Abstract
ABSTRACTDenosumab has been used successfully to treat disease‐associated osteoclast overactivity, including giant cell tumor of bone. Given its mechanism of action, denosumab is a potent potential treatment of other osteoclast bone dysplasias including central giant cell granuloma (CGCG), aneurysmal bone cyst (ABC), and cherubism. Relatively little is known about the safety and efficacy of denosumab in patients with these conditions, especially in children. We report on 3 pediatric patients treated with denosumab over a 3‐year period at UCLA Medical Center (Los Angeles and Santa Monica, CA, USA): a 12‐year‐old with recurrent ABC of the pelvis, a 14‐year‐old with CGCG of the mandible, and a 12‐year‐old with cherubism. All were started on a 1‐year course of 15 doses 120 mg s.c., given monthly with two loading doses on day 8 and 15. All patients demonstrated rapid and pronounced clinical improvement while on denosumab, including a significant reduction in pain and sclerosis of lytic lesions on radiographs. Within 1 month of initiating therapy, 2 patients experienced hypocalcemia (Common Terminology Criteria for Adverse Events [CTCAE] grade 2) and hypophosphatemia, with 1 patient experiencing symptoms. One patient went on to experience symptomatic rebound hypercalcemia (CTCAE grade 4) 5 months after completing therapy, requiring bisphosphonates and calcitonin. For the second patient, we developed a schedule to wean denosumab involving the progressive lengthening of time between doses from 1 to 4 months in 1‐month increments before cessation. We found that denosumab therapy results in significant clinical and radiographic improvement for pediatric patients with nonresectable ABC, CGCG, and cherubism. Problems with serum calcium may be more common in younger patients, with symptomatic and protracted rebound hypercalcemia after cessation of therapy the most significant. We present a potential solution to this problem with progressive spacing of doses. Potential serious adverse events from alterations in calcium homeostasis should be explored in prospective clinical trials. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Highlights
A monoclonal antibody against RANKL, has been used successfully to treat diseases associated with osteoclast overactivity, including giant cell tumor of bone (GCTB), osteoporosis, and lytic lesions associated with bony metastases.[1,2,3] Increasingly, denosumab has been used off‐ label for other disorders of bone thought to result, at least in part, from similar osteoclastic pathology
A gain‐of‐function mutation in SH3BP2 has been identified as a driver of cherubism; this mutation leads to osteoclastogenesis in the presence of RANKL and TNF‐α through interactions with a variety of proteins in hemopoietic progenitor cells.[4] osteoclast multinucleated giant cells have been identified in central giant cell granuloma (CGCG).[5]. These same cells have been found in pathological specimens of aneurysmal bone cyst (ABC), though it is hypothesized they are reactive in nature.[6,7] excess osteoclastogenesis has been consistently identified in patients with fibrous dysplasia (FD).[8]. The potential role of multinucleated giant cells in these conditions has led to the limited application of denosumab in their treatment
2 years later she presented with pain following a fall; it was found that her pelvic ABC had recurred, she underwent a second curettage and bone grafting
Summary
A monoclonal antibody against RANKL, has been used successfully to treat diseases associated with osteoclast overactivity, including giant cell tumor of bone (GCTB), osteoporosis, and lytic lesions associated with bony metastases.[1,2,3] Increasingly, denosumab has been used off‐ label for other disorders of bone thought to result, at least in part, from similar osteoclastic pathology. These include central giant cell granuloma (CGCG), aneurysmal bone cyst (ABC), cherubism, and fibrous dysplasia (FD).
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