Calcitonin Inhibits SDCP-Induced Osteoclast Apoptosis and Increases Its Efficacy in a Rat Model of Osteoporosis

Abstract

IntroductionTreatment for osteoporosis commonly includes the use of bisphosphonates. Serious side effects of these drugs are caused by the inhibition of bone resorption as a result of osteoclast apoptosis. Treatment using calcitonin along with bisphosphonates overcomes these side-effects in some patients. Calcitonin is known to inhibit bone resorption without reducing the number of osteoclasts and is thought to prolong osteoclast survival through the inhibition of apoptosis. Further understanding of how calcitonin inhibits apoptosis could prove useful to the development of alternative treatment regimens for osteoporosis. This study aimed to analyze the mechanism by which calcitonin influences osteoclast apoptosis induced by a bisphosphate analog, sintered dicalcium pyrophosphate (SDCP), and to determine the effects of co-treatment with calcitonin and SDCP on apoptotic signaling in osteoclasts.MethodsIsolated osteoclasts were treated with CT, SDCP or both for 48 h. Osteoclast apoptosis assays, pit formation assays, and tartrate-resistant acid phosphatase (TRAP) staining were performed. Using an osteoporosis rat model, ovariectomized (OVX) rats received calcitonin, SDCP, or calcitonin + SDCP. The microarchitecture of the fifth lumbar trabecular bone was investigated, and histomorphometric and biochemical analyses were performed.ResultsCalcitonin inhibited SDCP-induced apoptosis in primary osteoclast cultures, increased Bcl-2 and Erk activity, and decreased Mcl-1 activity. Calcitonin prevented decreased osteoclast survival but not resorption induced by SDCP. Histomorphometric analysis of the tibia revealed increased bone formation, and microcomputed tomography of the fifth lumbar vertebrate showed an additive effect of calcitonin and SDCP on bone volume. Finally, analysis of the serum bone markers CTX-I and P1NP suggests that the increased bone volume induced by co-treatment with calcitonin and SDCP may be due to decreased bone resorption and increased bone formation.ConclusionsCalcitonin reduces SDCP-induced osteoclast apoptosis and increases its efficacy in an in vivo model of osteoporosis.

Is there a relationship between solubility and resorbability of different calcium phosphate phases in vitro ?

“…Now, although pyrophosphate, a product of the conversion of adenosine triphosphate to adenosine monophosphate, is a less common ion in the body compared to the phosphate, it was still detected in extraosseous calcific deposits [74–76], while its proposed role in the regulation of bone remodeling has been on hold for many years now [77]. Finally, although CPP has been shown to induce the apoptosis of osteoclasts [78] and induce an intense inflammatory response [79–81], no in vitro hints of such effects were observed in this study. Also, although bisphosphonates as structural analogs of pyrophosphates inhibit the resorption of bone by inducing the apoptosis of osteoclasts, aside from the inhibited resorption of CPP we observed no markedly adverse effects on the interaction between the CP particles and the osteoclastic cells.…”

miR-29 Promotes Murine Osteoclastogenesis by Regulating Osteoclast Commitment and Migration

“…CTR is a G protein-coupled receptor that mediates the anti-apoptotic effect of calcitonin on mature osteoclasts while inhibiting their resorption activity (44). Thus, the targeting of CTR by miR-29 in mature osteoclasts could promote resorption.…”

Better Osteoporotic Fracture Healing with Sintered Dicalcium Pyrophosphate (SDCP) Treatment

“…The dosage used in the experimental design was the optimal dosage based on prior study (Sun et al 2002). Further, previous studies have demonstrated that osteoporosis can be established as early as 4 weeks after ovariectomy and that the bone mass of an ovariectomized rat can be increased after 4 weeks of SDCP treatment (Kuo et al 2012;Sun et al 2002). The exact mechanism by which SDCP influences callus remodeling could not be establish in the present study, though it seems to be quite different from that of bisphosphonates.…”