Systems analysis of the mechanism underlying the side effects in bone tissue by bisphosphonates

Abstract

As the elderly population grows around the world, the prevalence of osteoporosis continues to increase. To treat osteoporosis by increasing osteoblasts using parathyroid hormone or sex hormone were useful to prevent bone fractures in the past, but the prescription rates of the drugs dropped sharply or were discontinued due to side effects on other tissues. Recently, bisphosphonates have been used to treat osteoporosis by inhibiting osteoclasts. Although the side effects such as atypical bone fractures and jaw necrosis have been reported, the mechanism of side effects by bisphosphonates is not fully explained. The purpose of this study was to investigate the principles of bone remodeling and mechanisms of side effects of bisphosphonates using mathematical modeling from the perspective of bone tissue system. We formulated changes in cell population over time using mass action law and Hill function to simulate bone remodeling. Bisphosphonates improved bone mineral density by reducing the differentiation and activity of osteoclasts without significant change in osteoblasts activity. However, the simultaneous perturbation of other components in the bone remodeling network with bisphosphonate in aged bone tissue reduced the activities of osteoclasts and osteoblasts compared to single perturbation of each element. The combined perturbation of input or osteoblast differentiation or osteoblast apoptosis with bisphosphonates administration can reduce osteoblasts activity as well as osteoclasts activity severely. Reduced activities of osteoblasts and osteoclast by the input parameter’s perturbation can be restored by controlling the parameter of pre-osteoblast differentiation. In conclusion, it is difficult that bisphosphonate alone makes the side effects which serious inhibition of osteoclasts and osteoblasts may cause. The side effects in bone tissue by bisphosphonate can occur in suppression of osteoblasts differentiation or increase of osteoblasts apoptosis or input increase of bone remodeling. To prevent or treat the side effects by bisphosphonates, methods of increasing pre-osteoblasts differentiation can be used.