Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years

Ferrari, Serge; Adachi, Jonathan D.; Lippuner, Kurt; Zapalowski, Carol; Miller, Paul D.; Reginster, Jean Yves; Törring, Ove; Kendler, David L.; Daizadeh, Nadia; Wang, A.; O’Malley, Cynthia D.; Wagman, Rachel B.; Libanati, Cesar; Lewiecki, E. Michael

doi:10.1007/s00198-015-3179-x

Cited by 71 publications

(55 citation statements)

References 31 publications

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“…In women with osteoporosis, hip fracture risk is reduced by 40 % and non-vertebral fracture risk by 20 %, and efficacy may be sustained with long-term therapy [11,14]. Progressive increases in bone mineral density (BMD) are observed with long-term therapy with increments from baseline of 18 and 8 % observed in the lumbar spine and total hip region, respectively, after 8 years, and emerging evidence suggests that the proximal femur BMD achieved on therapy is a good indicator of an individual patient's risk of non-vertebral fracture [14,15].There are few reasons to stop denosumab therapy. Refractoriness to therapy has not been demonstrated.…”

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“…The usual reasons for discontinuing treatment exist (perceived intolerance or ineffectiveness, concerns about rare side effects, cost, etc.). In addition, physicians themselves may recommend that treatment be stopped after several years in patients whose BMD has increased sufficiently to move the patient above the threshold of osteoporosis and out of a high-risk category [15,21].The rebound in remodeling rates to values higher than pretreatment levels with rapid bone loss upon stopping denosumab is well documented. In the phase 2 study of Miller et al, follow-up after discontinuing denosumab treatment was available in 50 patients [3].…”

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Cancel the denosumab holiday

McClung

2016

Osteoporos Int

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Denosumab, a fully human IgG2 anti-RANK ligand antibody, quickly and substantially inhibits bone remodeling [1]. As expected by the pharmacology of denosumab, this inhibition of remodeling is completely reversible upon stopping treatment [2]. In clinical trials, discontinuing therapy after 2 years results in a rapid rebound in bone turnover markers, raising concern about whether that high remodeling rate and consequent rapid bone loss that occurs has clinical relevance beyond a simple waning of the treatment benefit [3,4]. Despite these concerns, many patients stop denosumab therapy, sometimes upon the advice of their physicians, especially in preparation for invasive dental procedures [5][6][7]. Three recent reports have described five patients in whom denosumab treatment was stopped because substantial gains on bone mineral density (BMD) had been achieved and who then experienced vertebral fractures within the first several months after discontinuing therapy. These cases re-focus our attention on the concern about a rebound in fracture risk and make it clear that a Bholiday^from denosumab therapy is not justified in patients with osteoporosis [8][9][10].It is well established that denosumab treatment of postmenopausal women with osteoporosis and of men and women receiving hormone ablation therapy for the management of prostate and breast cancer is associated with substantial (about 70 %) reduction in the risk of vertebral fracture [11][12][13]. In women with osteoporosis, hip fracture risk is reduced by 40 % and non-vertebral fracture risk by 20 %, and efficacy may be sustained with long-term therapy [11,14]. Progressive increases in bone mineral density (BMD) are observed with long-term therapy with increments from baseline of 18 and 8 % observed in the lumbar spine and total hip region, respectively, after 8 years, and emerging evidence suggests that the proximal femur BMD achieved on therapy is a good indicator of an individual patient's risk of non-vertebral fracture [14,15].There are few reasons to stop denosumab therapy. Refractoriness to therapy has not been demonstrated. Intolerance is uncommon. Although rare cases of atypical femoral fracture have been described in patients who have received denosumab (most often in patients with a history of previous bisphosphonate use), there is no clear signal of any risk associated with the duration of therapy [16]. However, despite the favorable benefit risk profile, many-perhaps most-patients will discontinue therapy. In observational studies, persistence of 83-95 % after one year of denosumab therapy (meaning the patient received a second dose six months after their initial dose) and 68 % at 24 months has been described [17][18][19][20]. Data regarding longer-term treatment or outside a clinical trial setting are not yet available. The usual reasons for discontinuing treatment exist (perceived intolerance or ineffectiveness, concerns about rare side effects, cost, etc.). In addition, physicians themselves may recommend that treatment be stopped after several ye...

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Cancel the denosumab holiday

McClung

2016

Osteoporos Int

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“…Also, the confidence intervals around estimates of fracture rate are wide as a result of small numbers of events, so circumspection in interpretation is necessary. With these caveats, the Papapoulos study does suggest long-term maintenance of reduced fracture rates to 8 years with denosumab, and no concrete evidence that sustained suppression of bone turnover results in a generalized increase in skeletal fragility.Also recently published in Osteoporosis International is an analysis of a subset of these data from some of the same investigators [11]. This paper re-presents data in Papapoulos, considering the non-vertebral fracture incidence to 7 years (3 years of denosumab or placebo in the core trial, plus 4 years of the study extension during which all subjects received denosumab).…”

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“…Also recently published in Osteoporosis International is an analysis of a subset of these data from some of the same investigators [11]. This paper re-presents data in Papapoulos, considering the non-vertebral fracture incidence to 7 years (3 years of denosumab or placebo in the core trial, plus 4 years of the study extension during which all subjects received denosumab).…”

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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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