Background: Fibrous Dyplasia (FD) is a rare bone disorder characterised by mosaic activating GNAS mutations leading to fibro-osseous replacement of normal bone pain, with consequent disordered architecture and compromised mechanical integrity, leading to pain, fractures and skeletal deformities. Fibrous Dysplasia/McCune Albright Syndrome (FD/MAS) describes the spectrum of clinical phenotypes encompassing monostotic and polyostotic involvement and extra-skeletal manifestations including hyperfunctioning endocrinopathies and cutaneous involvement. The role of denosumab in FD/MAS is an area of limited evidence regarding efficacy and safety data, with increasing observational data and ongoing trials.
Case Presentation: We describe a case of a 22-year-old man seen in the osteoporosis clinic with known McCune-Albright Sydrome with polyostotic fibrous dysplasia and associated gonadrotrophin independent precocious puberty with previous letrozole therapy, hyperthyroidism requiring previous thyroidectomy for toxic multinodular goitre and growth hormone excess on ongoing octreotide therapy. Biochemically, he had markedly elevated bone turnover markers, despite long-term continuous 3-monthly IV zoledronic acid therapy mainly for symptomatic management from childhood. Extensive craniofacial involvement from his fibrous dysplasia, evident from the preceding years in his transition from paediatric care, showed ongoing progression raising concern for secondary orbital content crowding and optic nerve compression with new developments of left optic nerve atrophy in adult years. Neurosurgical intervention was deemed too high risk given established left optic nerve atrophy and the potential for contralateral visual loss with attempted decompression. With multidisciplinary assessment taking into consideration these concerns, high dose denosumab at 120mg 4-weekly under hospital approval was commenced with cessation of bisphosphonate therapy. Denosumab therapy was complicated by mild symptomatic hypocalcaemia and hypophosphataemia within two months of therapy in the context of mild vitamin D deficiency during treatment (with normal pre-treatment levels). Ongoing hypocalcaemia required stepwise dose reduction (from 120mg 4-weekly to 60mg 6-weekly to 60mg 3-monthly), with a subsequent atraumatic left distal tibial fracture one month later and an atraumatic femoral fracture five months thereafter, both at fibrous dysplastic sites. Denosumab therapy was discontinued and he remains under close monitoring off anti-resorptive therapy, with expected rebound of his bone turnover markers, but clinically stable vision.
Discussion: Treatment in FD/MAS remains mainly based on expert consensus and mechanistic inference given the rarity of the condition. Bisphosphonate therapy has been historically used as a principal medical therapy and remains off label for use in Australia, with consistent evidence for improvement in bone turnover markers, but mixed results for clinical benefit (1). Improvement in pain scores is largely derived from open-label studies and observational data, with a lack of replication of benefits in pain or function improvement in the randomised setting (1,2).
Denosumab is an emergency therapeutic option in FD/MAS with limited but growing evidence particularly observational data showing benefit in suppression of bone turnover markers and potential improvement in pain scores, extending prior positive signals from earlier case reports and case series (3,4). Ongoing and completed small open label trials have also reflected improvements in pain score and biochemical bone turnover marker suppression, with ongoing evaluation to continue (5,6). However, evidence for longer term meaningful structural benefits and clinical outcomes including fracture risk, remain mixed and sparse. Volumetric reduction in dysplastic lesions was reported in an isolated case in an observational study but otherwise is not consistently reported (7).
Safety considerations remain an important consideration, with notable reports of rebound hypercalcaemia on cessation of therapy particularly in those with high skeletal burden and additionally uncertainty regarding long-term safety and adverse effects (5,6). There has been a single reported case of medication related osteonecrosis of the jaw in a Dutch observational study reviewing safety outcomes in FD/MAS patients, but otherwise there have been no reported atypical femoral fractures in this setting (8). Additional uncertainties also remain regarding appropriate dosing regimens, with an ongoing phase 2 trial investigating comparative efficacy and safety of moderate (120mg 3-monthly) compared to high dose (120mg weekly) regimens (9).
In this patient, significant bone turnover marker suppression was achieved following denosumab therapy, despite persistent activity on long-term bisphosphonates, with subsequent atraumatic fractures on therapy through dysplastic sites. Ongoing prospective studies will help better define efficacy, adverse event profiles and potentially identify and help risk stratify patients’ dosing regimens, in many of whom there is prior bisphosphonate use.
Conclusions: This case highlights the complexity of management of FD/MAS with multidisciplinary team input, in addition to important safety considerations with denosumab use in this rare population in the context of prior long-term bisphosphonate therapy.