Safety of Therapy with and Withdrawal from Denosumab in Fibrous Dysplasia and McCune-Albright Syndrome: an observational study.

Denosumab treatment can benefit patients with fibrous dysplasia/McCune-Albright Syndrome (FD/MAS) by suppressing the RANKL-mediated increased bone resorption. However, limited data of two pediatric cases indicate that a rebound phenomenon may occur after withdrawal. Therefore we studied the safety of denosumab discontinuation in FD/MAS. Thirty-seven patients using denosumab, mostly after unsuccessful bisphosphonate treatment, were included. Health records were screened for pain scores, side effects and bone turnover markers (BTMs) (calcium, alkaline phosphatase (ALP), procollagen 1 N-terminal propeptide (P1NP) and β-crosslaps (CTX)) during treatment, and for BTMs and clinical rebound effects after withdrawal. BTM levels after withdrawal were compared to pretreatment values. Data were calculated as median(IQR). BTMs normalized in 2/3 of patients and pain scores decreased significantly during treatment (p=0.002). 1 patient (2.7%) developed osteonecrosis of the jaw. Sixteen patients discontinued denosumab treatment after a median of 1.6(IQR 1.0) years because of insufficient effect on pain (n=10,63%), side effects (n=4,25%) or other (n=4,25%). Follow-up post-treatment was 3.2(2.8) years, wherein no fractures, pain flares or lesion progression occurred. Calcium remained normal in all but 1 patient, who had a mild asymptomatic hypercalcemia (2.73 mmol/L) 5 months after discontinuation. ALP passed pretreatment levels in 5/11 patients (46%), increased most after 6 months by 18(43) U/L and returned to baseline levels thereafter. P1NP exceeded pretreatment levels in 4/9 patients (44%), CTX in 8/9 (89%). P1NP rose most after 3 months and stabilized thereafter. CTX showed the highest relative elevation. Patients with high pretreatment levels responding well to denosumab seemed to have the highest rebound. These results suggest beneficial effects of denosumab on pain and BTMs, and show a biochemical but asymptomatic rebound phenomenon after withdrawal in adults with FD/MAS, mainly in case of high pretreatment levels, good response and multiple injections. Further studies on the safety of denosumab and withdrawal are needed and ongoing. This article is protected by copyright. All rights reserved.