Alfacalcidol prevents age-related bone loss and causes an atypical pattern of bone formation in aged male rats.
The current study was designed to investigate the skeletal effects of alfacalcidol in aged rats. Eighteen-month-old male rats were treated with 0, 0.1, or 0.2 microg/kg/d of alfacalcidol by daily oral gavage, 5 days/week for 12 weeks. At the beginning of the treatments, one group of rats was euthanized to serve as a baseline control. At the end of the study, the second lumbar vertebrae and the right tibial diaphysess were processed for bone histomorphometric analysis. The fourth lumbar vertebrae were subjected to strength testing. The control group of rats at 21 months of age had decreased serum testosterone levels and decreased cancellous bone mass associated with increased bone turnover on the trabecular surface. The older rats had increased bone turnover on the endocortical surface and decreased bone formation on the periosteal surface compared with the 18-month group. In contrast, alfacalcidol treatment increased cancellous and cortical bone mass in aged male rats. Trabecular bone resorption was decreased whereas bone formation was maintained or increased in the rats treated with alfacalcidol. In addition, endocortical bone formation was decreased whereas periosteal bone formation was increased in the rats treated with alfacalcidol compared with vehicle-treated rats. Marrow trabecular bone area was increased by alfacalcidol treatment in tibial diaphyses. Furthermore, bone strength of the lumbar vertebral body was increased after alfacalcidol treatment. An atypical pattern of bone formation on endosteal bone surfaces was seen in the rats treated with alfacalcidol. The atypical bone formation is characterized by small, focal packets of newly formed bone on trabecular and endocortical bone surfaces. This gave the appearance of the formation of "bone buds" emanating from trabecular surfaces. These bony outgrowths were mineralized and demonstrated significant fluorochrome label indicating recent mineralization. Also, lamellae of the bony buds did not run parallel to those of the trabecular plate to which they are attached. Arrest lines presented in most of the "bone buds". In summary, alfacalcidol treatment increased cancellous and cortical bone mass and improved bone strength, resulting in the prevention of age-related bone loss in aged male rats. An atypical pattern of bone formation observed in this study may be a result of minimodeling based bone formation stimulated by alfacalcidol treatment.
Li
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Osteoporosis Research, Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, CT 06340, USA. mei_li@groton.pfizer.com
Healy
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Li
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Simmons
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Jee
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Shen
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Thompson
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D000375:Aging / Q000473:pathology*; D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000187:drug effects / Q000502:physiology; D001862:Bone Resorption / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D002113:Calcification, Physiologic / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006887:Hydroxycholecalciferols / Q000494:pharmacology*; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010012:Osteogenesis / Q000187:drug effects* / Q000502:physiology; D010024:Osteoporosis / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D010521:Periosteum / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000097:blood; D013977:Tibia / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D016474:Weight-Bearing / Q000502:physiology
D006887:Hydroxycholecalciferols; D013739:Testosterone; C008088:alfacalcidol