Fracture Intervention Trial Long-term Extension Research Articles

Annals for Educators - 2 July 2019.

Annals for Educators - 2 July 2019.

Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research.

Bisphosphonates (BPs) are the most commonly used medications for osteoporosis. This ASBMR report provides guidance on BP therapy duration with a risk-benefit perspective. Two trials provided evidence for long-term BP use. In the Fracture Intervention Trial Long-term Extension (FLEX), postmenopausal women receiving alendronate for 10 years had fewer clinical vertebral fractures than those switched to placebo after 5 years. In the HORIZON extension, women who received 6 annual infusions of zoledronic acid had fewer morphometric vertebral fractures compared with those switched to placebo after 3 years. Low hip T-score, between -2 and -2.5 in FLEX and below -2.5 in HORIZON extension, predicted a beneficial response to continued therapy. Hence, the Task Force suggests that after 5 years of oral BP or 3 years of intravenous BP, reassessment of risk should be considered. In women at high risk, for example, older women, those with a low hip T-score or high fracture risk score, those with previous major osteoporotic fracture, or who fracture on therapy, continuation of treatment for up to 10 years (oral) or 6 years (intravenous), with periodic evaluation, should be considered. The risk of atypical femoral fracture, but not osteonecrosis of the jaw, clearly increases with BP therapy duration, but such rare events are outweighed by vertebral fracture risk reduction in high-risk patients. For women not at high fracture risk after 3 to 5 years of BP treatment, a drug holiday of 2 to 3 years can be considered. The suggested approach for long-term BP use is based on limited evidence, only for vertebral fracture reduction, in mostly white postmenopausal women, and does not replace the need for clinical judgment. It may be applicable to men and patients with glucocorticoid-induced osteoporosis, with some adaptations. It is unlikely that future trials will provide data for formulating definitive recommendations. © 2015 American Society for Bone and Mineral Research.

A model of BMD changes after alendronate discontinuation to guide postalendronate BMD monitoring.

Women stopping alendronate are commonly monitored with serial bone mineral density (BMD) measurements, yet no information exists on how frequently or for whom these measurements should be performed. The objective of the study was to develop a tool to guide post-alendronate BMD monitoring. A predictive model was constructed to estimate the time until a given percentage of women's BMD T-scores drop below a given threshold that indicates a management change (such as retreatment) would be considered. This model was then used to estimate the time it would take for groups of women defined by their baseline BMDs to drop below the given threshold. Data were derived from the Fracture Intervention Trial Long Term Extension (FLEX), the largest multicenter clinical trial of its type to date. Four hundred four women who had received an average of 5.1 years of alendronate during the Fracture Intervention Trial and were subsequently observed for 5 treatment-free years (on placebo) during the FLEX trial were used to estimate the change in BMD over time. If a management change such as alendronate reinitiation would be considered when BMD T-score drops below -2.5, the model shows that women with total hip BMD greater than -1.9 T-scores at the time of alendronate discontinuation have less than a 20% probability that at follow-up, monitoring BMD will be below the threshold within 5 years. The model performed similarly, and results are provided over a range of management change thresholds from -1.75 to -3 T-scores. Using the tool developed in this analysis, it is possible to estimate when BMD repeat measurement after alendronate discontinuation could potentially be useful. Measuring BMD within 5 years after alendronate discontinuation is unlikely to change management for women with total hip BMD 0.6 T-scores above a prespecified retreatment threshold within the range of -1.75 to -3 T-scores.

Fracture prediction after discontinuation of 4 to 5 years of alendronate therapy: the FLEX study.

Discontinuation of bisphosphonate therapy after 3 to 5 years is increasingly considered, but methods to monitor fracture risk after discontinuation have not been established. To test methods of predicting fracture risk among women who have discontinued alendronate therapy after 4 to 5 years. The prospective Fracture Intervention Trial Long-term Extension (FLEX) study randomized postmenopausal women aged 61 to 86 years previously treated with 4 to 5 years of alendronate therapy to 5 more years of alendronate or placebo from 1998 through 2003; the present analysis includes only the placebo group. Hip and spine dual-energy x-ray absorptiometry (DXA) were measured when placebo was begun (FLEX baseline) and after 1 to 3 years of follow-up. Two biochemical markers of bone turnover, urinary type 1 collagen cross-linked N-telopeptide (NTX) and serum bone-specific alkaline phosphatase (BAP), were measured at FLEX baseline and after 1 and 3 years. Symptomatic spine and nonspine fractures occurring after the follow-up measurement of DXA or bone turnover. During 5 years of placebo, 94 of 437 women (22%) experienced 1 or more symptomatic fractures; 82 had fractures after 1 year. One-year changes in hip DXA, NTX, and BAP were not related to subsequent fracture risk, but older age and lower hip DXA at time of discontinuation were significantly related to increased fracture risk (lowest tertile of baseline femoral neck DXA vs other 2 tertiles relative hazard ratio, 2.17 [95% CI, 1.38-3.41]; total hip DXA relative hazard ratio, 1.87 [95% CI, 1.20-2.92]). Among postmenopausal women who discontinue alendronate therapy after 4 to 5 years, age and hip BMD at discontinuation predict clinical fractures during the subsequent 5 years. Follow-up measurements of DXA 1 year after discontinuation and of BAP or NTX 1 to 2 years after discontinuation are not associated with fracture risk and cannot be recommended. clinicaltrials.gov Identifier: NCT00398931.

Predicting Fracture Risk After Alendronate Discontinuation

Because the balance between potential benefits and risks of bisphosphonates becomes less clear after extended use, some authorities recommend interrupting bisphosphonate therapy after about 5 years. However, the best way to follow patients who discontinue these drugs is unknown. In this post hoc analysis, investigators examined fracture data from the Fracture Intervention Trial Long-Term Extension Trial in which …

Commentary:Drug-Associated Atypical Femoral Fractures (DaAFFs): Balancing the Facts

The nitrogen-containing bisphosphonates (N-BPs), stable analogs of the naturally occurring pyrophosphate, are the most widely utilized drug class for osteoporosis and the first line of treatment in metastatic bone disease. They selectively bind bone mineral and are ingested by osteoclasts to impair their ability to resorb bone. Therefore, in conditions where bone resorption exceeds bone formation, N-BPs slow down the ongoing bone loss and, in doing so, reduce the risk of fracture in osteoporosis and skeletal-related events in metastatic cancer. Equally effective is denosumab, a fully human monoclonal antibody inhibiting the receptor activator of nuclear factor B ligand (RANKL), a protein essential for osteoclast development, activity, and survival. However, an unusual atraumatic or minimal-trauma fracture, the atypical femoral fracture (AFF), has been reported with increasing frequency in bisphosphonate users since the first case reports were published in 2005 and were recently reported in denosumab users. This fracture occurs between the lesser trochanter and the femoral condyles and has specific radiological features (1, 2). It also occurs in bisphosphonateor denosumabnaive individuals and in patients on weak non-bisphosphonate antiresorptive agents (3, 4). Despite its rarity, there is considerable concern among physicians and patients regarding the long-term use of bisphosphonates for fracture prevention. The first suggestions of an association of AFFs with bisphosphonates came from case reports and case series followed by observational studies that, while being hypothesis-generating, remain fraught with limitations. Because no ICD code is yet available for low-trauma AFF, certain studies have failed even to separate low-energy from high-energy fractures. The indication bias is inherent within most, if not all, such studies. Patients using antiresorptives are, by indication, at a high risk of fracture, which does not allow the attribution of AFFs to antiresorptive use as opposed to the pre-existing osteoporosis. Also, there is inconsistency of defining AFFs, and there is no radiographic adjudication for a good number of them. Furthermore, a Dutch cohort study over 11 years reported that AFFs occurred with the same frequency in non-bisphosphonate users (5). Other epidemiological studies from Europe and North America have had no access to radiographs, preventing the identification of features that are required to classify a fracture as atypical. These studies were thus performed on all subtrochanteric fractures. The outcomes, to no surprise, are at best contradictory. The rarity of AFFs prohibits the conduct of randomized safety trials that could potentially determine whether the risk of such fractures is increased in bisphosphonate or denosumab users. The only “prospective” evidence comes from the reanalysis of data from over 14 000 patients enrolled in the alendronate Fracture Intervention Trial (FIT), FIT Long-term Extension (FLEX), and the Zoledronic Acid Once Yearly (HORIZON) trials. There was no increase in subtrochanteric and femoral shaft fracture risk, or indeed the risk of any fracture, in bisphosphonatetreated patients compared with the placebo group (6). This analysis has nonetheless been rightly criticized for its lack of access to patient radiographs and the relatively short duration of bisphosphonate exposure. It was also underpowered, considering the rarity of these fractures. There is no apparent dose response between bisphosphonates and AFFs. This is highlighted in cancer patients with bone metastasis who are regularly treated with bisphosphonates or denosumab. The yearly amount of these potent antiresorptive medications prescribed could be up

BMD changes and predictors of increased bone loss in postmenopausal women after a 5-year course of alendronate

Management of women discontinuing bisphosphonates after 3 to 5 years of treatment is controversial. Little is known about how much bone mineral density (BMD) is lost after discontinuation or whether there are risk factors for greater rates of bone loss post-discontinuation. We report patterns of change in BMD and prediction models for the changes in BMD in postmenopausal women during a 5-year treatment-free period after alendronate (ALN) therapy. We studied 406 women enrolled in the Fracture Intervention Trial (FIT) who had taken ALN for a mean of 5 years and were then enrolled in the placebo arm of the FIT Long-Term Extension (FLEX) trial for an additional 5 years, describing 5-year percent changes in total hip, femoral neck, and lumbar spine BMD over the treatment-free period. Prediction models of 5-year percent changes in BMD considered all linear combinations of candidate risk factors for bone loss such as BMD at the start of the treatment-free period, the change in BMD on ALN, age, and fracture history. Serum for three markers of bone turnover was available in 76 women, and these bone turnover markers were included as candidate predictors for these 76 women. Mean 5-year BMD changes were -3.6% at the total hip, -1.7% at the femoral neck, and 1.3% at the lumbar spine. Five-year BMD losses of >5% were experienced by 29% of subjects at the total hip, 11% of subjects at the femoral neck, and 1% of subjects at the lumbar spine. Several risk factors such as age and BMI were associated with greater bone loss, but no models based on these risk factors predicted bone loss rates. Although about one-third of women who discontinued ALN after 5 years experienced >5% bone loss at the total hip, predicting which women will lose at a higher rate was not possible.

Bisphosphonate Duration of Therapy for Management of Osteoporosis

Recent controversy has raised questions about the duration of therapy with bisphosphonates for the treatment of osteoporosis. The optimal duration of use has not been established. In post-menopausal women with osteoporosis and high risk of fractures the potential benefits of treatment have outweighed the likely risks. Bisphosphonateswere shown to reduce the risk of fracture by as much as 60% in registration trials (Table 1). The study information reviewed by the U.S. Food and Drug Administration (FDA) for initial drug approval was based on treatment durations of 3 years in which clear evidence of vertebral fracture risk reduction with alendronate, risedronate, ibandronate, and zoledronic acid was demonstrated. Reduction of non-vertebral fracture was demonstrated for all of the bisphosphonates except ibandronate. Since then, longer term extension trials have shown a small but statistically significant benefit to continued treatment with alendronate, risedronate, and zoledronic acid beyond the initial treatment periods. No long-term safety concerns were identified in these trials. There are no extension trials with ibandronate. In the last few years, reports of osteonecrosis of the jaw and femoral head fractures have led the Food and Drug Administration (FDA) as well as bone and mineral clinicians to rethink long-term bisphosphonate therapy. The FDA safety review focused on trials in which the bisphosphonate was administered at least 3 years and fracture data were captured systematically and completely. Thus, the Fosamax Fracture Intervention Trial Long-term Extension (FLEX), Reclast Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (HORIZON-PFT), and the Actonel Vertebral Efficacy with Risedro-

Nuevos datos sobre el tratamiento con bisfosfonatos: ¿son aconsejables unas vacaciones terapéuticas?

Bisphosphonates are potent antiresorptive agents proven to be highly effective in vertebral and non-vertebral fractures. However, the reported complications associated with long-term use have led to questions on indefinite treatment. After administration of alendronate there is a high retention of the drug due to slow skeletal release as a result of bone resorption (half-life of more than 10 years), and it seems logical to propose a cessation of treatment (drug holidays) after prolonged treatment. The largest study published to date that assesses the effects on bone mineral density (BMD) and fractures with maintained or discontinued alendronate treatment is the FLEX (Fracture Intervention Trial Long-term Extension) trial. This study showed that discontinuation of alendronate for up to 5 years, after 5 years of treatment, the anti-resorptive effect is slowly lost, mainly in the lumbar spine (approximately 1.5% in 5 years), as well as a slow and progressive loss of femur BMD (<3% in 5 years), but maintains its vertebral (morphometric) and non-vertebral anti-fracture efficacy. In this context, the American Society for Bone and Mineral Research recommended that continued use of bisphosphonates beyond 5 years should be reevaluated annually, assessing factors such as BMD, particularly in the hip region, fracture history, newly diagnosed underlying conditions or initiation of other medications known to affect skeletal status, and new research findings in a rapidly evolving field. However, the molecular differences between bisphosphonates, provides them different affinity and antiresorptive potency, so we can not extrapolate these recommendations to bisphosphonates other than alendronate.

Analysis Downplays Bisphosphonates' Risk

The risk of subtrochanteric and diaphyseal femur fractures is not significantly increased in women taking bisphosphonates, even among those treated for up to 10 years, a secondary analysis of data from three large randomized bisphosphonate trials suggests. The findings follow several case reports that hinted at an increased risk of these atypical fractures in bisphosphonate users. However, the current study, which included a review of 283 hip or femur fractures in 14,195 women with 51,287 patient-years of follow-up showed that only 12 subtrochanteric or diaphyseal femur fractures occurred in 10 women, for a rate of 2.3 per 10,000 patient-years, Dennis M. Black, PhD, of the University of California, San Francisco and his colleagues wrote. The data analyzed in the current study were from the phase III Fracture Intervention Trial (FIT), the FIT Long-Term Extension (FLEX) trial, and the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (HORIZON-PFT) (N. Engl. J. Med. 2010 March 24[doi10.1056/NEJMoa1001086]). Even in the FLEX trial, which included up to 10 years of treatment with alendronate, the risk of femur fracture and atypical femur fracture was low, with no significantly increased risk of fracture among those who continued treatment for the full 10 years and those who discontinued treatment. “Although we can confidently conclude that absolute rates of such fractures are low, wide confidence intervals (resulting from the very low incidence of events) preclude definitive conclusions regarding the relative risk of treatment,” the investigators wrote. However, using data they analyzed, the investigators estimated that 3 years of bisphosphonate treatment in 1,000 women with osteoporosis would prevent about 100 fractures, including 71 vertebral fractures and 29 nonvertebral fractures—including 11 hip fractures. Balanced against the annual rate of 2.3 subtrochanteric and diaphyseal femur fractures seen in the three trials, “the hypothetical risk is quite small,” the researchers concluded. Additional research is needed to more fully address the matter of bisphosphonate use and the risk of subtrochanteric and diaphyseal fractures, Elizabeth Shane, MD, of Columbia University, New York wrote in an accompanying editorial. It is reasonable to consider drug holidays, particularly in those with substantially reduced levels of bone turnover markers, but again, the evidence of persistent antifracture efficacy after discontinuation must be balanced with data showing that 10 vs. 5 years of alendronate use is associated with significantly fewer new vertebral and nonvertebral fractures in those with bone mineral density T scores of −2.5 or lower, she wrote. This study was supported by Merck and Novartis. The investigators reported support from those and other pharmaceutical manufacturers, as well. Sharon Worcester is with the Southeast bureau of Elsevier Global Medical News. The data on bisphosphonates are good, and this is one area where we may be able to change outcomes (reducing fractures). There are obviously patients for whom these drugs are contraindicated for various reasons, including esophageal sensitivity, but it behooves us to consider their use in many more patients than are currently receiving them. The minuscule risks of complications such as jaw osteonecrosis and atypical fractures, in my opinion, are far outweighed by the drugs' benefits. —Karl Steinberg, MD, CMD Editor in Chief

Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: The FLEX Trial

In the Fracture Intervention Trial (FIT) Long Term Extension (FLEX) Trial, 10 years of alendronate (ALN) did not significantly reduce the risk of nonvertebral fractures (NVFs) compared with 5 years of ALN. Continuing ALN reduced the risk of clinical but not morphometric vertebral fractures regardless of baseline vertebral fracture status. In previous studies, ALN efficacy for NVF prevention in women without prevalent vertebral fracture was limited to those with femoral neck (FN) T-scores of -2.5 or less. To determine whether the effect of long-term ALN on fracture differs by vertebral fracture status and femoral neck (FN) T-score, we performed a post hoc analysis using FLEX data, a randomized, double-blind, placebo-controlled trial among 1099 postmenopausal women originally randomized to ALN in the FIT with mean ALN use of 5 years. In the FLEX Trial, women were randomized to placebo (40%) or ALN 5 mg/day (30%) or ALN 10 mg/day (30%) for an additional 5 years. Among women without vertebral fracture at FLEX baseline (n = 720), continuation of ALN reduced NVF in women with FLEX baseline FN T-scores of -2.5 or less [relative risk (RR) = 0.50, 95% confidence interval (CI) 0.26-0.96] but not with T-scores of greater than -2.5 and -2 or less (RR 0.79, 95% CI 0.37-1.66) or with T-scores of greater than -2 (RR 1.41, 95% CI 0.75-2.66; p for interaction = .019). Continuing ALN for 10 years instead of stopping after 5 years reduces NVF risk in women without prevalent vertebral fracture whose FN T-scores, achieved after 5 years of ALN, are -2.5 or less but does not reduce risk of NVF in women whose T-scores are greater than -2.

Bisphosphonates and Fractures of the Subtrochanteric or Diaphyseal Femur

A number of recent case reports and series have identified a subgroup of atypical fractures of the femoral shaft associated with bisphosphonate use. A population-based study did not support this association. Such a relationship has not been examined in randomized trials. We performed secondary analyses using the results of three large, randomized bisphosphonate trials: the Fracture Intervention Trial (FIT), the FIT Long-Term Extension (FLEX) trial, and the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial (PFT). We reviewed fracture records and radiographs (when available) from all hip and femur fractures to identify those below the lesser trochanter and above the distal metaphyseal flare (subtrochanteric and diaphyseal femur fractures) and to assess atypical features. We calculated the relative hazards for subtrochanteric and diaphyseal fractures for each study. We reviewed 284 records for hip or femur fractures among 14,195 women in these trials. A total of 12 fractures in 10 patients were classified as occurring in the subtrochanteric or diaphyseal femur, a combined rate of 2.3 per 10,000 patient-years. As compared with placebo, the relative hazard was 1.03 (95% confidence interval [CI], 0.06 to 16.46) for alendronate use in the FIT trial, 1.50 (95% CI, 0.25 to 9.00) for zoledronic acid use in the HORIZON-PFT trial, and 1.33 (95% CI, 0.12 to 14.67) for continued alendronate use in the FLEX trial. Although increases in risk were not significant, confidence intervals were wide. The occurrence of fracture of the subtrochanteric or diaphyseal femur was very rare, even among women who had been treated with bisphosphonates for as long as 10 years. There was no significant increase in risk associated with bisphosphonate use, but the study was underpowered for definitive conclusions.

Mineralization density distribution of postmenopausal osteoporotic bone is restored to normal after long-term alendronate treatment: qBEI and sSAXS data from the fracture intervention trial long-term extension (FLEX)

Long-term treatment studies showed that the therapeutic effects of alendronate (ALN) were sustained over a 10-year treatment period. However, data on the effects on intrinsic bone material properties by long-term reduction of bone turnover are still sparse. We analyzed transiliacal bone biopsies of a subgroup of 30 Fracture Intervention Trial Long-Term Extension (FLEX) participants (n = 6 were treated for 10 years with ALN at dose of 10 mg/day, n = 10 were treated for 10 years with ALN at dose of 5 mg/day, and n = 14 were treated for 5 years with ALN plus a further 5 years with placebo) by quantitative backscattered electron imaging (qBEI) and scanning small-angle X-ray scattering (sSAXS) to determine the bone mineralization density distribution (BMDD) and the mineral particle thickness parameter T. BMDD data from these FLEX participants were compared with those from a previously published healthy population (n = 52). Compared with 5 years of ALN plus 5 years of placebo 10 years of ALN treatment (independent of the dose given) did not produce any difference in any of the BMDD parameters: The weighted mean (Ca(mean)), the typical calcium concentration (Ca(peak)), the heterogeneity of mineralization (Ca(width)), the percentage of low-mineralized bone areas (Ca(low)), and the portion of highly mineralized areas (Ca(high)) were not different for the patients who continued ALN from those who stopped ALN after 5 years. Moreover, no significant differences for any of the BMDD parameters between the FLEX participants and the healthy population could be observed. In none of the investigated cases were abnormally high mineralization or changes in mineral particle thickness observed (Ca(high) and T were both in the normal range). The findings of this study support the recommendation that antiresorptive treatment with ALN should be maintained for 5 years. Even with longer treatment durations of up to 10 years, though, no negative effects on bone matrix mineralization were observed.

Effects of Continuing or Stopping Alendronate After 5 Years of Treatment: The Fracture Intervention Trial Long-Term Extension (FLEX): A Randomized Trial

Effects of Continuing or Stopping Alendronate After 5 Years of Treatment: The Fracture Intervention Trial Long-Term Extension (FLEX): A Randomized Trial

Continuing alendronate for an additional 5 years maintained bone mineral density in postmenopausal women

Source Citation Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a rand...

Continuing alendronate for an additional 5 years maintained bone mineral density in postmenopausal women

Source Citation Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927-38. 17190893

Effects of Continuing or Stopping Alendronate After 5 Years of Treatment. The Fracture Intervention Trial Long-term Extension (FLEX): A Randomized Trial

Pharmacokinetic studies have shown that bisphosphonates remain in the bone matrix for many years and are gradually released as bone is resorbed. The terminal half-life of one of these drugs, alendronate, exceeds 10 years, raising the possibility that some of its skeletal effects may continue for years after treatment ceases. In the Fracture Intervention Trial, a randomized, double-blind, placebo-controlled trial conducted at 10 clinical centers in the US, 1,099 postmenopausal women who had taken alendronate for an average of 5 years were randomly assigned to take alendronate in a dose of 5 or 10 mg daily or placebo for 5 years longer. All participants had low bone mineral density (BMD) at the femoral neck at the outset. Follow-up for clinical fractures averaged 4.2 years. Adding 5 years of alendronate therapy in a daily dose of 5 or 10 mg maintained total hip BMD compared with placebo. The mean total hip BMD declined 1% in women taking the medication and 3.4% in placebo recipients. Similar changes were found for the femoral neck and trochanter when analyzed separately. Lumbar spine BMD increased by 5.3% in the alendronate group and 1.5% in placebo patients. Comparable differences were found for total-body and forearm BMD. At each site, the gain in BMD after 10 years on alendronate was significantly greater than when treatment was limited to 5 years. Markers of bone turnover remained close to baseline during continued alendronate therapy but increased gradually in women taking placebo. Despite a lack of significant differences between treatment groups for all clinical fractures or nonvertebral fractures, the risk of clinical vertebral fracture was significantly lower for women who continued on alendronate (2.4% versus 5.3% in placebo recipients). The relative risk was 0.45, with a 95% confidence interval of 0.24-0.85. Loss of height did not differ significantly. No histomorphometric differences were found when 18 iliac crest biopsies were examined. Women in the two groups had similar numbers of serious adverse effects, and there were no significant group differences in rates of withdrawal because of adverse events or in mortality rates. Continuing alendronate therapy for as long as 10 years maintains bone mass, reduces bone remodeling, and does not increase the risk of fracture. Maintaining active treatment may be especially beneficial for women who are at high risk of clinical vertebral fracture as evidenced by a history of fracture or very low BMD.

Effects of Continuing or Stopping Alendronate After 5 Years of Treatment: The Fracture Intervention Trial Long-Term Extension (FLEX): A Randomized Trial

Effects of Continuing or Stopping Alendronate After 5 Years of Treatment: The Fracture Intervention Trial Long-Term Extension (FLEX): A Randomized Trial