Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.

CONTEXT: The optimal duration of treatment of women with postmenopausal osteoporosis is uncertain. OBJECTIVE: To compare the effects of discontinuing alendronate treatment after 5 years vs continuing for 10 years. DESIGN AND SETTING: Randomized, double-blind trial conducted at 10 US clinical centers that participated in the Fracture Intervention Trial (FIT). PARTICIPANTS: One thousand ninety-nine postmenopausal women who had been randomized to alendronate in FIT, with a mean of 5 years of prior alendronate treatment. INTERVENTION: Randomization to alendronate, 5 mg/d (n = 329) or 10 mg/d (n = 333), or placebo (n = 437) for 5 years (1998-2003). MAIN OUTCOME MEASURES: The primary outcome measure was total hip bone mineral density (BMD); secondary measures were BMD at other sites and biochemical markers of bone remodeling. An exploratory outcome measure was fracture incidence. RESULTS: Compared with continuing alendronate, switching to placebo for 5 years resulted in declines in BMD at the total hip (-2.4%; 95% confidence interval [CI], -2.9% to -1.8%; P<.001) and spine (-3.7%; 95% CI, -4.5% to -3.0%; P<.001), but mean levels remained at or above pretreatment levels 10 years earlier. Similarly, those discontinuing alendronate had increased serum markers of bone turnover compared with continuing alendronate: 55.6% (P<.001) for C-telopeptide of type 1 collagen, 59.5% (P < .001) for serum n = propeptide of type 1 collagen, and 28.1% (P<.001) for bone-specific alkaline phosphatase, but after 5 years without therapy, bone marker levels remained somewhat below pretreatment levels 10 years earlier. After 5 years, the cumulative risk of nonvertebral fractures (RR, 1.00; 95% CI, 0.76-1.32) was not significantly different between those continuing (19%) and discontinuing (18.9%) alendronate. Among those who continued, there was a significantly lower risk of clinically recognized vertebral fractures (5.3% for placebo and 2.4% for alendronate; RR, 0.45; 95% CI, 0.24-0.85) but no significant reduction in morphometric vertebral fractures (11.3% for placebo and 9.8% for alendronate; RR, 0.86; 95% CI, 0.60-1.22). A small sample of 18 transilial bone biopsies did not show any qualitative abnormalities, with bone turnover (double labeling) seen in all specimens. CONCLUSIONS: Women who discontinued alendronate after 5 years showed a moderate decline in BMD and a gradual rise in biochemical markers but no higher fracture risk other than for clinical vertebral fractures compared with those who continued alendronate. These results suggest that for many women, discontinuation of alendronate for up to 5 years does not appear to significantly increase fracture risk. However, women at very high risk of clinical vertebral fractures may benefit by continuing beyond 5 years. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT 00398931.

Skeletal consequences of hormone therapy discontinuance: a systematic review.

UNLABELLED: Although hormone therapy protects against bone loss after menopause, currently it is not recommended once menopausal symptoms have subsided. We reviewed randomized clinical trials to quantify bone loss after stopping hormone therapy and summarize treatment options for women who discontinue hormone treatment. We conducted a search of MEDLINE and EMBASE for randomized, controlled trials measuring bone mineral density (BMD) after hormone therapy discontinuation. Other known published and unpublished data were also included. Eleven studies fulfilled the search criteria. In each, bone loss was rapid after stopping hormone therapy, with BMD declines ranging from 2.3% to 6.2% in the first year. Increases in bone turnover markers also occurred rapidly when hormone therapy was stopped. Limited data addressing treatment after hormone therapy is stopped exist; only 2 studies specifically evaluated therapy to protect bone after hormone discontinuation. Taken together, these 2 studies demonstrate that alendronate produced significant increases relative to placebo in spine, hip, and total body BMD in women with low bone density who had discontinued hormone therapy within the past 3 months, preventing the rapid bone loss seen on discontinuation of hormone therapy. Among treatment options for preventing bone loss on discontinuation of hormone therapy for which randomized clinical trial data are available, alendronate prevented bone loss or increased bone density in postmenopausal women with low bone density. Women who are discontinuing hormone therapy should be counseled about potential bone loss and effective treatment options. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to state that discontinuation of replacement menopausal hormone therapy, which protects against bone loss, is not recommended after menopause symptoms have subsided; recall that it may accelerate bone loss; and explain that there is bone loss preventive treatment for women after discontinuation of hormone therapy.

How useful are measures of BMD and bone turnover?

Measurements of bone mineral density (BMD) and biochemical markers of bone turnover are useful in the diagnosis and management of osteoporosis, as well as in research relating to the pathogenesis and treatment of the disease. Recent challenges to the utility of these measures have resulted in some confusion among both researchers and clinicians. BMD accounts for the great majority of bone strength and is the current gold standard for the diagnosis of osteoporosis, as well as for prediction of fracture risk. Although bone turnover increases sharply after menopause, biochemical markers of bone turnover have limited usefulness in fracture risk prediction. Persistently elevated bone turnover throughout the menopause is associated with structural decrements, cannot be measured routinely and non-invasively. In research applications, both BMD and markers of bone turnover are used to identify candidate agents in preclinical and clinical studies. In addition, head-to-head comparisons of treatments utilize these measures, because fracture endpoint trials would need to be extraordinarily large and complex. Analyses that have suggested that change in BMD or bone turnover 'explains' little of change in fracture risk with treatment appear to be flawed. Although neither can perfectly predict fracture, they are our current best alternatives.

Bone mineral density, soft tissue body composition, strength, and functioning after hip fracture.

BACKGROUND: Although substantial decrements in bone, muscle, and functional ability have been reported to follow the occurrence of hip fracture in elderly women, little is known about the interrelation of these consequences. The authors evaluated the associations among physiologic and functional factors during recovery from hip fracture to determine whether any consistent sequence of events followed and whether markers of functional outcomes could be identified. METHODS: Two hundred five community-dwelling women aged 65 years and older who sustained hip fracture between 1992 and 1995 and were admitted to one of two acute care hospitals in metropolitan Baltimore, Maryland, participated in a 1-year prospective cohort study. Bone mineral density, lean mass, and fat mass were measured by dual-energy X-ray absorptiometry during the hospitalization and 2, 6, and 12 months later. Functional limitations were self-reported and grip strength was measured during interviews at the same time points. Correlation coefficients were calculated for all possible pairs of measures and time points. RESULTS: Losses of femoral neck bone mineral density and lean body mass and gains in fat mass were observed. Grip strength showed early improvement but declined by 1 year to levels close to those seen during hospitalization. Functional outcomes showed minimal correlation with bone or body composition and only moderate correlation with strength. CONCLUSIONS: Physiologic and functional declines follow hip fracture in elderly women. These are largely independent of one another and suggest that interventions to maximize recovery must simultaneously target multiple areas, including bone, muscle, strength, and function.

Osteoporosis and fracture risk in women of different ethnic groups.

UNLABELLED: Osteoporosis and 1-year fracture risk were studied in 197,848 postmenopausal American women from five ethnic groups. Weight explained differences in BMD, except among blacks, who had the highest BMD. One SD decrease in BMD predicted a 50% increased fracture risk in each group. Despite similar relative risks, absolute fracture rates differed. INTRODUCTION: Most information about osteoporosis comes from studies of white women. This study describes the frequency of osteoporosis and the association between BMD and fracture in women from five ethnic groups. MATERIALS AND METHODS: This study was made up of a cohort of 197,848 community-dwelling postmenopausal women (7784 blacks, 1912 Asians, 6973 Hispanics, and 1708 Native Americans) from the United States, without known osteoporosis or a recent BMD test. Heel, forearm, or finger BMD was measured, and risk factor information was obtained; 82% were followed for 1 year for new fractures. BMD and fracture rates were compared, adjusting for differences in covariates. RESULTS: By age 80, more than one-fifth of women in each ethnic group had peripheral BMD T scores <-2.5. Black women had the highest BMD; Asian women had the lowest. Only the BMD differences for blacks were not explained by differences in weight. After 1 year, 2414 new fractures of the spine, hip, forearm, wrist, or rib were reported. BMD at each site predicted fractures equally well within each ethnic group. After adjusting for BMD, weight, and other covariates, white and Hispanic women had the highest risk for fracture (relative risk [RR] 1.0 [referent group] and 0.95, 95% CI, 0.76, 1.20, respectively), followed by Native Americans (RR, 0.87; 95% CI, 0.57, 1.32), blacks (RR, 0.52; 95% CI, 0.38, 0.70), and Asian Americans (RR, 0.32; 95% CI, 0.15, 0.66). In age- and weight-adjusted models, each SD decrease in peripheral BMD predicted a 1.54 times increased risk of fracture in each ethnic group (95% CI, 1.48-1.61). Excluding wrist fractures, the most common fracture, did not materially change associations. CONCLUSIONS: Ethnic differences in BMD are strongly influenced by body weight; fracture risk is strongly influenced by BMD in each group. Ethnic differences in absolute fracture risk remain, which may warrant ethnic-specific clinical recommendations.

Putting evidence-based medicine into clinical practice: comparing anti-resorptive agents for the treatment of osteoporosis.

OBJECTIVE: To compare the effectiveness of antiresorptive agents in reducing the risk of vertebral and non-vertebral fractures using data from published meta-analyses and the technique of adjusted indirect comparisons. RESEARCH DESIGN AND METHODS: Pairs of agents were compared by adjusted indirect comparison of 0.56 [0.40, 0.78], respectively) in reducing the their effects relative to a common comparator (placebo) using meta-analyses published by The Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group. RESULTS: Adjusted indirect comparisons identified only one pair of agents that had significantly different effects on vertebral fracture incidence: alendronate was 34% more effective than calcitonin (Relative Risk: 0.66, 95% Confidence Interval: 0.48-0.90). Alendronate was significantly more effective than risedronate, calcitonin, estrogen, etidronate, and raloxifene (Relative Risks: 0.70 [0.49, 0.99], 0.64 [0.42, 0.98], 0.59 [0.41, 0.84], 0.52 [0.32, 0.82], and incidence of non-vertebral fractures. No other significant pairwise differences were observed. CONCLUSIONS: The results suggest that there are differences in anti-fracture efficacy among antiresorptive agents, particularly for non-vertebral fractures. Direct head-to-head comparisons would be needed to confirm these findings but are unlikely to be conducted.

Bone mineral density thresholds for pharmacological intervention to prevent fractures.

BACKGROUND: Treatment intervention thresholds for prevention of osteoporotic fractures can be derived from reports from the World Health Organization (diagnostic criteria) and National Osteoporosis Foundation (treatment criteria). It is not known how well these thresholds work to identify women who will fracture and are therefore candidates for treatment interventions. We used data from the National Osteoporosis Risk Assessment (NORA) to examine the effect of different treatment thresholds on fracture incidence and numbers of women with fractures within the year following bone mineral density measurement. METHODS: The study comprised 149 524 white postmenopausal women aged 50 to 104 years (mean age, 64.5 years). At baseline, bone mineral density was assessed by peripheral bone densitometry at the heel, finger, or forearm. New fractures during the next 12 months were self-reported. RESULTS: New fractures were reported by 2259 women, including 393 hip fractures; only 6.4% had baseline T scores of -2.5 or less (World Health Organization definition for osteoporosis). Although fracture rates were highest in these women, they experienced only 18% of the osteoporotic fractures and 26% of the hip fractures. By National Osteoporosis Foundation treatment guidelines, 22.6% of the women had T scores of 2.0 or less, or -1.5 or less with 1 or more clinical risk factors. Fracture rates were lower, but 45% of osteoporotic fractures and 53% of hip fractures occurred in these women. CONCLUSIONS: Using peripheral measurement devices, 82% of postmenopausal women with fractures had T scores better than -2.5. A strategy to reduce overall fracture incidence will likely require lifestyle changes and a targeted effort to identify and develop treatment protocols for women with less severe low bone mass who are nonetheless at increased risk for future fractures.

Predictors of bone loss after hip fracture.

Although accelerated bone mineral density (BMD) loss follows hip fracture, little is known about factors associated with this loss. We examined potential predictors of BMD loss in a cohort of community-dwelling women who had sustained hip fracture and who were followed for 1 year after fracture. BMD was measured at the femoral neck, intertrochanteric region, and total body, during hospitalization and 2, 6, and 12 months later. Demographic, health, lifestyle, clinical, surgical, and functional characteristics at baseline, and postfracture activity were evaluated for associations with baseline BMD and BMD 1 year later. To examine possible BMD-dependent effects, high and low baseline BMD groups were defined. None of the studied factors consistently predicted either baseline BMD or BMD at 1 year after fracture, among women with either high or low baseline BMD. Baseline BMD was the only factor that substantially and consistently predicted change, explaining 70% to 90% of variation. These results suggest that BMD will not be preserved by general rehabilitative measures and that prompt, specific intervention to minimize bone loss after hip fracture is an essential element of clinical management of the hip fracture patient.

Gender differences in mortality after hip fracture: the role of infection.

UNLABELLED: Possible explanations for the observed gender difference in mortality after hip fracture were examined in a cohort of 804 men and women. Mortality during 2 years after fracture was identified from death certificates. Men were twice as likely as women to die, and deaths caused by pneumonia/influenza and septicemia showed the greatest increase. INTRODUCTION: Men are more likely to die after hip fracture than women. Gender differences in predisposing factors and causes of death have not been systematically studied. MATERIALS AND METHODS: Participants (173 men and 631 women) in the Baltimore Hip Studies cohort enrolled in 1990 and 1991, at the time of hospitalization for hip fracture, were followed longitudinally for 2 years. Cause-specific mortality 1 and 2 years after hip fracture, identified from death certificates, was compared by gender and to population rates. RESULTS AND CONCLUSIONS: Men were twice as likely as women to die during the first and second years after hip fracture (odds ratio [OR], 2.28; 95% CI, 1.47, 3.54 and OR, 2.21; 95% CI, 1.48, 3.31). Prefracture medical comorbidity, type of fracture, type of surgical procedure, and postoperative complications did not explain the observed difference. Greatest increases in mortality, relative to the general population, were seen for septicemia (relative risk [RR], 87.9; 95% CI, 16.5, 175 at 1 year and RR, 32.0; 95% CI, 7.99, 127 at 2 years) and pneumonia (RR, 23.8; 95% CI, 12.8, 44.2 at 1 year and RR, 10.4; 95% CI, 3.35, 32.2 at 2 years). The magnitude of increase in deaths caused by infection was greater for men than for women in both years. Mortality rates for men and women were similar if deaths caused by infection were excluded (3.46 [1.79, 6.67] and 2.47 [1.63, 3.72] at 1 year and 0.96 [0.48, 1.91] and 1.26 [0.80, 1.98] at 2 years). Deaths related to infections (pneumonia, influenza, and septicemia) seem to be largely responsible for the observed gender difference. In conclusion, an increased rate of death from infection and a gender difference in rates persists for at least 2 years after the fracture.

Recency and duration of postmenopausal hormone therapy: effects on bone mineral density and fracture risk in the National Osteoporosis Risk Assessment (NORA) study.

OBJECTIVES: Results from the Women's Health Initiative showed that postmenopausal hormone replacement therapy (HRT) prevents fractures but has an overall unfavorable risk:benefit ratio, leading to the recommendation that HRT be used only for women with troublesome menopause symptoms, and for as short a time as possible. This recommendation has important implications for the timing and duration of HRT and the prevention of osteoporosis. The large number of women participating in the National Osteoporosis Risk Assessment (NORA) program provided the opportunity to evaluate bone mineral density (BMD) and 1-year fracture risk in analyses stratified by duration and recency of HRT. DESIGN: Participants were 170,852 postmenopausal women aged 50 to 104, without known osteoporosis, who were recruited from primary physicians offices across the US. BMD was measured at one of four peripheral sites, and the 1-year risk of osteoporotic fracture was assessed by questionnaire. RESULTS: At baseline, current HRT users had the highest T-scores at every age. Among current hormone users, women who had used HRT longest had the highest BMD levels. Women who had stopped HRT more than 5 years previously, regardless of duration of use, had T-scores similar to never-users. Current but not past hormone use at baseline was associated with a 25% to 29% lower risk of osteoporotic fracture (P < 0.0001) in 1 year, compared with nonusers. These findings were independent of age, ethnicity, body mass index, lifestyle, years postmenopausal, and site of BMD measurement. CONCLUSIONS: We conclude that postmenopausal BMD and fracture are closely associated with current, but not prior, HRT use. Use of HRT for 5 years or less, as proposed for treatment of symptomatic women during menopause transition, is unlikely to preserve bone or significantly reduce fracture risk in later years.

The epidemiology of osteoporosis and fractures in geriatric medicine.

Several conclusions can be drawn from this article, the most important of which are as follows: 1. Low bone mass is widely prevalent among older men and women and is associated with important fracture consequences. 2. The prevalence of osteoporosis and fracture is projected to increase over the next several decades. 3. Although Caucasian women are at greatest risk, substantial numbers of men and women of non-Caucasian heritage are also affected. 4. The population burden of disease consequences, including mortality, morbidity, and social and personal cost, is anticipated to increase as well. 5. In the group at greatest risk (Caucasian women), osteoporosis and fracture have well-established risk factors, many of which are modifiable. 6. Relevance of these risk factors for groups other than Caucasian women appears likely but requires further investigation. 7. Personal and societal costs associated with osteoporosis are enormous; as such, identification of persons at risk and prevention and treatment of this disease should be public health priorities.

Should a diagnosis of osteopenia trigger clinical action?

Osteopenia is far more widespread than osteoporosis, its incidence in the older age-groups being roughly three times that of osteoporosis. Furthermore, almost one-sixth of the young-adult population are--by definition--osteopenic (< 1% have osteoporosis). The National Osteoporosis Foundation guidelines suggest intervention at T-scores of -2.0 or lower; however, risk factors are built into various sets of guidelines, such that intervention may be desirable at T-scores of -1.0. The risk of fracture is, in fact, greater at lower bone mineral densities (BMD) throughout the entire range of BMD values. Thus, osteopenia is a management issue. This article considers the risks of fracture in terms of BMD and other factors, and recommends action that answers the prevention needs of the individual patient.

Hip fracture: risk factors and outcomes.

Hip fracture is an important public health and personal burden, and this burden is anticipated to increase over the next several decades. Although white women experience the greatest lifetime risk of hip fracture, risk extends to men and to nonwhite populations. Bone strength, risk of falling, and individual clinical characteristics combine to affect the risk of hip fracture. Nearly $9 billion were expended in 1995 in the United States for the management of hip fractures. Hip fracture has important sequelae, including loss of bone and muscle mass. Mortality is significantly increased after hip fracture, and functional recovery is limited to less than 50% of those who fracture. About 25% of patients reside in long-term care facilities for a year or more after fracture, and the impact of hip fracture on health-related quality of life is considerable and long lasting.

Prediction of fracture risk in postmenopausal white women with peripheral bone densitometry: evidence from the National Osteoporosis Risk Assessment.

Low bone mineral density (BMD) is a risk factor for fracture. Although the current "gold standard" test is DXA of the hip and spine, this method is not universally available. No large studies have evaluated the ability of new, less expensive peripheral technologies to predict fracture. We studied the association between BMD measurements at peripheral sites and subsequent fracture risk at the hip, wrist/forearm, spine, and rib in 149,524 postmenopausal white women, without prior diagnosis of osteoporosis. At enrollment, each participant completed a risk assessment questionnaire and had BMD testing at the heel, forearm, or finger. Main outcomes were new fractures of the hip, wrist/forearm, spine, or rib within the first 12 months after testing. After 1 year, 2259 women reported 2340 new fractures. Based on manufacturers' normative data and multivariable adjusted analyses, women who had T scores < or = -2.5 SD were 2.15 (finger) to 3.94 (heel ultrasound [US]) times more likely to fracture than women with normal BMD. All measurement sites/devices predicted fracture equally well, and risk prediction was similar whether calculated from the manufacturers' young normal values (T scores) or using SDs from the mean age of the National Osteoporosis Risk Assessment (NORA) population. The areas under receiver operating characteristic (ROC) curves for hip fracture were comparable with those published using measurements at hip sites. We conclude that low BMD found by peripheral technologies, regardless of the site measured, is associated with at least a twofold increased risk of fracture within 1 year, even at skeletal sites other than the one measured.

The role of the primary care physician in diagnosis and management of osteoporosis.

It is estimated that 28,000,000 women in the United States have low bone mass (osteopenia) or osteoporosis. More than 1.5 million osteoporotic fractures occur annually. Because osteoporosis is asymptomatic until fracture occurs, early diagnosis requires both an awareness of risk and specific testing. The National Osteoporosis Foundation (NOF) has published guidelines for diagnosis and treatment, but these have important limitations. Bone mineral density (BMD) testing is the method of choice for diagnosis, and is more predictive of fracture risk than hypertension is of stroke or hypercholesterolemia is of myocardial infarction. Although the diagnosis of osteoporosis, as defined by the World Health Organization, is a T-score of < or =-2.5, the association between BMD and fracture risk is a continuous rather than threshold effect, and NOF guidelines suggest treating at higher T-scores, depending on risk factors. Important risk factors include age, current smoking, low body weight (<127 lbs.), maternal history of fracture, and personal history of fracture. Data from the National Osteoporosis Risk Assessment (NORA) study are presented, demonstrating the usefulness of peripheral BMD measurements in identifying postmenopausal women at risk of fracture. Several therapeutic options, including hormone replacement therapy, raloxifene, calcitonin, alendronate, and risendronate, are now available to the clinician. It can be argued that we currently have all necessary tools to eliminate osteoporosis and osteoporotic fracture.