Oral Presentation 33rd ASM of the Australian & New Zealand Bone & Mineral Society 2023
Polyostotic fibrous dysplasia: will denosumab reduce his bone pain? (#24)
Case Summary
A 43 year-old Scottish self-employed carpenter presented to Endocrinology Clinic in 2019 for management of polyostotic fibrous dysplasia. He migrated to Australia in 2012 and had a medical history of polyostotic fibrous dysplasia since childhood.
Multiple skeletal sites including both lower limbs, left clavicle, left sided ribs, proximal humerus, scapula, and skull were involved. These resulted in complications of severe restrictive ventilatory defects from the left thoracic cage deformity, dilated cardiomyopathy with ejection fraction of 46% and compression of the left superior vena cava and internal jugular vein. His main symptoms were dyspnoea on exertion, severe pain around left clavicle especially in the context of carpentry work. Pertinent examinations findings included facial asymmetry, a large rounded bony lesion on the left clavicle and oedematous left upper limb. (Figure 1).
His fasting metabolic bone study at initial endocrinology assessment (Table 1) demonstrated ALP of 466U/L (30-110unit/L) and elevated bone turnover markers (CTX 2590ng/L [100-600ng/L]). There was no evidence of renal phosphate wasting. His FEV1 was of 49% with reduced lung volumes. The biopsy of the left clavicle showed no malignant cells on histopathology in 2014 and 2017 but did show fibrous tissue.
CT chest showed left sided reduced size of the hemithorax (Figure2) and CT venogram confirmed vascular compression of the left SVC and IJV. Bone scan showed increased osteoblastic activity throughout the entire skeleton apart from the right hemithorax, and more intense uptake in the calvarium, the left clavicle, left ribs and scapula (Figure 3).
5mg of intravenous zoledronic acid was given in July 2021. The patient experienced a severe reaction including worsening bone pains. The repeat bone scan performed 6 months post zolendronic acid did not result in significant reduction in the intensity of the bone activity (Figure 4). The patient did not receive further IV bisphosphonate given his severe reaction, minimal changes to his pain and no improvement radiologically.
His case was discussed at the orthopaedic oncology multidisciplinary meeting with cardiothoracic surgeon for consideration of total claviclectomy given the extent of his respiratory compromise. The operation was abandoned due to the high risks of surgery including major vascular damage and uncontrollable bleeding into the thorax. The consensus was that forequarter amputation would be necessary if the lesion of the clavicle continued to expand with neurovascular compromise.
The patient continues to be reviewed by endocrinology, orthopaedic oncology and respiratory. More recently, the use of RANKL inhibitor, denosumab has been discussed as case reports suggest successful response to the treatment of patients with fibrous dysplasia. He is planned to receive the first dose of denosumab in upcoming weeks.
Brief outline of the literature
Fibrous dysplasia of bone (FD) is a rare bone disease that accounts for approximately 5 to 7 percent of benign bone tumours and is caused by the postzygotic mutation in the guanine nucleotide stimulatory protein (GNAS) gene. This leads to the abnormal cellular response leading overproduction of IL-6 and receptor activator of nuclear factor-kB ligand (RANKL) resulting in high proliferative partially mineralised fibrous osseous tissue. FD may occur in single (monostotic) or multiple bones (polyostotic fibrous dysplasia) and is associated with other endocrinopathies. People with FD commonly suffer from pain from the affected skeletal sites, fractures, and disability. Management options for FD have been mainly surgical targeting stabilising impending fractures and correcting deformities. The first line pharmacological management has been supplementation of hypophosphatemia if present and vitamin D repletion. Otherwise, analgesics have been recommended (1).
Bisphosphonates are suggested with a hypothesis of normalising bone turnover and thereby reducing pain symptoms and preventing the progression of FD lesions. However, previous open-label studies have shown that those with high burden of skeletal disease, bisphosphonate treatment was not adequate to control the pain nor reducing the bone-turnover markers. Continuation of bisphosphonate is not recommended if there is no clinical improvement (2).
This case highlights the challenge in managing FD where surgery is not an option, and bisphosphate therapy being ineffective.
The use of denosumab may provide clinical benefits in patients not responding to bisphosphonate therapy. Studies have suggested the positive correlation with the upregulation of RANKL expression in skeletal lesions with skeletal burden score in patients with FD (3, 4). Positive outcomes including improvement in pain and lung function in those with thoracic involvement. A 60mg dose of denosumab resulted in sustained reduction of bone turn over markers however, 6 monthly injections may be insufficient to maintain the suppressed bone turnover markers in patients with FD. Three-monthly intervals were shown to be efficient in maintaining the decreased BTMs by more than 50% from baseline values. Case studies have shown that this was well tolerated. The optimal duration of denosumab therapy and further management once in clinical and biochemical remission remains unclear. Another study trialling bisphosphonate to aid cessation of denosumab showed rebound hypercalcaemia to be present in a few patients post cessation of denosumab particularly in those with high disease burden, requiring an additional dose of denosumab (5). Close monitoring of calcium, vitamin D and renal function is recommended to prevent severe hypo and hypercalcaemia.
Take home messages:
- Polyostotic fibrous dysplasia is rare bone disease affecting either one or multiple skeletal sites (monostotic and polyostotic fibrous dysplasia).
- There is yet no approved medical treatment to control pain and disease activity in FD.
- Bisphosphonates have been used in the management of patients with FD related bone pain however, those with high skeletal burden, may not respond to treatment with these agents.
- Denosumab been shown to be effective in those with FD refractory or intolerant to bisphosphonates therapy. Larger controlled studies are needed until then, this should be used with cautions.
Figure 2. CT of chest showing left sided hemithorax and fibrous dysplasia involvement in vertebral bodies and sternum.
Table 1. Biochemistry including bone turnover markers
Figure 3. Nuclear medicine Bone scan (945MBq Tc-9mM HDP) done on 24/02/2021 (pre-bisphosphonate treatment) showing intense activity throughout mainly on the left side.
Figure 4. Repeat Nuclear bone scan (6 months post the zoledronic acid)
- Javaid, M.K., Boyce, A., Appelman-Dijkstra, N. et al. Best practice management guidelines for fibrous dysplasia/McCune-Albright syndrome: a consensus statement from the FD/MAS international consortium. Orphanet J Rare Dis 14, 139 (2019).
- Majoor BC, Appelman-Dijkstra NM, Fiocco M, van de Sande MA, Dijkstra PS, Hamdy NA. Outcome of Long-Term Bisphosphonate Therapy in McCune-Albright Syndrome and Polyostotic Fibrous Dysplasia. Journal of Bone and Mineral Research. 2017;32(2):264-76.
- Majoor BCJ, Papapoulos SE, Dijkstra PDS, Fiocco M, Hamdy NAT, Appelman-Dijkstra NM. Denosumab in Patients With Fibrous Dysplasia Previously Treated With Bisphosphonates. J Clin Endocrinol Metab. 2019;104(12):6069-78.
- Meier ME, van der Bruggen W, van de Sande MAJ, Appelman-Dijkstra NM. Regression of fibrous dysplasia in response to denosumab therapy: A report of two cases. Bone Reports. 2021;14:101058.
- de Castro LF, Michel Z, Pan K, Taylor J, Szymczuk V, Paravastu S, et al. Safety and Efficacy of Denosumab for Fibrous Dysplasia of Bone. New England Journal of Medicine. 2023;388(8):766-8.