Cancel the denosumab holiday

Abstract

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...

Guidelines for the diagnosis and management of osteoporosis in Poland : Update 2017

“…Control of the patient's adherence to therapy, assessment of therapy efficacy, decision on a drug holiday, or drug switching depend on applied medication [8,10], periodic densitometric examination, optimally, assessment of bone markers and X-ray examination, e.g. when the patient's height decreases significantly.…”

Goal-Directed Treatment for Osteoporosis: A Progress Report From the ASBMR-NOF Working Group on Goal-Directed Treatment for Osteoporosis

“…For non-bisphosphonates, a drug holiday is not appropriate because BMD declines rapidly after treatment is stopped. (46,47) Therefore, after a T-score goal is achieved with a non-bisphosphonate, treatment should generally be continued with an agent that maintains BMD, possibly a bisphosphonate (at least short term). (33) Additional medications that can maintain treatment effects after achieving treatment goals would enhance the goaldirected treatment strategy.…”

Tumor Cell Dormancy and Reactivation in Bone: Skeletal Biology and Therapeutic Opportunities

“…Similar findings were demonstrated in a phase III prevention study and an extension of the FREEDOM (A Study to Evaluate Denosumab in the Treatment of Postmenopausal Osteoporosis) trial . Although these studies have not clearly demonstrated a subsequent increased risk of fracture, experts in the field are suggesting the cancellation of DMab holidays, or advising in the case treatment cessation is required, that bisphosphonate treatment is applied to prevent rebound bone loss . Given the rapid bone loss, a pathological increase in osteoclast activity is the likely cause and has been suggested in small cohort studies through serum analyses, although the mechanism for this remains to be determined.…”