Review ArticleDiscontinuation of Denosumab therapy for osteoporosis: A systematic review and position statement by ECTS
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
References (44)
Bisphosphonates: the first 40 years
Bone
(2011)- et al.
Diagnosis and management of osteoporosis in postmenopausal women and older men in the UK. National Osteoporosis Guideline Group (NOGG) update 2013
Maturitas
(2013) - et al.
Drug holidays from bisphosphonates and denosumab in postmenopausal osteoporosis: EMAS position statement
Maturitas
(2017) - et al.
Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial
Bone
(2008) - et al.
The effect of bisphosphonate treatment on osteoclast precursor cells in postmenopausal osteoporosis: THE TRIO Study
Bone
(2016) - et al.
Importance of prompt antiresorptive therapy in postmenopausal women discontinuing teriparatide or denosumab: the denosumab and teriparatide follow-up study (DATA-Follow-Up)
Bone
(2017) - et al.
Bisphosphonate binding affinity as assessed by inhibition of carbonated apatite dissolution in vitro
J Biomed Mater Res A
(2008) - 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) - et al.
The effects of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomised extension to the HORIZON-pivotal fracture trial (PFT)
J Bone Miner Res
(2012) - et al.
Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task force of the American Society for Bone and Mineral Research
J Bone Miner Res
(2016)
Effects of teriparatide treatment and discontinuation in postmenopausal women and eugonadal men with osteoporosis
J Clin Endocrinol Metab
Sustained nonvertebral fragility fracture reduction after discontinuation of teriparatide treatment
J Bone Miner Res
Withdrawal of hormone replacement therapy is associated with significant vertebral bone loss in postmenopausal women
Osteoporos Int
The effect of cessation of raloxifene treatment on bone turnover in postmenopausal women
Bone
Denosumab for prevention of fractures in postmenopausal women with osteoporosis
N Engl J Med
10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension
Lancet Diabetes Endocrinol
Observations following discontinuation of long-term denosumab therapy
Osteoporos Int
Frequency of discontinuation of injectable osteoporosis therapies in US patients over 2 years
Osteoporos Int
Effect of denosumab on bone mineral density and biochemical markers of bone turnover: six-year results of a phase 2 clinical trial
J Clin Endocrinol Metab
Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass
J Clin Endocrinol Metab
Rebound-associated bone loss after non-renewal of long-term denosumab treatment offsets 10-year gains at the total hip within 12 months
J Bone Miner Res
Significant bone loss after stopping denosumab treatment
J Bone Miner Res
Cited by (348)
Multicentric carpotarsal osteolysis syndrome with variants of MAFB gene: a case report and literature review
2024, Pediatric RheumatologyInsights and implications of sexual dimorphism in osteoporosis
2024, Bone ResearchEfficacy of Osteoporosis Medications in Patients with Type 2 Diabetes
2024, Current Osteoporosis ReportsPrevention of Skeletal-Related Events With Extended-Interval Denosumab: A Review of the Literature
2024, Annals of Pharmacotherapy