Safety of therapy with and withdrawal from denosumab in fibrous dysplasia and McCune-Albright syndrome: an observational study

Abstract

Denosumab (Dmab) treatment can benefit patients with fibrous dysplasia/McCune-Albright syndrome (FD/MAS) by suppressing the receptor activator of nuclear factor κB ligand (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 Dmab discontinuation in FD/MAS. Thirty-seven patients using Dmab, mostly after unsuccessful bisphosphonate (BP) 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 [B-CTX, also termed β-C-terminal telopeptide]) 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 (interquartile range [IQR]). BTMs normalized in two-thirds of patients and pain scores decreased significantly during treatment (p = 0.002). One patient (2.7%) developed osteonecrosis of the jaw. Sixteen patients discontinued Dmab treatment after a median of 1.6 years (IQR 1.0 years) because of insufficient effect on pain (n = 10, 63%), side effects (n = 4, 25%), or other reasons (n = 4, 25%). Follow-up posttreatment was 3.2 (2.8) years, wherein no fractures, pain flares, or lesion progression occurred. Calcium remained normal in all but one patient, who had a mild asymptomatic hypercalcemia (2.73 mmol/L) 5 months after discontinuation. ALP passed pretreatment levels in five of 11 patients (46%), increased most after 6 months by 18 (43) U/L, and returned to baseline levels thereafter. P1NP exceeded pretreatment levels in four of nine patients (44%), CTX in eight of nine patients (89%). P1NP rose most after 3 months and stabilized thereafter. CTX showed the highest relative elevation. Patients with high pretreatment levels responding well to Dmab seemed to have the highest rebound. These results suggest beneficial effects of Dmab 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 Dmab and withdrawal are needed and ongoing.

RANKL inhibition with denosumab improves fibrous dysplasia by decreasing lesional cell proliferation and increasing osteogenesis

“…The onset of rebound ranged from 3 to 8 months post-discontinuation, and was associated with severe hypercalcemia in 1 subject, highlighting an important and potentially life-threatening complication. Previous reports of postdiscontinuation hypercalcemia in FD have been limited to 2 children 6,13 , and a retrospective review of clinically-treated adults did not identify symptomatic hypercalcemia 22 . In our study, the subject with severe hypercalcemia had extremely elevated baseline bone turnover, with the highest Skeletal Burden Score and P1NP level in the cohort.…”

Successful treatment with denosumab for pelvic fibrous dysplasia

“…[ 11 , 12 ] Meier et al investigated adverse events of denosumab (60 mg every 3–6 months) in 37 patients with FD and found that 1 patient (2.7%) had hypercalcemia 5 months after its discontinuation. [ 17 ] In the present case, close clinical monitoring with laboratory data was performed after discontinuation of denosumab treatment. No increase in serum calcium level was observed.…”

“…No increase in serum calcium level was observed. In a study by Meier et al, 1 patient (2.7%) with FD developed osteonecrosis of the jaw with a median cumulative dose of 660 mg. [17] Palmerini et al reported a 6% incidence of osteonecrosis of jaw in 97 patients with GCTB who were treated with denosumab for a median of 20 months. [19] TRACP-5b has been used as a marker of bone resorption in patients with osteoporosis or GCTB.…”

“…Writingreview & editing: Shiro Imagama, Yoshihiro Nishida. Boyce, 2012 [12] Ganda, 2013 [10] Majoor, 2019 [9] 12 PFD (7) MAS ( 4 Meier, 2021 [17]…”

The Efficacy of Denosumab in Patients With Rheumatoid Arthritis: A Systematic Review and Pooled Analysis of Randomized or Matched Data

“…Our data found that denosumab was not associated with increased risk of serious adverse events. However, recently, several studies reported that the rapid bone loss and the rebound fractures may occur when treatment is stopped ( 39 , 40 ), which needs to be considered when choosing this agent.…”