Denosumab in Patients With Fibrous Dysplasia Previously Treated With Bisphosphonates

Bas C. J. Majoor; Socrates E. Papapoulos; P. D. Sander Dijkstra; Marta Fiocco; Neveen A. T. Hamdy; Natasha M. Appelman-Dijkstra


J Clin Endocrinol Metab. 2019;104(12):6069-6078. 

In This Article

Abstract and Introduction


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.


Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare disorder characterized by replacement of bone by highly vascularized fibrous tissue in one (monostotic) or more skeletal sites (polyostotic) that may be associated with skeletal morbidity.[1,2] The disorder is caused by postzygotic, somatic activating mutations of GNAS leading to overproduction of cAMP and abnormal cellular responses, such as increased production of the bone resorbing factors IL-6 and receptor activator of nuclear factor-κB ligand (RANKL).[3–5] Extraskeletal distribution of the GNAS mutation may be associated with manifestations in other tissues, particularly endocrine glands, such as endocrinopathies and café-au-lait skin patches in MAS and therefore the disease is referred to as FD/MAS.[6]

Although there is as yet no approved medical treatment of FD/MAS, several studies have reported clinical and biochemical improvement in patients treated with different bisphosphonate regimens.[7–14] However, response to bisphosphonates may be inadequate in decreasing pain symptoms, particularly in patients with polyostotic disease and high skeletal burden.[12,13] Recent case reports suggest successful response to treatment of patients with FD/MAS with the RANKL inhibitor, denosumab.[15–18] In this case series we report the clinical and biochemical outcomes of treatment of 12 patients with bisphosphonate-refractory FD/MAS treated consecutively with denosumab.