Use of Denosumab in Children With Osteoclast Bone Dysplasias: Report of Three Cases.

Denosumab 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.

Acromegaly: A Dental Disease?

Acromegaly is a serious disease that affects the pituitary gland causing unusual growth in patients. There are various dental manifestation of the condition and it is plausible that a dentist will be the first to recognize the problem. This article describes the disease and the dental implications for patients who have it.

Increased prevalence of bisphosphonate-related osteonecrosis of the jaw with vitamin D deficiency in rats.

Necrotic bone exposure in the oral cavity has recently been reported in patients treated with nitrogen-containing bisphosphonates as part of their therapeutic regimen for multiple myeloma or metastatic cancers to bone. It has been postulated that systemic conditions associated with cancer patients combined with tooth extraction may increase the risk of osteonecrosis of the jaw (ONJ). The objective of this study was to establish an animal model of bisphosphonate-related ONJ by testing the combination of these risk factors. The generation of ONJ lesions in rats resembling human disease was achieved under the confluence of intravenous injection of zoledronate (ZOL; 35 microg/kg every 2 weeks), maxillary molar extraction, and vitamin D deficiency [VitD(-)]. The prevalence of ONJ in the VitD(-)/ZOL group was 66.7%, which was significantly higher (p < .05, Fisher exact test) than the control (0%), VitD(-) (0%), and ZOL alone (14.3%) groups. Similar to human patients, rat ONJ lesions prolonged the oral exposure of necrotic bone sequestra and were uniquely associated with pseudoepitheliomatous hyperplasia. The number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end label-positive (TUNEL(+)) osteoclasts significantly increased on the surface of post-tooth extraction alveolar bone of the VitD(-)/ZOL group, where sustained inflammation was depicted by [(18)F]fluorodeoxyglucose micro-positron emission tomography (microPET). ONJ lesions were found to be associated with dense accumulation of mixed inflammatory/immune cells. These cells, composed of neutrophils and lymphocytes, appeared to juxtapose apoptotic osteoclasts. It is suggested that the pathophysiologic mechanism(s) underpinning ONJ may involve the interaction between bisphosphonates and compromised vitamin D functions in the realm of skeletal homeostasis and innate immunity.