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INTRODUCTION: Hyperkyphosis commonly affects older people but is not widely acknowledged as a clinically actionable problem, especially in men. There are several techniques to quantify kyphosis including the blocks and Cobb angle measurements. This study includes both kyphosis measures to investigate whether older men with accentuated kyphosis may be at increased mortality risk. METHODS: Men aged ≥65 years (N = 5994) were recruited to participate in the MrOS prospective cohort study from 2000 to 2002 (baseline). Our primary cohort included 2931 enrollees (mean age 79.3 years; SD 5.2) who underwent blocks-measured kyphosis from 2006 to 2009. Our secondary cohort included 2351 participants who underwent radiographic Cobb angle measurements at baseline. Cox proportional hazards analyses were used to determine association between kyphosis and all-cause mortality while adjusting for prevalent radiographic vertebral fractures, bone mineral density, incident fractures, gait speed, timed chair stands, self-reported health, alcohol use, medical co-morbidities, and physical activity. RESULTS: During a mean follow-up of 8.3 (SD 3.2) years, 1393 participants died in the primary cohort. In this group, compared to men with 0-1 block kyphosis, increasing blocks-measured kyphosis was associated with increased mortality (HR: 1.26-1.53, p trend <0.001). With addition of prevalent vertebral fracture to adjusted models, the association remained significant in participants with severe kyphosis (3+ blocks-measured). Similarly, with addition of chair stand performance the association remained significant for 4+ blocks kyphosis. Walking speed did not attenuate the association of kyphosis and mortality. In the secondary cohort, there were no significant associations between radiographic Cobb angle kyphosis and mortality. CONCLUSIONS: Increasing blocks-measured kyphosis was associated with a greater risk of mortality in older men, indicating that hyperkyphosis identified on physical exam should be considered a clinically significant finding that may warrant further evaluation and treatment.

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PURPOSE: To examine the association of polycystic ovary syndrome (PCOS) and pregnancy-induced hypertension (PIH) within a large population of pregnant women in an integrated healthcare system. METHODS: This retrospective study utilized a source cohort of 1023 women with PCOS and 1023 women without PCOS who had a delivered pregnancy within Kaiser Permanente Northern California. Preexisting hypertension was defined by hypertension diagnosis, treatment, or elevated blood pressure prior to 20 weeks of gestation. The development of PIH, including gestational hypertension, preeclampsia/eclampsia, or HELLP (hemolysis, elevated liver enzymes, and low platelet count), was ascertained by chart review. Among women without preexisting hypertension who had a singleton pregnancy, the association of PCOS and PIH was examined using multivariable logistic regression. RESULTS: Among 1902 women (910 PCOS) with singleton pregnancy, 101 (11.1%) PCOS and 36 (3.6%) non-PCOS women had preexisting hypertension and were excluded. Of the remaining 1765 women, those with PCOS (compared to non-PCOS) were slightly older (mean age 31.2 versus 30.7), more likely to be obese (39.6% versus 15.1%), nulliparous (63.8% versus 43.4%), and conceive with fertility treatment (54.1% versus 1.9%); they also had a higher incidence of PIH (10.8% versus 6.6%), including gestational hypertension (5.8% versus 3.6%) and preeclampsia or HELLP (4.9% versus 3.0%; all p<0.05). PCOS was associated with increased odds of PIH (odds ratio, OR 1.7, 95% confidence interval, CI 1.2-2.4), remaining significant after adjusting for age, race/ethnicity, nulliparity, and fertility treatment; however, findings were attenuated and no longer significant after adjusting for weight status (OR 1.1, CI 0.7-1.7). Maternal PCOS was also associated with preeclampsia/HELLP in unadjusted but not adjusted (OR 1.0, CI 0.5-1.9) analyses. Nulliparity and higher prepregnancy BMI were associated with PIH in both groups. CONCLUSION: Compared to women without PCOS, women with PCOS are at higher risk for PIH but this association was not independent of weight status.

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PURPOSE: Hyperkyphosis, accentuated curvature of the thoracic spine, is often attributed to osteoporosis, yet its underlying pathophysiology is not well understood. Bone turnover markers (BTM) reflect the dynamic process of bone formation and resorption. This study examined the association between serum BTM levels and kyphosis in community-dwelling older adults. METHODS: Between 2003 and 2006, 760 men and women in the Rancho Bernardo Study age 60 and older had blood drawn and kyphosis measured. Fasting serum was assayed for N-telopeptide (NTX) and procollagen type 1 n-terminal propeptide (P1NP), markers of bone resorption and formation, respectively. Participants requiring two or more 1.7 cm blocks under their head to achieve a neutral supine position were classified as having accentuated kyphosis. Analyses were stratified by sex and use of estrogen therapy (ET). Odds of accentuated kyphosis were calculated for each standard deviation increase in log-transformed BTM. RESULTS: Mean age was 75 years. Overall, 51% of 341 non-ET using women, 41% of 111 ET-using women, and 75% of 308 men had accentuated kyphosis. In adjusted models, higher P1NP and NTX were associated with decreased odds of accentuated kyphosis in non-ET using women (P1NP: OR = 0.78 [95% CI, 0.58-0.92]; NTX: OR = 0.68 [95% CI, 0.54-0.86]), but not in men or ET-using women (p > 0.05). CONCLUSIONS: The selective association of higher bone turnover with reduced odds of accentuated kyphosis in non-ET using women suggests that elevated BTM were associated with a lower likelihood of hyperkyphosis only in the low estrogen/high BTM environment characteristic of postmenopausal women who are not using ET.

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•Tumor characteristics of 5 cases of ovarian tumor of low malignant potential (LMP) with BRCA mutation were examined.•Young age, BRCA1 mutation, and presence of invasive implants may be characteristics of BRCA carriers with ovarian LMP.

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Recently, several virus studies have shown that protein glycosylation play a fundamental role in the virus-host cell interaction. Glycosylation characterization of the envelope proteins in both insect and mammalian cell-derived dengue virus (DENV) has established that two potential glycosylation residues, the asparagine 67 and 153 can potentially be glycosylated. Moreover, it appears that the glycosylation of these two residues can influence dramatically the virus production and the infection spreading in either mosquito or mammalian cells. The Sanofi Pasteur tetravalent dengue vaccine (CYD) consists of four chimeric viruses produced in mammalian vero cells. As DENV, the CYDs are able to infect human monocyte-derived dendritic cells in vitro via C-type lectins cell-surface molecules. Despite the importance of this interaction, the specific glycosylation pattern of the DENV has not been clearly documented so far. In this paper, we investigated the structure of the N-linked glycans in the four CYD serotypes. Using MALDI-TOF analysis, the N-linked glycans of CYDs were found to be a mix of high-mannose, hybrid and complex glycans. Site-specific N-glycosylation analysis of CYDs using nanoLC-ESI-MS/MS demonstrates that both asparagine residues 67 and 153 are glycosylated. Predominant glycoforms at asparagine 67 are high mannose-type structures while mainly complex- and hybrid-type structures are detected at asparagine 153. In vitro studies have shown that the immunological consequences of infection by the CYD dengue viruses 1-4 versus the wild type parents are comparable in human monocyte-derived dendritic cells. Our E-protein glycan characterizations of CYD are consistent with those observations from the wild type parents and thus support in vitro studies. In addition, these data provide new insights for the role of glycans in the dengue virus-host cell interactions.

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CONTEXT: Hospitalized patients experience symptoms including pain and anxiety that may negatively affect their well-being and overall quality of life (QOL), even when medical interventions are deemed successful. OBJECTIVES: The objective of the study was to assess the efficacy of prescriptive live therapeutic harp sounds on patient symptoms and QOL. METHODS: The study was a two-period, two-treatment arm crossover, randomized clinical trial. Individuals were randomized to harp music and standard care for the first 24 hours of the hospital stay, followed by 24 hours of only standard care, or vice versa. The harp intervention was 30-40 minutes of prescriptive live therapeutic harp sounds in the form of solo harp pieces and improvisations. Patients recorded well-being and symptom scores on linear analogue scales. Entry criteria included at least 18 years and a score of 3 or below on a 1-5 linear analogue scale indicating compromised overall QOL. RESULTS: Ninety-two eligible patients participated in the clinical trial. All the QOL variables had significantly higher percentages of patients with improvements during the harp treatment than during standard care. Five symptoms--fatigue, anxiety, sadness, relaxation, and pain--were significantly improved following therapeutic harp treatment. Approximately 30% to 50% of patients showed a significant increase in the QOL measures after harp treatment. CONCLUSION: There is evidence of strong positive effects on the QOL of hospitalized patients who received therapeutic harp sound treatment along with standard care.

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OBJECTIVE: POROS evaluates a 3-step fracture risk screening program in women 50-64 not previously diagnosed with osteoporosis. This report details the research design and baseline characteristics. METHODS: Recruiting from 6 primary care sites, baseline characteristics, including fracture risk factors, were assessed via self-administered questionnaires (SAQs). Subjects with >or=1 risk factor were randomized to Intervention or Non-Intervention. Those without any risk factors were placed in the No Risk Factors group. Bone turnover was measured in the Intervention group via urine N-telopeptide (NTx) testing. Subjects with NTx>50 had central hip and spine Dual-energy X-ray Absorptiometry (dxa). All groups were followed for 24 months, completing SAQs on osteoporosis management and fractures. At baseline, comparisons were made on demographics, health status, and prevalence of fracture risk factors. RESULTS: 2839 women were enrolled and included in baseline analyses (1464 Intervention, 372 Non-Intervention, and 1003 No Risk Factors). The mean age was 56.1 and 81.1% were postmenopausal. As expected by randomization, the Intervention and Non-Intervention groups had similar baseline characteristics. The most commonly reported fracture risk factors were body mass index <24 kg/m(2) and needing to use arms to stand from a chair. Subjects in the No Risk Factors group were more likely to be younger, heavier, Hispanic, in good health, a non-smoker, and to drink less alcohol. CONCLUSION: A stepwise screening program, utilizing data on fracture risk factors and high bone turnover prior to obtaining central bone density, can contribute significantly to fracture risk assessment in perimenopausal and younger postmenopausal women.

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The incidence of osteoporotic fractures increases with advancing age and is associated with significant health care expenditures, particularly related to hip fractures and loss of quality of life. Unfortunately, few studies have included subjects 80 years of age and older to help guide management of elderly patients who are living in the community or in long-term care facilities. Treating this age group encompasses the same general measures and pharmacologic therapies as in younger adults. Focusing on fall prevention and adequate vitamin D is essential. All prevention strategies in the elderly for fracture risk reduction should include simple vitamin D and calcium supplementation. However, for those at high risk of fracture, adding pharmacologic therapy should be considered. This article reviews recent research findings of general measures and pharmacologic therapy that are applicable to managing osteoporosis in the elderly.

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UNLABELLED: Many physicians remain uncertain about prescribing hormone therapy for symptomatic women at the onset of menopause. The American Society for Reproductive Medicine (ASRM) convened a multidisciplinary group of healthcare providers to discuss the efficacy and risks of hormone therapy for symptomatic women, and to determine whether it would be appropriate to treat women at the onset of menopause who were complaining of menopausal symptoms. MAJOR FINDINGS: Numerous controlled clinical trials consistently demonstrate that hormone therapy, administered via oral, transdermal, or vaginal routes, is the most effective treatment for vasomotor symptoms. Topical vaginal formulations of hormone therapy should be preferred when prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy. Data from the Women's Health Initiative indicate that the overall attributable risk of invasive breast cancer in women receiving estrogen plus progestin was 8 more cases per 10,000 women-years. No increased risk for invasive breast cancer was detected for women who never used hormone therapy in the past or for those receiving estrogen only. Hormone therapy is not effective for the treatment of cardiovascular disease and that the risk of cardiovascular disease with hormone therapy is principally in older women who are considerably postmenopause. CONCLUSIONS: Healthy symptomatic women should be offered the option of hormone therapy for menopausal symptoms. Symptom relief with hormone therapy for many younger women (at the onset of menopause) with menopausal symptoms outweighs the risks and may provide an overall improvement in quality of life. Hormone therapy should be individualized for symptomatic women. This involves tailoring the regimen and dose to individual needs.

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It is common clinical practice to obtain a bone density measurement at both the hip and spine to evaluate osteoporosis. With aging, degenerative changes in the lumbar spine may elevate the bone mineral density (BMD) results giving false assurances that the fracture risk at the spine is low. We examined the association of spine osteoarthritis and bone mineral density in 1082 community-dwelling ambulatory older women aged 50-96 years who participated in a 1992-1996 osteoporosis research clinic visit. The BMD was measured at the hip and posteroanterior (PA) and lateral lumbar spine using dual energy X-ray absorptiometry (DXA). Spine osteoarthritis was identified on the PA lumbar spine DXA images by a musculoskeletal radiologist. Forty percent of women had evidence of spine osteoarthritis (OA). Women with spine OA had a mean age of 77.4 yr (95% confidence interval [CI]: 76.5-78.2), were significantly older than women without spine OA (mean age, 66.8 yr; 95% CI: 65.9-67.7), and were more likely to have prevalent radiographic fractures (14.2% vs. 9.5%; p<0.05). Age-adjusted BMD at the femoral neck, total hip, PA spine, and lateral spine was significantly higher in women with spine OA. Women with spine OA were more likely to have osteoporosis by the World Health Organization classification at the femoral neck and total hip than those without spine OA, but less likely based on the PA spine (14.4% vs. 24.5%). Despite higher BMD levels, women with OA of the lumbar spine had higher prevalence of osteoporosis at the hip and more radiographic vertebral fractures. In elderly women 65 yr and older who are likely to have spine OA, the DXA measurement of the spine may not be useful in assessing fracture risk, and DXA of the hip is recommended for identification of osteoporosis.

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UNLABELLED: Many physicians remain uncertain about prescribing hormone therapy for symptomatic women at the onset of menopause. The American Society for Reproductive Medicine (ASRM) convened a multidisciplinary group of healthcare providers to discuss the efficacy and risks of hormone therapy for symptomatic women, and to determine whether it would be appropriate to treat women at the onset of menopause who were complaining of menopausal symptoms. MAJOR FINDINGS: Numerous controlled clinical trials consistently demonstrate that hormone therapy, administered via oral, transdermal, or vaginal routes, is the most effective treatment for vasomotor symptoms. Topical vaginal formulations of hormone therapy should be preferred when prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy. Data from the Women's Health Initiative indicate that the overall attributable risk of invasive breast cancer in women receiving estrogen plus progestin was 8 more cases per 10,000 women-years. No increased risk for invasive breast cancer was detected for women who never used hormone therapy in the past or for those receiving estrogen only. Hormone therapy is not effective for the treatment of cardiovascular disease and that the risk of cardiovascular disease with hormone therapy is principally in older women who are considerably postmenopause. CONCLUSIONS: Healthy symptomatic women should be offered the option of hormone therapy for menopausal symptoms. Symptom relief with hormone therapy for many younger women (at the onset of menopause) with menopausal symptoms outweighs the risks and may provide an overall improvement in quality of life. Hormone therapy should be individualized for symptomatic women. This involves tailoring the regimen and dose to individual needs.

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OBJECTIVES: To determine the efficacy of alendronate treatment on risk of vertebral fracture in a subgroup of women from the Fracture Intervention Trial who had bone mineral density T scores between -1.6 and -2.5 at the femoral neck and to describe how soon after initiation of therapy alendronate becomes effective and whether it is consistent in women with and without existing radiographic vertebral fracture. PATIENTS AND METHODS: From May 1992 to March 1997, postmenopausal women aged 55 to 80 years were randomized to receive alendronate at 5 mg/d for 2 years and 10 mg/d thereafter or placebo for up to 4.5 years (mean, 3.8 years) in a controlled, double-blind, multicenter study. RESULTS: A total of 3737 postmenopausal women were included in the study, 1878 in the alendronate group and 1859 in the placebo group. Risk of vertebral fracture was significantly reduced by alendronate compared with placebo for clinical (relative risk [RR], 0.40; 95% confidence interval [CI], 0.19-0.76; P=.005) and radiographic (RR, 0.57; 95% CI, 0.41-0.81; P=-.002) fracture. The reductions in vertebral fracture risk were consistent in women with and without an existing radiographic vertebral fracture for clinical (RR, 0.34; 95% CI, 0.12-0.84; and RR, 0.46; 95% CI, 0.16-1.17; respectively) and radiographic (RR, 0.53; 95% CI, 0.34-0.82; and RR, 0.64; 95% CI, 0.38-1.10; respectively) fractures. In both groups, the effect of alendronate on clinical vertebral fracture was noted soon after therapy was initiated. The absolute risk of vertebral fracture was low in women without a baseline radiographic fracture. CONCLUSIONS: In women with low bone mass who do not meet the bone mineral density criterion for osteoporosis, alendronate is effective in reducing the risk of vertebral fractures. The absolute benefit of this therapy in women with a T score between -1.6 and -2.5 is greater in women with an existing vertebral fracture and/or with other risk factors. The effect of alendronate occurs early.

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OBJECTIVES: Kyphosis is considered a clinical sign of osteoporotic vertebral fractures. We examined the association of radiographically defined kyphosis with vertebral fractures to determine if this belief was true. METHODS: A total of 1407 ambulatory white adults, aged 50-96 years, from the middle-class community of Rancho Bernardo, California, USA, attended a 1992-96 research clinic visit. Bone mineral density (BMD) was measured at the hip and spine, and lateral thoracolumbar spine radiographs were obtained. The degree of kyphosis was determined using the modified Cobb method. RESULTS: A total of 114 of 553 men (20.6%) and 188 of 854 women (22.0%) had one or more thoracic vertebral fractures. Degenerative disc disease was observed in 45.4% of men and 56.7% of women. The mean age-adjusted Cobb angle was significantly higher (p < 0.001) in men and women with vertebral fractures in comparison to those without vertebral fractures: men 51.3 degrees vs 41.5 degrees, respectively, and women 56.4 degrees vs 46.3 degrees. The prevalence of vertebral fracture increased with higher Cobb angles and there was no significant difference by sex. The proportion of women with osteoporosis increased with the increase of Cobb angle. In the upper quartile of the Cobb angle distribution (> or = 55.5 degrees ), only 36.2% of men and 36.9% of women had prevalent thoracic vertebral fractures; and osteoporosis using WHO BMD criteria was present at the total hip in 9.7% of men and 32.7% of women. CONCLUSION: The majority of men and women with exaggerated kyphosis (the upper quartile of the Cobb angle) had no evidence of thoracic vertebral fractures or osteoporosis. Degenerative disc disease, not vertebral fractures, was the most common finding associated with radiographically defined angle of kyphosis in men and women. Thus kyphosis per se should not be considered diagnostic of osteoporosis. Nevertheless, patients with exaggerated kyphosis should be evaluated for underlying osteoporotic fracture.

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BACKGROUND: Previous bone mineral density (BMD) studies have suggested Asian women have lower BMD and Hispanic women have similar or higher BMD compared with Caucasian women, partially explained by ethnic differences in body size. This study compared the effect of different variables representing body size on BMD in postmenopausal women aged 50-69 years from three ethnic groups in San Diego County, CA: 354 Caucasians, 285 Filipinas, and 164 Hispanics. METHODS: In all three groups, BMD was measured by DXA (Hologic 2000) at the hip, lumbar spine, and total body. Lifestyle variables and anthropometric measures were assessed by standard methodology; medication and supplement use were validated by a nurse. RESULTS: Regardless of the variables used to represent body size in the regression modelling, either body mass index or lean and fat tissue mass, ethnic differences were minimal across the three groups. The only significant differences observed using the two fully adjusted models (age, height, body mass index or lean and fat tissue mass, smoking, alcohol, exercise, current oestrogen and calcium supplement use, and osteoarthritis) were at the total body BMD site where Filipinas had significantly higher BMD than the Caucasians or Hispanics, whose total body BMD was similar to one another. The independent variables in the fully adjusted models explained approximately 20-40% of the variation in BMD at each of the four sites. Income or occupation did not help explain BMD differences, but a pattern of increased BMD among those with some college education in all three groups was observed. CONCLUSIONS: Accounting for body size using either body mass index or fat and lean tissue mass along with height and other lifestyle variables minimizes ethnic differences and explains a considerable amount of variation in mean BMD among older ethnic minority and Caucasian women.

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OBJECTIVE: Many studies have found increased bone mineral density (BMD) in patients with osteoarthritis (OA). As a result, clinicians may not consider osteoporosis in patients with OA. We examined the relation between hand OA and BMD levels among 1779 community-dwelling, ambulatory white adults aged 50-96 years. METHODS: BMD was measured by dual energy x-ray absorptiometry at the hip, lateral and anteroposterior (AP) lumbar spine, and total body. Both hands of each subject were systematically examined for bony enlargement, swelling, and deformity. RESULTS: Using the American College of Rheumatology criteria for epidemiologic studies, the clinical diagnosis of hand OA was made in 6.6% of men and 14.5% of women. In women, BMD measurements adjusted for age, body mass index, smoking, alcohol, exercise, and current estrogen use were significantly lower only at the hip in those with versus those without hand OA. In contrast, men with hand OA had higher multiply-adjusted mean BMD levels at all sites compared to those without hand OA. These differences were statistically significant only at the AP spine; the absent difference for lateral spine BMD suggests that degenerative changes may explain the higher AP spine BMD levels. Patterns in both men and women were similar in those with isolated hand OA or hand OA in the presence of knee or hip OA. CONCLUSION: OA was not associated with increased BMD levels in men or women. Contrary to expectations the only significant difference was that women with hand OA had lower hip BMD. Thus evaluation for osteoporosis should not be overlooked in women with hand OA.

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Insomnia is a problem in all stages of life but is particularly common after age 65. A number of factors--including advanced age, psychosocial influences, medical illness, and the use of medications and alcohol--may disturb sleep architecture. Evaluation of insomnia in the older patient requires a careful history and physical examination, supplemented by a sleep diary. Treatment of underlying conditions and nonpharmacologic improvements in sleep hygiene are first-line therapy, but pharmacologic agents such as benzodiazepines, nonbenzodiazepine hypnotics, or antidepressants may be needed. Nonbenzodiazepines with rapid elimination may offer a lower side-effect profile than other hypnotic agents when used for insomnia in the older population.

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BACKGROUND: Many elderly female residents of long-term care facilities have osteoporosis and could benefit from intervention to increase bone density. OBJECTIVE: To examine the efficacy and safety of alendronate for treatment of osteoporosis in elderly female residents of long-term care facilities. DESIGN: Multicenter, randomized, double-blind, placebo-controlled 2-year study. SETTING: 25 long-term care facilities. PATIENTS: 327 elderly women with osteoporosis. INTERVENTION: Patients were randomly assigned to receive alendronate, 10 mg/d, or placebo. All patients also received vitamin D, 400 IU/d, and some patients received supplemental calcium (total intake, approximately 1500 mg/d). MEASUREMENTS: Bone mineral density (BMD) of the spine and hip and biochemical markers of bone turnover. RESULTS: Alendronate produced significantly greater increases in BMD than did placebo (24-month differences: spine, 4.4% [95% CI, 3.3% to 5.5%]; femoral neck, 3.4% [CI, 2.3% to 4.4%]). Alendronate produced greater decreases from baseline in biochemical markers of bone turnover than did placebo (P < 0.001). CONCLUSION: Alendronate increased BMD at both the spine and hip in elderly female residents of long-term care facilities.

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OBJECTIVES: To evaluate the effect of alendronate on the occurrence rate of multiple svmptomatic fractures and on the risk of multiple symptomatic fractures (likelihood of having more than one fracture diagnosed because of the symptoms the fractures caused over the study period) among women with osteoporosis. DESIGN: Primary analysis of data from a randomized, placebo-controlled, double-blind trial. SETTING: Eleven community-based clinical research centers. PARTICIPANTS: Subset of women enrolled in the Fracture Intervention Trial: aged 55 to 81 and having at least one morphometric vertebral fracture at baseline (n=2,027) or having no vertebral fracture but meeting prevailing World Health Organization bone mineral density criteria for osteoporosis (T-score < or =2.5 at the femoral neck)(n = 1,631). INTERVENTION: All participants reporting calcium intake of 1,000 mg/day or less received a supplement of 500 mg calcium and 250 IU cholecalciferol. Participants were randomly assigned to placebo or alendronate sodium (5 mg/day for 2 years and 10 mg/day for the remainder of the study). Average total follow-up was 4.3 years. MEASUREMENTS: Symptomatic fractures were diagnosed by personal physicians and confirmed by review of radiological data by an expert committee blinded to treatment assignments. RESULTS: Eighty-six of 1,817 women receiving placebo experienced multiple symptomatic fractures during the follow-up period, compared with 51 of 1,841 receiving alendronate. Reduction of risk for multiple symptomatic fractures combined was 42% (relative risk (RR) = 0.58, 95% confidence interval (CI) = 0.41, 0.81) and for multiple symptomatic vertebral fractures was 84% (RR = 0.16,95% Cl = 0.05, 0.42). Cumulative incidence curves showed divergence after as little as 3 months of treatment, with a statistically significant (P = .044) reduction at 6 months for multiple symptomatic vertebral fractures. When all fractures over the follow-up period were included, the occurrence rates of all symptomatic fractures and symptomatic vertebral fractures were 34% and 63% lower, respectively, with alendronate than with placebo. These reductions were sustained during the follow-up period. All reductions in risk were consistent across predefined subgroups: age (<75 vs > or =75), morphometric vertebral fracture(present vs absent), prior clinical fracture since age 45 (yes vs no), and whether the subject had fallen in the 12 months before randomization. CONCLUSIONS: These data demonstrate that treatment with alendronate reduces the risk of multiple symptomatic fractures during a treatment period averaging 4.3 years. The reductions were consistent across prespecified sub-groups. This effect is evident early in treatment and is sustained.

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