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

Black, Dennis M.; Schwartz, Ann V.; Ensrud, Kristine E.; Cauley, Jane A.; Levis, Silvina; Quandt, Sara A.; Satterfield, Suzanne; Wallace, Robert B.; Bauer, Douglas C.; Palermo, Lisa; Wehren, Lois E.; Lombardi, Antonio; Santora, Arthur C.; Cummings, Steven R.

doi:10.1097/01.ogx.0000259157.48200.87

Cited by 227 publications

(376 citation statements)

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“…However, there is a wide range of values of C-telopeptide, indicating that >50 % of patients have bone resorption rates well within the postmenopausal normal range at the time they are due for re-dosing. This appears to contrast with similar data from alendronate and zoledronate, which seem to produce more consistent suppression of resorption [3,10]. Also contrasting with bisphosphonates is the continued increase in bone density with long-term use, albeit not at the same rate observed in the first 1-2 years of treatment.…”

contrasting

confidence: 78%

“…Do these drugs continue to prevent fractures and, if so, is their continued use necessary for sustained fracture prevention? For alendronate, some of these questions were answered by the FLEX trial, which suggested that dose reduction with long-term use did not reduce efficacy, and that for patients whose femoral neck bone density was no longer in the osteoporotic range, drug discontinuation did not negatively impact on fracture rate [3,4]. Similar data have now been published from the zoledronate extension studies [5].…”

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confidence: 91%

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Denosumab after 8 years

Reid

2015

Osteoporos Int

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It is now more than 20 years since the alendronate phase 3 program produced the first trials demonstrating global antifracture efficacy for an osteoporosis medication [1,2]. This brought the osteoporosis field into the era of evidence-based medicine. The euphoria that followed from knowing that the interventions we were prescribing really were preventing fractures soon passed as durations of therapy reached 3 years, the endpoint of most fracture prevention clinical trials. A series of unanswered questions then arose. How long should treatment be continued? Are there long-term side-effects? Do these drugs continue to prevent fractures and, if so, is their continued use necessary for sustained fracture prevention? For alendronate, some of these questions were answered by the FLEX trial, which suggested that dose reduction with long-term use did not reduce efficacy, and that for patients whose femoral neck bone density was no longer in the osteoporotic range, drug discontinuation did not negatively impact on fracture rate [3,4]. Similar data have now been published from the zoledronate extension studies [5].In the last decade, osteonecrosis of the jaw (ONJ) and transverse stress fractures of the femoral shaft, referred to as an atypical femoral fractures (AFFs), have emerged as significant new safety concerns associated with the long-term use of anti-resorptive drugs. Most information on these problems is from case series or from analyses of medical claims databases.Some such studies have even suggested that the incidence of atypical femoral fractures attributable to bisphosphonate use might exceed the number of hip fractures prevented by these drugs [6], though other analyses do not support this conclusion [7]. In this context, longer-term data from clinical trials become critically important in assessing the ongoing safety and efficacy of medications for osteoporosis. Longer clinical trials are desirable, though maintaining patients at high risk of fracture on placebo raises ethical and practical issues. The next-best option is to continue long-term follow-up of the cohorts of patients involved in the pivotal clinical trials. While not as robust as a longterm randomized controlled trial because a control group is not continued on placebo, this strategy does provide longitudinal data on a well-characterized cohort, allowing fracture rates and adverse events to be related to duration of therapy. It also allows documentation of chronic effects on bone turnover markers and bone density. The loss of a control group for these measures is not such a problem, since current technology usually generates stable measurements, and the evolution of these parameters in placebo-treated women with osteoporosis is already well documented.The recent report by Papapoulos et al. in Osteoporosis International provides important new information regarding the efficacy and safety of the anti-RANKL monoclonal antibody, denosumab [8]. This drug is a potent antiresorptive which reduces median bone formation rate to zero after 2-3 years use ...

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confidence: 78%

mentioning

confidence: 91%

Denosumab after 8 years

Reid

2015

Osteoporos Int

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“…Outcomes for patients who had been adherent to oral bisphosphonates for at least 2 years (and may or may not be adherent in the third year) were measured through month 36 from the index date because the effects of bisphosphonates last beyond the treatment period [19]. Patients were considered to remain at high risk of fracture if they satisfied at least one of the following three criteria: 1) Low post-treatment T-score -defined as a T-score of ≤-2.5 at any of the following skeletal sites (spine, femur neck or total hip) during months 13-36 from the index date.…”

Section: Outcome Definitionsmentioning

confidence: 99%

Proportion of osteoporotic women remaining at risk for fracture despite adherence to oral bisphosphonates

Imel

Eckert

Modi

et al. 2016

Bone

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“…In an extension of the Fracture Intervention Trial (Fracture Intervention Trial Long-term Extension [FLEX]), postmenopausal women who had been treated with alendronate for a mean of 5 years were randomized to treatment with either 5 or 10 mg daily of alendronate or placebo for an additional 5 years. (6) In the group assigned to placebo, bone mineral density (BMD) in the hip declined substantially although it remained above pretreatment values at the end of the study. Biochemical markers of bone turnover increased modestly.…”

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confidence: 99%

“…The incidence of all clinical fractures and of nonvertebral fractures was similar in the continuation and discontinuation groups, but the risk of clinical (but not morphometric) vertebral fractures was significantly lower in those who continued alendronate therapy. However, reduction in nonvertebral fractures with bisphosphonate therapy has generally been demonstrated only in women with osteoporosis, (6)(7)(8) and because many of the women in FLEX did not have osteoporosis, the power to show an effect would likely be reduced. Post hoc subgroup analysis of the FLEX study indicated that the risk of both nonvertebral and clinical vertebral fractures increased with lower baseline BMD or prevalent vertebral fracture.…”

mentioning

confidence: 99%