title: Denosumab treatment for fibrous dysplasia.
abstract: Fibrous dysplasia (FD) is a skeletal disease caused by somatic activating mutations of the cyclic adenosine monophosphate (cAMP)-regulating protein, α-subunit of the Gs stimulatory protein (G(s) α). These mutations lead to replacement of normal bone by proliferative osteogenic precursors, resulting in deformity, fracture, and pain. Medical treatment has been ineffective in altering the disease course. Receptor activator of NF-κB ligand (RANKL) is a cell-surface protein involved in many cellular processes, including osteoclastogenesis, and is reported to be overexpressed in FD-like bone cells. Denosumab is a humanized monoclonal antibody to RANKL approved for treatment of osteoporosis and prevention of skeletal-related events from bone metastases. We present the case of a 9-year-old boy with severe FD who was treated with denosumab for a rapidly expanding femoral lesion. Immunohistochemical staining on a pretreatment bone biopsy specimen revealed marked RANKL expression. He was started on monthly denosumab, with an initial starting dose of 1 mg/kg and planned 0.25 mg/kg dose escalations every 3 months. Over 7 months of treatment he showed marked reduction in pain, bone turnover markers (BTMs), and tumor growth rate. Denosumab did not appear to impair healing of a femoral fracture that occurred while on treatment. With initiation of treatment he developed hypophosphatemia and secondary hyperparathyroidism, necessitating supplementation with phosphorus, calcium, and calcitriol. BTMs showed rapid and sustained suppression. With discontinuation there was rapid and dramatic rebound of BTMs with cross-linked C-telopeptide (reflecting osteoclast activity) exceeding pretreatment levels, accompanied by severe hypercalcemia. In this child, denosumab lead to dramatic reduction of FD expansion and FD-related bone pain. Denosumab was associated with clinically significant disturbances of mineral metabolism both while on treatment and after discontinuation. Denosumab treatment of FD warrants further study to confirm efficacy and determine potential morbidity, as well as to determine the mechanism of RANKL in the pathogenesis of FD and related bone marrow stromal cell diseases.
authors.affiliation: Skeletal Clinical Studies Unit, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Boyce
authors.forename: William H
authors.initials: WH
authors.lastname: Chong
authors.forename: Jack
authors.initials: J
authors.lastname: Yao
authors.forename: Rachel I
authors.initials: RI
authors.lastname: Gafni
authors.forename: Marilyn H
authors.initials: MH
authors.lastname: Kelly
authors.forename: Christine E
authors.initials: CE
authors.lastname: Chamberlain
authors.forename: Carol
authors.initials: C
authors.lastname: Bassim
authors.forename: Natasha
authors.initials: N
authors.lastname: Cherman
authors.forename: Michelle
authors.initials: M
authors.lastname: Ellsworth
authors.forename: Josephine Z
authors.initials: JZ
authors.lastname: Kasa-Vubu
authors.forename: Frances A
authors.initials: FA
authors.lastname: Farley
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Molinolo
authors.forename: Nisan
authors.initials: N
authors.lastname: Bhattacharyya
authors.forename: Michael T
authors.initials: MT
authors.lastname: Collins
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D001706:Biopsy; D001859:Bone Neoplasms / Q000556:secondary; D001842:Bone and Bones / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002648:Child; D000069448:Denosumab; D005357:Fibrous Dysplasia of Bone / Q000188:drug therapy*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D009154:Mutation; D009362:Neoplasm Metastasis; D010024:Osteoporosis; D053245:RANK Ligand / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053245:RANK Ligand; D000069448:Denosumab