Zoledronic Acid Inhibits Human Osteoblast Activities

Abstract

Background: Bisphosphonates are potent inhibitors of bone resorption. These kinds of drugs, which are used for the treatment of osteolytic diseases, have been associated with the occurrence of oral osteonecrosis, especially in patients over 60 years old. Current studies have demonstrated that the cytotoxic effects of bisphosphonates on osteoblasts play an important role in oral osteonecrosis development. Objective: The aim of this study was to evaluate the effect of long-term application of a highly potent bisphosphonate - zoledronic acid (ZA) - on human osteoblasts in vitro. Methods: Human osteoblasts (MG63 cell line) were seeded for 72 h in wells of 24-well plates. The Dulbecco's modified Eagle's medium (DMEM) was then replaced by culture medium without fetal bovine serum (FBS), and the cells were incubated for an additional 24 h, after which ZA was added to the DMEM without FBS and incubated in contact with osteoblasts for 7, 14 or 21 days. Cell viability (CV), total protein production (TPP), alkaline phosphatase (ALP) activity, mineral nodule formation (MNF), and gene expression of ALP and osteocalcin (OCN), as well as cell morphology by scanning electronic microscopy, were evaluated. Data were statistically analyzed by Kruskal-Wallis and Mann-Whitney tests, with a significance level of 5%. Results: The cytotoxic effects of ZA on osteoblasts were characterized by reduction of CV, TPP, ALP and MNF production. In addition, ZA MNF caused a decrease in gene expression of ALP and OCN, as well as intense cell morphology alterations. All these negative effects of ZA were concentration and period dependent. Conclusion: Both concentrations of ZA (1 and 5 μ<smlcap>M</smlcap>) caused cytotoxic effects to osteoblasts which reduced the production and expression of proteins that play an important role in bone matrix synthesis and mineralization.

The effect of laser therapy on the expression of osteocalcin and osteopontin after tooth extraction in rats treated with zoledronate and dexamethasone

“…Contrasting data exist on the effect of zoledronate on osteoblasts: while some studies support a stimulatory effect [34], others report a cytotoxic effect, probably depending on dosage and models used [35].…”

Severe compromise of preosteoblasts in a surgical mouse model of bisphosphonate-associated osteonecrosis of the jaw

“…These findings confirm the compromise of the entire osteoblastic lineage including preosteoblasts, osteoblasts, and osteocytes (Koch et al 2011;Manzano-Moreno et al 2015). On another hand, in vitro studies report cytotoxic effects of bisphosphonates on osteoblastic cells, decreasing their viability and osteogenic ability in a dose-dependent manner (Pozzi et al 2009;Basso et al 2013). …”

“…The long-term use of intravenous third-generation amino-bisphosphonates (risedronate and zoledronic acid [ZOL]), the most powerful antiresorptive agents, is considered a critical risk factor related to the development of BONJ (Wessel, Dodson, and Zavras 2008;Basso et al 2013). The pathogenesis of BONJ remains unknown and several hypothesis have been proposed; nevertheless, the suppression of bone remodeling induced by bisphosphonates seems to be the most consistent with their intrinsic mechanism of action (Mawardi et al 2011; R. H.…”

Effect of zoledronic acid on vertebral marrow adiposity in postmenopausal osteoporosis assessed by MR spectroscopy

“…Accumulating evidence indicates that not only the wellknown actions on osteoclasts are important to shed light on the anti-fracture effects of bisphosphonates but also theirs effects on other effector cells such as osteoblasts, osteocytes, and adipocytes, which may explain the differences among bisphosphonates and may help to explain their pharmacological effects [3][4][5][6].…”