Abstract
Alendronate, a nitrogen-containing bisphosphonate, is well established as a treatment for osteoporosis through regulation of osteoclast activity. Previously, the pharmacological effects of bisphosphonates on cells outside the bone environment have been considered irrelevant because bisphosphonates target bone. Here we show that administration of alendronate impairs muscle regeneration in mice after bone fracture. A series of injections of alendronate alone or bone fracture alone did not affect muscle regeneration induced by cold injury. In contrast, alendronate treatment plus bone fracture severely impaired the regeneration of muscle that closely contacts the bone fracture site after cold injury. After cold injury, M-cadherin-positive myogenic cells disappeared in the damaged muscle areas of mice receiving the combination of alendronate treatment and bone fracture. The present results suggest that the muscle regeneration capacity is impaired by bone fracture in mice receiving alendronate treatment. The present research on the pharmacological effects of alendronate on muscle regeneration will aid in understanding of the in vivo action of alendronate on skeletal muscles.
Highlights
Bisphosphonates are non-metabolic synthetic analogues of pyrophosphate and well established as leading drugs for the treatment of osteoporosis and other diseases characterized by an increase in bone resorption [1, 2]
Consistent with our previous study using immortalized human myogenic cells in vitro [12], the results suggest that alendronate does not cause damage to myofibers even when mice receive a combination of bone fracture and alendronate treatment
The pharmacological effects of bisphosphonates on cells outside the bone environment has remained to be examined in osteoporosis patients treated with bisphosphonates for many years
Summary
Bisphosphonates are non-metabolic synthetic analogues of pyrophosphate and well established as leading drugs for the treatment of osteoporosis and other diseases characterized by an increase in bone resorption [1, 2]. Bisphosphonates inhibit osseous resorption, depending on their two key properties: their high affinity to bone mineral and their inhibition of osteoclast activity. Their backbone structure, called P-C-P and containing two phosphate groups and a carbon atom, is required for both binding to bone mineral and antiresorptive activity [2]. The acidic pH in the resorption space modifies one or both phosphate groups and dramatically reduces the affinity of bisphosphonates for bone mineral. Osteoclasts are exposed to a locally high concentration of bisphosphonates and preferentially internalize them. Osteoclasts are intended target cells of bisphosphonates because
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