alendronate treatment for 5 yr and its withdrawal. Four hundred and forty-seven postmenopausal women with normal bone mass entered a 3-yr randomized trial followed by a 2-yr open label extension. Three hundred and eleven women completed the first 3 yr, and 263 consented to continue and completed the extension. We are reporting data from groups using the dose of alendronate currently approved for osteoporosis prevention (5 mg) or from the group in which alendronate treatment was withdrawn: 52 women received alendronate (5 mg) for 5 yr (group I), 56 received 3 yr of placebo followed by alendronate (5 mg) for 2 yr (group II), and 52 received alendronate (20 mg) for 2 yr followed by 3 yr off therapy (group III). In group I, alendronate (5 mg) increased bone mineral density (BMD) at the spine and trochanter by 2.5-3.2% (P < 0.001 vs. baseline) and stabilized total body and femoral neck BMD (change vs. baseline, P = NS) over 5 yr. By the end of 5 yr, BMD was comparable at the spine, hip, and total body in groups I and III. The 3-yr decrease in BMD after withdrawal of alendronate (20 mg) in group III was 1.8-5.7% (P < 0.01 vs. baseline) and similar to the 3-yr decrease in BMD in group II during the initial 3 yr. In conclusion, alendronate (5 mg) for 5 yr or alendronate (20 mg) for 2 yr followed by 3 yr off therapy prevented postmenopausal bone loss. After withdrawal of alendronate (20 mg), bone loss resumed at the normal early postmenopausal rate.

Skeletal benefits of alendronate: 7-year treatment of postmenopausal osteoporotic women. Phase III Osteoporosis Treatment Study Group.

We report here the second 2-yr extension of a clinical trial among postmenopausal women; 235 women continued blinded treatment with 5 or 10 mg alendronate daily, and 115 women who had been treated with alendronate for 5 yr were switched to blinded placebo. Continuous treatment with alendronate (10 mg daily) for 7 yr increased lumbar spine bone mineral density (BMD) by 11.4% compared to baseline. After the initial 18 months, each additional year of treatment through yr 7 increased spine BMD by 0.8% for the 10-mg dose and 0.6% for the 5-mg dose, with significant increases during yr 6-7. Previously reported increases in BMD at other skeletal sites and decreases in biochemical markers of bone turnover remained stable during yr 6-7. Among women previously taking alendronate for 5 yr who were switched to placebo, there was no significant decline in BMD at the spine or hip, whereas small, but significant, decreases in BMD at the forearm and total body and small increases in biochemical markers were observed. The safety and tolerability profiles were similar to those of placebo. This is the largest published long-term study of antiresorptive therapy. Our findings indicate that long-term alendronate treatment is well tolerated and effective for 7 yr. Increases in spinal BMD continue for at least 7 yr, and other skeletal benefits are maintained. Discontinuation does not lead to accelerated bone loss, but continuous treatment yields better skeletal benefits than shorter treatment.