Oral Presentation ANZBMS-MEPSA-ANZORS 2022

CASE:

This case reviews the role and current evidence for treatment for polyostotic fibrous dysplasia (FD)/McCune-Albright Syndrome (MAS), with focus on denosumab in the adult patient with high skeletal burden. Our case is that of a 49-year-old mother-of-one with severe, disabling FD/MAS (figure 1a). In infancy she was noted to have Coast-of -Maine-shaped Café au Lait spots on her nape and trunk. At age 3 she suffered a fractured femur and went on to suffer fractures at a rate of “one-per-year” during childhood. She was treated for precocious puberty, her only MAS-associated endocrinopathy. She had hypophosphataemia, managed with calcitriol and phosphate replacement.

By her late teens she was wheelchair-bound with pan-skeletal fibrous dysplasia.  Following a fractured femur at age 20, she was commenced on pamidronate and risedronate, continuing for 5 years. Alkaline phosphatase (ALP) reduced to 400-500 IU/L (reference interval 30 – 110) (figure 2), her pain improved, her bone mineral density increased, and she was able to mobilise without a wheelchair. Interestingly around this time she developed compressive optic neuropathy, which, despite multiple decompressive surgeries, would ultimately leave her blind. She went on to have Zoledronic acid (ZA) therapy (figure 2) but despite this suffered frequent fractures and required admissions to manage pain. Her ALP never reduced below 300IU/L. She developed a non-healing left pre-tibial ulcer related to underlying bone disease (figure 1b) and she later proceeded to a below knee amputation. She has required multiple operations including bilateral hip replacements. At age 39, after a successful pregnancy, she was treated with further ZA, but her ALP and pain did not improve.

Despite years of cumulative bisphosphonate use, she had ongoing pain, recurrent fractures and ALP remained persistently greater than 300 IU/L (figure 2). Therefore, 7 years ago, denosumab was commenced (60mg subcutaneously 6-monthly). There was reduction in ALP and pain improved. Prior to the second dose it was noted that she developed rebound increase in ALP, in keeping with the expected wear-off of action of denosumab (figure 2). Denosumab therapy has continued with dramatic suppression of bone turnover markers after each dose (table 1) followed by rebound rise prior to the next dose. She continues to have reasonable control of background chronic pain, has suffered only one fracture, and has not required admission for pain relief. Based on recent case reports and series, we hypothesise that increasing dose and frequency of denosumab could lead to further biochemical and clinical improvement.

LABORATORY AND IMAGING:

LITERATURE REVIEW

FD is a rare, heterogenous, debilitating disorder with no known cure. An activating post-zygotic mosaic mutation of the gene coding for the alpha subunit of the G-coupled protein receptor (GNAS Ch20q.13.3) results in stimulation of immature bone marrow stromal cells, producing fibro-osseus bone tissue.[1] Distorted bone architecture causes skeletal deformities, recurrent fractures, pain, nerve impingement and disability depending on location and extent of diseased bone. 90% of all skeletal burden is present by mid adolescence and fracture rate peaks in childhood although high skeletal burden and young age at first fracture are associated with high risk of recurrent fractures throughout life.[2]

FD can occur as part of MAS, a syndrome defined by the constellation of skin manifestations, hyperfunctioning endocrinopathies and FD. To date there are no approved disease modifying therapies. Recommended main stay of treatments are supportive care, treatment of phosphate deficiency and endocrinopathies, physical therapies, selective orthopaedic procedures, analgesia, and parenteral bisphosphonate therapy.[3] It is recognised that those with MAS have limited response to bisphosphonates likely due to high skeletal burden of disease. [4]

However, there is hope on the horizon with mouse-models and biomarkers improving the understanding of the pathogenesis of fibrous dysplasia. [5] Receptor-activating-nuclear- kappa-B ligand (RANK-L) has been implicated in the disease pathogenesis and therefore anti-RANK-L therapy (denosumab) is a plausible therapeutic option.[6, 7] The first case reported from a decade ago demonstrated striking reduction in tumour growth and related pain in a child with severe FD treated with denosumab, however, cessation of therapy led to severe hypercalcaemia and rebound elevation in BTM.[8] Observational data from adults with FD has demonstrated that even after non-response to bisphosphonate therapy, denosumab reduces BTM, pain and disease burden. [9-11] Frequent dosing interval (3 months versus 6 months) was supported, and higher dose (120mg) may be required for those with more severe disease.[11] Reassuringly, severe rebound hypercalcaemia has not been reported in adult cohorts. Despite the overall heterogeneity and non-standardised outcomes this is promising data, although many questions remain. The optimal time to start denosumab is unclear- presumably children would benefit prior to onset of advanced skeletal disease but safety concerns remain. Regression of bone lesions has been seen in adults and whether adults with high disease burden, such as with our patient, derive greater benefit is unclear. The optimal dose and frequency of dosing needs to be refined and monitoring of adverse events undertaken. Further trials are underway.

Other therapy modalities are under investigation. IL-6 has also been implicated in the pathogenesis of FD, but a recent randomised controlled trial of IL-6 inhibitor tocilizumab did not show reduction in pain or BTM compared to placebo.[12]

KEY POINTS:

• Polyostotic Fibrous Dysplasia/MAS is a rare, debilitating condition with no known cure
• This case highlights the difficulties in treating FD/MAS
• RANK-L has been demonstrated to have a role in pathogenesis and the use of anti-RANK-L therapy denosumab has shown promise in case series
• The exact benefit, timing of use, dose, frequency, safety profile and issues around cessation need to be further delineated
• Other treatments such as IL-6 inhibitors have not shown improved outcomes in recent trials.