Moira Cheung

Mice Lacking the Calcineurin Inhibitor Rcan2 Have an Isolated Defect of Osteoblast Function

Calcineurin-nuclear factor of activated T cells signaling controls the differentiation and function of osteoclasts and osteoblasts, and regulator of calcineurin-2 (Rcan2) is a physiological inhibitor of this pathway. Rcan2 expression is regulated by T(3), which also has a central role in skeletal development and bone turnover. To investigate the role of Rcan2 in bone development and maintenance, we characterized Rcan2(-/-) mice and determined its skeletal expression in T(3) receptor (TR) knockout and thyroid-manipulated mice. Rcan2(-/-) mice had normal linear growth but displayed delayed intramembranous ossification, impaired cortical bone formation, and reduced bone mineral accrual during development as well as increased mineralization of adult bone. These abnormalities resulted from an isolated defect in osteoblast function and are similar to skeletal phenotypes of mice lacking the type 2 deiodinase thyroid hormone activating enzyme or with dominant-negative mutations of TRα, the predominant TR isoform in bone. Rcan2 mRNA was expressed in primary osteoclasts and osteoblasts, and its expression in bone was differentially regulated in TRα and TRβ knockout and thyroid-manipulated mice. However, in primary osteoblast cultures, T(3) treatment did not affect Rcan2 mRNA expression or nuclear factor of activated T cells c1 expression and phosphorylation. Overall, these studies establish that Rcan2 regulates osteoblast function and its expression in bone is regulated by thyroid status in vivo.

Drugs Used in Paediatric Bone and Calcium Disorders

Calcium and bone disorders in children and adolescents are treated with a wide variety of drugs. Several of these drugs have been used for many years on the basis of accepted practice, without being subjected to rigorous trials. Bisphosphonates are the mainstay treatment for children with osteoporosis, but newer, more potent compounds such as zoledronate and risedronate have begun to replace the older-generation bisphosphonates. Hypocalcaemia is managed with calcium and vitamin D and its metabolites. In difficult cases that are secondary to hypoparathyroidism, subcutaneous injections or infusions of parathyroid hormone have been used. Multiple daily phosphate supplements and calcitriol are the standard treatment for hypophosphataemic rickets, but trials of an anti-fibroblast growth factor 23 antibody appear promising, and the results are eagerly awaited. Many new medications are undergoing clinical trials and are starting to emerge as viable treatment options for children. Some of these drugs target specific diseases, such as recombinant alkaline phosphatase for hypophosphatasia and a C-type natriuretic peptide analogue for achondroplasia. Other drugs, such as denosumab and odanacatib, have been used successfully in the adult population, and the appropriate use of these drugs in children is now being evaluated.

Bone signaling pathways and treatment of osteoporosis

Osteoporotic fractures are a major healthcare burden costing over US

Paediatric Bone Physiology and Monitoring the Safety and Efficacy of Bone Drugs in Children

50 billion/per year. Bone turnover is a continuous process regulated by the coupled activities of osteocytes, osteoclasts and osteoblasts that maintain bone mass and strength. Osteoclastic bone resorption is regulated by the RANKL/osteoprotegerin/RANK pathway, while osteoblastic bone formation is controlled by canonical Wnt signaling. Antiresorptive bisphosphonates remain the mainstay of treatment but recombinant parathyroid hormone is increasingly being used as an anabolic agent. Nevertheless, these drugs are limited by patient compliance, efficacy and cost. Cathepsin K inhibitors and RANKL antibodies have been developed as new antiresorptive drugs, while short-acting calcilytics and antibodies to Dickkopf-1 and sclerostin are promising anabolics. The recent identification of adipocytes and duodenal enterochromaffin cells as novel regulators of bone mass represent exciting opportunities for future drug development.

Hearing the patient's voice: a focus group listening to the child and parent experiences of living with rare bone diseases

Many childhood diseases and their treatments can have adverse effects on the developing skeleton and the accrual of bone mass essential for normal adult bone health. Treatment with anti-resorptive and bone anabolic drugs can reduce such detrimental effects, but may also adversely affect bone development. Thus, in paediatric patients it is prudent to assess the skeleton carefully prior to commencing treatment, and to perform regular re-evaluation to monitor skeletal responses and to rapidly identify adverse events. The longitudinal follow-up of adult patients is relatively straightforward but similar longitudinal evaluation of the developing skeleton in paediatric patients is significantly more difficult and the data interpretation complex. This chapter highlights the underlying physiological basis for these difficulties and describes the modalities used for monitoring the efficacy and safety of skeletal pharmacology in paediatric patients.