Efecto de los bisfosfonatos sobre el osteoblasto

Abstract

ABSTRACT Bisphosphonates (BPs) are a family of inorganic pyrophosphate synthetic analogues in which the oxygen linking the phosphates has been replaced by carbon. They are widely used to treat bone disorders, including osteoporosis, Paget´s disease, hypercalcemia of malignancy, fibrous dysplasia, and bone metastases of breast and prostate cancer. There are two main types: non-nitrogen-containing BPs and nitrogen-containing BPs. These two types of BPs have different intracellular targets and different action mechanisms with the aim to inhibit osteoclast-mediated bone resorption. BPs are widely prescribed due to their ability to inhibit osteoclast formation and activity. In this sense, its activity in vitro and in vivo is well documented. However, the mechanisms underlying their action on bone and their effects on osteoblasts are not fully understood. Although useful in the treatment of some bone diseases, BPs have also been associated with the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ). The physiopathology of BRONJ in not well known, although various proposals have been made, including: a decrease in bone turnover and subsequent accumulation of microfractures, a toxic effect on osteoblasts, an antiangiogenic effect, producing avascular necrosis, and a reduction in the viability of fibroblasts and oral keratinocytes. The principal aims of this thesis were to evaluate the effect of different concentrations of three nitrogen-containing BPs (pamidronate, alendronate, and ibandronate) and one non-nitrogen-containing BP (clodronate) on growth, differentiation, and antigenic profile of osteoblasts, using the MG-63 cell line. The literature review of in vitro studies demonstrated a role for BPs in osteoblast stimulation. However, their indirect effects on bone remodeling do not explain the behavior of these drugs in vivo. When we studied the effect of low concentrations of nitrogen-containing bisphosphonates, we observed an increase on MG-63 osteoblast-like cells proliferation, modulating their expression of co-stimulatory molecules associated with immune function, and decreasing their differentiation capacity. Similar results were obtained on osteoblasts treated with a non nitrogen-containing bisphosphonate (clodronate). However, high doses of nitrogen-containing or non-nitrogen-containing BPs reduced the proliferation of MG-63 osteoblast-like cells by arresting cell cycle and inducing apoptosis/necrosis. These findings suggest that BPs exert their effect on osteoblasts by altering their physiology in different ways, which would explain the disruption of their repair capacity and may be directly related to the development of BRONJ.