Elsevier

Bone

Volume 105, December 2017, Pages 11-17
Bone

Review Article
Discontinuation of Denosumab therapy for osteoporosis: A systematic review and position statement by ECTS

https://doi.org/10.1016/j.bone.2017.08.003Get rights and content

Highlights

  • Discontinuation of denosumab treatment potentially leads to a high risk of multiple vertebral fractures

  • Patients at high fracture risk should either continue denosumab therapy or be switched to an alternative treatment

  • Treatment with denosumab should not be stopped without considering an alternative (antiresorptive) treatment

Abstract

Introduction

The optimal duration of osteoporosis treatment is controversial. As opposed to bisphosphonates, denosumab does not incorporate into bone matrix and bone turnover is not suppressed after its cessation. Recent reports imply that denosumab discontinuation may lead to an increased risk of multiple vertebral fractures.

Methods

The European Calcified Tissue Society (ECTS) formed a working group to perform a systematic review of existing literature on the effects of stopping denosumab and provide advice on management.

Results

Data from phase 2 and 3 clinical trials underscore a rapid decrease of bone mineral density (BMD) and a steep increase in bone turnover markers (BTMs) after discontinuation of denosumab. Clinical case series report multiple vertebral fractures after discontinuation of denosumab and a renewed analysis of FREEDOM and FREEDOM Extension Trial suggests, albeit does not prove, that the risk of multiple vertebral fractures may be increased when denosumab is stopped due to a rebound increase in bone resorption.

Conclusion

There appears to be an increased risk of multiple vertebral fractures after discontinuation of denosumab although strong evidence for such an effect and for measures to prevent the occurring bone loss is lacking. Clinicians and patients should be aware of this potential risk. Based on available data, a re-evaluation should be performed after 5 years of denosumab treatment. Patients considered at high fracture risk should either continue denosumab therapy for up to 10 years or be switched to an alternative treatment. For patients at low risk, a decision to discontinue denosumab could be made after 5 years, but bisphosphonate therapy should be considered to reduce or prevent the rebound increase in bone turnover. However, since the optimal bisphosphonate regimen post-denosumab is currently unknown continuation of denosumab can also be considered until results from ongoing trials become available. Based on current data, denosumab should not be stopped without considering alternative treatment in order to prevent rapid BMD loss and a potential rebound in vertebral fracture risk.

Introduction

The optimal duration of osteoporosis treatment remains controversial. Ever since bisphosphonates were introduced in clinical practice some 40 years ago there have been discussions on how long these drugs can be used safely for the therapy of osteoporosis [1]. It is well recognised that the antiresorptive effect after stopping treatment with bisphosphonates persists for months or years due to their high affinity for binding hydroxyapatite. Alendronate and zoledronic acid are known to have a more sustained effect on bone mineral density (BMD) and bone turnover markers (BTMs) than risedronate presumably because of their greater binding affinity to hydroxyapatite [2]. There is evidence that treatment of women with postmenopausal osteoporosis with alendronate for as long as 10 years and zoledronic acid for 6 years is not associated with increased fracture risk, but even leads to a further decrease in clinical vertebral fractures in patients continuing alendronate [3], and morphometric vertebral fractures in patients continuing zoledronic acid [4] compared to individuals who went on with placebo after 5 years of alendronate and 3 years of zoledronic acid. Nevertheless, due to their long-term retention in the skeleton, there has been concern that prolonged use of bisphosphonates and a sustained suppression of bone turnover might lead to so-called ‘frozen’ or ‘brittle’ bone. Although this has not been demonstrated some rare but serious potential side-effects of long-term bisphosphonate use such as atypical femur fractures (AFF) and osteonecrosis of the jaw (ONJ) make a re-assessment of the benefit-to-risk ratio after several years of treatment imperative. The American Society for Bone and Mineral Research (ASBMR) Task Force suggests that after 3 years of treatment with intravenous zoledronic acid or 5 years with oral bisphosphonates a treatment break often referred to as ‘drug holiday’ should be considered, unless there are characteristics indicative of high fracture risk as for example, older age, low hip T-score or high fracture risk score, previous major osteoporotic fractures, or fractures on therapy [5]. Similar recommendations have been issued by the UK National Osteoporosis Guideline Group (NOGG) [6] and by the European Menopause and Andropause Society (EMAS) [7]. This concept of a treatment break does not apply to drugs other than bisphosphonates, since for drugs without skeletal retention the fracture risk is expected to increase after drug discontinuation. For example, after teriparatide discontinuation BMD progressively declines [8], so that the risk of fracture maybe increasing later on [9], and reversibility of drug effect as measured by BMD and BTMs has been shown for postmenopausal estrogen therapy and estrogen receptor modulators [10], [11].

Denosumab is a fully human monoclonal antibody with high affinity and specificity for human receptor activator of NF-κB ligand (RANKL) which neutralizes the activity of human RANKL, thereby inhibiting osteoclast formation, function and survival. There is ample data demonstrating that denosumab decreases bone resorption and increases bone mass and strength in both trabecular and cortical bone, with the pivotal randomized, double-blind, placebo-controlled, phase 3 Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 months (FREEDOM) trial in women with postmenopausal osteoporosis showing that denosumab treatment reduced the incidence of new vertebral fractures, nonvertebral fractures, and hip fractures when compared to placebo [12]. The long-term efficacy and safety of denosumab has been evaluated in the FREEDOM Extension Trial with results published for up to 10 years of denosumab exposure, demonstrating a continuing increase in BMD, a sustained reduction of BTMs, a low fracture incidence (similar to rates observed during the FREEDOM trial) and a consistent safety profile [13]. Notably, adverse events such as serious infections, cellulitis and eczema showed no evidence of increased frequency through 10 years of denosumab exposure and the rates of bone related adverse events such as atypical femur fractures (AFF) remained low, with 13 cases of osteonecrosis of the jaw (ONJ) reported to date [13].

Despite the fact that the concept of a treatment break does not apply to drugs without skeletal retention, we notice in clinical practice that after 5 years of denosumab treatment many patients are now being taken off the drug [14]. Also, patients are often advised by dentists that medication should be stopped temporarily before a dental procedure to avoid the risk of ONJ. Recently, there has been concern that discontinuation of denosumab will lead to an increased risk of multiple vertebral fractures associated with rapid bone loss when treatment is stopped. Here, we performed a systematic review to assemble relevant evidence on the clinical consequences following withdrawal of denosumab treatment for osteoporosis and on options to prevent bone loss afterwards. Based on available data and expert opinion we provide advice for physicians on how long to continue denosumab treatment in the setting of osteoporosis and how to deal with patients who discontinue the drug. The treatment duration with denosumab in other settings (oncology conditions, Paget's disease, fibrous dysplasia, avascular necrosis, bone marrow oedema) is beyond the scope of this paper.

Section snippets

Methods

The systematic review was performed under the auspices of the European Calcified Tissues Society (ECTS) Professional Practice Committee. We searched electronic databases (PubMed/MEDLINE) and ClinicalTrials.gov using MeSH terms “Denosumab” and “Osteoporosis” up to May 31st 2017. The review included randomized controlled trials as well as observational studies which investigated the effect of denosumab discontinuation on bone mineral density (BMD), bone turnover markers (BMTs), bone

Results

As part of the search for the systematic review we identified 901 abstracts on PubMed, 71 clinical trials on ClinicalTrials.gov and 25 abstracts of past annual meetings of the societies mentioned in the Methods Sections using the terms stated in the Methods Section. After eliminating publications which did not describe effects of discontinuation of denosumab or duplicates we retained 24 relevant contributions (Fig.1).

Denosumab treatment duration in patients with low and high risk for fracture

Since osteoporosis is a chronic condition, continued treatment is a prerequisite in many patients to sustain therapeutical benefits as is the case with other chronic diseases. However, as in any chronic disease, it is important to define targets to achieve the therapeutical goal. In the setting of cardiovascular diseases, blood pressure, blood glucose and lipid concentrations constitute well-defined targets to decrease the incidence of stroke or myocardial infarction. In the setting of

Summary and conclusion

In contrast to the discontinuation of bisphosphonates, withdrawing other bone active drugs results in rapid loss of their effects on BMD and BTMs. BMD gains achieved with estrogens, SERMs, denosumab or teriparatide therapy are lost over 1–2 years. With regards to denosumab, markers of bone turnover rebound to values well above baseline for 1–2 years after stopping therapy corresponding to the interval of rapid decrease of the significant gains in BMD. Concern has been raised early on that this

Disclosures

Dr. Tsourdi has no conflicts of interest.

Dr. Langdahl has received fees for lectures and participation in advisory boards from Amgen, Merck, Eli Lilly, and UCB and research support for her institution from Eli Lilly, Amgen, and Novo Nordisk.

Dr. Cohen-Solal has received fees for lectures from Amgen and Eli Lilly.

Dr. Aubry-Rozier has no conflicts of interest.

Dr. Eriksen has received fees for consultancies, lectures and participation in advisory boards from Amgen, Eli Lilly, MSD, IDS, and EffRx

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