Denosumab in Patients With Fibrous Dysplasia Previously Treated With Bisphosphonates

Abstract

Context Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone disorder commonly treated with bisphosphonates, but clinical and biochemical responses may be incomplete. Objective To evaluate the efficacy and tolerability of the receptor activator of nuclear factor-κB ligand inhibitor denosumab in the treatment of patients with FD/MAS refractory to bisphosphonate therapy. Design Case series. Setting Academic center of expertise for rare bone diseases. Patients Data were collected from 12 consecutive patients with FD/MAS with persistent pain and increased biochemical markers of bone turnover (BTMs) after long-term treatment with bisphosphonates (median, 8.8 years) and were treated with subcutaneous denosumab 60 mg at 3- or 6-month intervals with a follow-up for at least 12 months. Main outcome(s) Sustained reduction of BTMs and bone pain. Results A 60 mg dose of denosumab once every 3 months, but not once every 6 months, induced a sustained reduction of BTMs. After a median treatment period of 15.5 months (range, 12 to 19) serum alkaline phosphatase activity and propeptide of type 1 procollagen levels were respectively reduced from 212 ± 39.4 IU/L to 79 ± 6.0 IU/L (P = 0.004) and from 346.2 ± 111.1 ng/mL to 55.7 ± 16.6 ng/mL (P = 0.023) and normalized in 70% and 75% of patients, respectively. Although not quantitavely measured, 10 patients reported a reduction in bone pain of whom 6 reported complete elimination of pain. Treatment with denosumab was well tolerated. Conclusion Our results indicate that 60 mg of denosumab every 3 months is a promising, well-tolerated treatment of most patients with FD/MAS refractory to bisphosphonate therapy. These results together with those of previously published case reports provide the necessary background for the design of a larger, controlled study.

Advances in Models of Fibrous Dysplasia/McCune-Albright Syndrome

“…Presently, there is minimal evidence for the use of denosumab and other anti-resorptive agents in FD, although there are case reports suggesting potential clinical benefits (8,(11)(12)(13)(14)(15)(16). However, there are major concerns about rebound fractures and FD lesion progression after drug cessation (17)(18)(19).…”

Denosumab Reduces Lesional Fluoride Skeletal Burden on Na[18F]F PET-CT in Patients With Fibrous Dysplasia/McCune–Albright Syndrome

“…with 15 years of experience in reading PET-CT, taking both PET-CT and low-dose CT into account and who was blinded for the biochemical results and treatment. PET-CT images were quantified using the standardized uptake value (SUV, in g/mL) which is the local activity-concentration of the 18 F-fluoride anion (in Bq/mL) normalized for the injected Na[ 18 F]F activity (in Bq) per unit bodyweight (in g), as bodyweight seemed the optimal measure of volume of distribution for Na[ 18 F]F SUVs and normalizing for CT-based skeletal volume (SV) or lean body mass did not improve results ( 3 , 4 , 12 , 15 ). The SUV cut-off to discern normal, healthy bone from pathological Na[ 18 F]F uptake strongly varied among patients and scans and was therefore individually defined as previously published ( 4 , 16 , 17 ).…”

“…TLF is based on both the volume of increased bone activity (FTV) and its mean level of bone activity (mean standardized Na[ 18 F]F uptake value, SUV mean ). In previous observations high correlations between molecular imaging and BTMs were mainly driven by the volumetric parameter FTV, without a significant contribution of the intensity parameter SUV mean , for which the optimal normalization method is still under debate ( 12 ). Therefore FTV is to be preferred over the compound parameter TLF.…”

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

“…Currently, an initial treatment scheme of 60 mg Dmab every 3 months is recommended based our previous cohort study, which analyzed a subset of the patients included in this present study. (35) On the other hand, this heterogeneity in treatment schemes as well as in patient characteristics makes this study generalizable to the clinical situation. Last, the amount of patients who ceased Dmab treatment was rather small, 14 patients, although this is still the largest case series until now.…”