Denosumab treatment for fibrous dysplasia

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 (Gsα). These mutations lead to replacement of normal bone by proliferative osteogenic precursors, resulting in...

Full description

Saved in:

Bibliographic Details
Published in:	Journal of bone and mineral research Vol. 27; no. 7; pp. 1462 - 1470
Main Authors:	Boyce, Alison M, Chong, William H, Yao, Jack, Gafni, Rachel I, Kelly, Marilyn H, Chamberlain, Christine E, Bassim, Carol, Cherman, Natasha, Ellsworth, Michelle, Kasa-Vubu, Josephine Z, Farley, Frances A, Molinolo, Alfredo A, Bhattacharyya, Nisan, Collins, Michael T
Format:	Journal Article
Language:	English
Published:	Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-07-2012 Wiley Wiley Subscription Services, Inc
Subjects:	Antibodies, Monoclonal - chemistry Antibodies, Monoclonal, Humanized - pharmacology Biological and medical sciences Biopsy Bone and Bones - pathology Bone healing Bone marrow Bone Neoplasms - secondary Bone turnover Calcitriol Calcium Cell Membrane - metabolism Cell Proliferation Child Denosumab Femur Fibrous dysplasia Fibrous Dysplasia of Bone - drug therapy Fractures Fundamental and applied biological sciences. Psychology Growth rate Humans HYPERCALCEMIA Immunohistochemistry - methods Male MCCUNE-ALBRIGHT SYNDROME Monoclonal antibodies Mutation Neoplasm Metastasis NF- Kappa B protein Osteoporosis Osteoprogenitor cells Pain RANK LIGAND RANK Ligand - metabolism Skeleton and joints Supplementation TRANCE protein Tumors Vertebrates: osteoarticular system, musculoskeletal system Endocrinopathy Hydroelectrolytic balance disorder Calcium Diseases of the osteoarticular system Monoclonal antibody Denosumab Inorganic element Genetic disease Hypercalcemia Osteoarticular system Metabolic disorder Vertebrata Mammalia Treatment MCCUNE-ALBRIGHT SYNDROME Fibrous dysplasia Pseudohypoparathyroidism RANK LIGAND Albright disease Osteochondrodysplasia
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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 (Gsα). 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. © 2012 American Society for Bone and Mineral Research.
Bibliography:	istex:5FA42126F2B32B5312281765E13031695F7964F2 ark:/67375/WNG-ZDN0FBQX-S ArticleID:JBMR1603 ObjectType-Case Study-2 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0884-0431 1523-4681
DOI:	10.1002/jbmr.1603