Calcitonin inhibits SDCP-induced osteoclast apoptosis and increases its efficacy in a rat model of osteoporosis.
BACKGROUND
Treatment 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.


METHODS
Isolated 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.


RESULTS
Calcitonin 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.


CONCLUSIONS
Calcitonin reduces SDCP-induced osteoclast apoptosis and increases its efficacy in an in vivo model of osteoporosis.
Department of Orthopaedic, Taipei Medical University Hospital, Taipei, Taiwan, Republic of China.
Yi-Jie
YJ
Kuo
Fon-Yih
FY
Tsuang
Jui-Sheng
JS
Sun
Chi-Hung
CH
Lin
Chia-Hsien
CH
Chen
Jia-Ying
JY
Li
Yi-Chian
YC
Huang
Wei-Yu
WY
Chen
Chin-Bin
CB
Yeh
Jia-Fwu
JF
Shyu
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002116:Calcitonin / Q000494:pharmacology*; D002131:Calcium Pyrophosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000473:pathology; D020935:MAP Kinase Signaling System; D010010:Osteoclasts / Q000187:drug effects* / Q000502:physiology; D010024:Osteoporosis / Q000188:drug therapy* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
D050071:Bone Density Conservation Agents; D019253:Proto-Oncogene Proteins c-bcl-2; C476842:sintered beta-dicalcium pyrophosphate; D002116:Calcitonin; D048049:Extracellular Signal-Regulated MAP Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D002131:Calcium Pyrophosphate