Why use parenteral therapies for osteoporosis?

Treatment options for osteoporosis have dramatically changed over the past 15 years. The newer parenteral therapies, zoledronic acid, denosumab and teriparatide, are all effective treatment options with differing mechanisms of action. Here we review these new agents and compare their relative merits with existing oral medications for osteoporosis. Key Points Treatment of osteoporosis reduces mortality, as well as preventing further fractures, yet fewer than 20% of people in Australia with a previous osteoporotic fracture are actually treated for osteoporosis. Treatment options for osteoporosis now include bone-building (anabolic) and antiresorptive drugs, a choice of oral or parenteral administration, and varying dosing regimens from daily through to yearly administration. Longer dosing intervals for zoledronic acid and denosumab largely eliminate the issue of self-determined adherence and persistence. A parenteral route of administration for treatment of osteoporosis does not automatically confer better efficacy. </ul

Characterization of normal murine carpal bone development prompts re-evaluation of pathological osteolysis as the cause of human carpal-tarsal osteolysis disorders

Multicentric carpal-tarsal osteolysis; multicentric osteolysis, nodulosis, and arthropathy; and Winchester syndromes, skeletal dysplasias characterized by carpal/tarsal and epiphyseal abnormalities, are caused by mutations in v-maf musculoaponeurotic fibrosarcoma oncogene ortholog B (MAFB), matrix metalloproteinase (MMP) 2, and MMP14, respectively; however, the underlying pathophysiology is unclear. Osteoclast-mediated osteolysis has been regarded as the main mechanism, but does not explain the skeletal distribution. We hypothesized that MAFB, MMP-2, and MMP-14 have integral roles in carpal/tarsal and epiphyseal bone development. Normal neonatal mouse forepaws were imaged by micro-computed tomography and examined histologically. Murine forepaw ossification occurred sequentially. Subarticular regions of endochondral ossification showed morphologic and calcification patterns that were distinct from archetypical physeal endochondral ossification. This suggests that two different forms of endochondral ossification occur. The skeletal sites showing the greatest abnormality in the carpal-tarsal osteolysis syndromes are regions of subarticular ossification. Thus, abnormal bone formation in areas of subarticular ossification may explain the site-specific distribution of the carpal-tarsal osteolysis phenotype. MafB, Mmp-2, and Mmp-14 were expressed widely, and tartrate-resistant acid phosphatase staining notably was absent in the subarticular regions of the cartilage anlagen and entheses at a time point most relevant to the human osteolysis syndromes. Thus, abnormal peri-articular skeletal development and modeling, rather than excessive bone resorption, may be the underlying pathophysiology of these skeletal syndromes

A novel mutation of the primary protein kinase C phosphorylation site in the calcium-sensing receptor causes autosomal dominant hypocalcemia

Objective: The calcium-sensing receptor (CASR) is a key controller of calcium homeostasis by regulating parathyroid hormone (PTH) secretion and renal calcium reabsorption. CASRT888 is a protein kinase C (PKC) phosphorylation site in the receptor's intracellular domain that has previously been identified as a critical negative regulator of CASR downstream signaling in vitro, but whose importance in vivo is unknown. Case report: The proband presented with mild symptomatic hypocalcemia following treatment for nephrotic syndrome due to minimal change glomerulonephropathy. Laboratory tests revealed inappropriately normal PTH concentrations and relative hypercalciuria typical of autosomal dominant hypocalcemia. His asymptomatic father had similar laboratory test results. Design and methods: The CASR gene was sequenced. To investigate the molecular consequences of CASRT888M mutation, site-directed mutagenesis was used to modify the wild-type (wt)-CASR gene, with the resulting mutant being transfected transiently into HEK-293 cells. Results: A novel CASR missense mutation, T888M, was identified in both cases. The CASRT888M mutant exhibited enhanced sensitivity to extracellular calcium concentration, both for intracellular calcium (Cai2+) mobilization and for ERK phosphorylation, despite having unaltered levels of cell surface expression. Furthermore, CASRT888M elicited sustained Ca i2+ mobilization rather than high frequency Ca i2+ oscillations, and, unlike the wt-CASR, the response was resistant to acute inhibition by the PKC activator, phorbol 12-myristate 13-acetate. Conclusions: The clinical and functional data provide the first genotype-phenotype correlation for a mutation at T888, indicating its critical physiological importance in CASR signaling. Thus, CASRT888 represents a functionally important, inhibitory phosphorylation site that contributes to the control of PTH secretion. © 2011 European Society of Endocrinology