Recombinant Osteoprotegerin for Juvenile Paget's Disease

Juvenile Paget's disease, a genetic bone disease characterized by accelerated bone turnover, results from inactivating mutations in the gene encoding osteoprotegerin -a key regulator of osteoclastogenesis.The effects of recombinant osteoprotegerin were investigated in two adult siblings with juvenile Paget's disease.Bone resorption (assessed by N-telopeptide excretion) was suppressed by once-weekly subcutaneous doses of 0.3 to 0.4 mg per kilogram of body weight.After 15 months of treatment, radial bone mass increased in one patient by 9 percent and in the other by 30 percent, skeletal bisphosphonate retention decreased by 37 percent and 55 percent, respectively, and there was radiographic improvement.Apart from mild hypocalcemia and hypophosphatemia, no apparent adverse events occurred.he change in the size and shape of the skeleton during growth and its renewal during adult life depend on the closely coordinated activity of bone-resorbing cells (osteoclasts) and bone-forming cells (osteoblasts).The receptor activator of nuclear factor-k B (RANK) ligand (RANKL)-osteoprotegerin-RANK system constitutes a critical mechanism for signaling between osteoblasts and osteoclasts.1 In response to factors such as parathyroid hormone that stimulate the remodeling cycle, the cytokine RANKL is expressed and secreted by osteoblasts.The interaction of RANKL with RANK, located on preosteoclasts, stimulates the differentiation of these cells into active, bone-resorbing osteoclasts.In parallel with the production of RANKL, osteoblasts secrete another molecule, osteoprotegerin, which binds to RANKL and inhibits the RANKL-RANK interaction.Osteoprotegerin is thus an endogenous inhibitor of osteoclast activity.2,3 Juvenile Paget's disease (Mendelian Inheritance in Man number 239000) is a rare, autosomal recessive bone disease characterized by greatly accelerated bone turnover.It presents in infancy or childhood with progressive deformity, growth retardation, and deafness (due to cochlear involvement).Most cases of juvenile Paget's disease arise from inactivating mutations in the gene that encodes osteoprotegerin, member 11B of the superfamily of tumor-necrosis-factor receptors ( TNFRSF11B ).[4][5][6] The osteoprotegerinknockout mouse recapitulates the juvenile Paget's disease phenotype in humans 7,8thus, the disease appears to result from osteoprotegerin deficiency.We report the effects of treatment with recombinant osteoprotegerin in two adult siblings with juvenile Paget's disease.