ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Bone Miner Res. 2019;34(12):2171–2182.

In brief: The effect of RANKL inhibition on fibrous dysplasia development is explored here using a mouse model of a fibrous dysplasia-like disorder. Anti-mouse RANKL monoclonal antibody treatment prevented the development and growth of lesions. However, after discontinuation of anti-mouse RANKL antibody treatment, disease progression resumed and newly formed bone was remodelled into fibrous dysplasia.

Commentary: Fibrous dysplasia (FD) is a rare skeletal disease caused by mosaic gain-of-function mutations in Gsα causing fibro-osseous tissue and under-mineralized bone, rich in osteoclasts, to replace normal bone. Enhanced bone resorption driven by RANKL is a recurrent histological feature of FD and likely a major cause of pain and fragility of affected bones (1). Therefore, inhibition of RANKL appeared to be an attractive therapeutic approach. Consistently, in an early case report, the anti-RANKL monoclonal antibody Denosumab reduced bone turnover, bone pain and also was suggested to reduce growth of FD lesions. However, discontinuation of treatment was followed by life-threatening hypercalcemia, raising serious safety concerns (1,2).

In the current study, mice with a constitutively active Gsα (EF1α-Gs αR201C), which develop an FD-like phenotype, were treated with an anti-mouse RANKL monoclonal antibody (a denosumab analogue). The treatment not only prevented lesion formation but also promoted differentiation of FD cells to bone-forming osteoblasts that produced highly mineralized bone matrix. Thus, it raised the hope for an efficient treatment that can both limit the development of new FD lesions and reduce the size of current lesions. However, the report also shows that discontinuation of treatment is followed by rebound of bone resorption and FD, highlighting the safety concerns previously observed in humans with anti-RANKL monoclonal antibody therapy and that further work to elucidate prevention and management of relapse after treatment discontinuation is needed.

Nevertheless, this report represents an important proof-of-concept showing that RANKL inhibition, maybe in combination with a bisphosphonate or other anti-resorptive agent, have the potential to act as an effective therapeutic option to limit development and normalize the bone at FD lesions.

Reference:

1. Collins MT, de Castro LF, Boyce AM, Denosumab for fibrous dysplasia: Promising, but questions remain. J Clin Endocrinol Metab, 2020.

2. Boyce AM, et al., Denosumab treatment for fibrous dysplasia. J Bone Miner Res, 2012;27(7):1462–70.