# Supra-Physiological Levels of Magnesium Counteract the Inhibitory Effect of Zoledronate on RANKL-Dependent Osteoclastogenesis

## TL;DR

High magnesium levels can reverse the bone damage caused by certain drugs used to treat osteoporosis and cancer.

## Contribution

Supra-physiological magnesium counteracts zoledronate's inhibition of RANKL-dependent osteoclast formation.

## Key findings

- Magnesium promotes osteoclast formation in RANKL-dependent models.
- This effect may help treat osteonecrosis of the jaw caused by denosumab.
- Magnesium's effect is enhanced in the presence of zoledronate.

## Abstract

Bisphosphonates (BPs) are drugs used to cure metabolic diseases like osteoporosis and several cancers, such as multiple myeloma and bone metastases. They exert their effect by reducing the activity of osteoclasts that are cells responsible for bone destruction. For this reason, they are classified among anti-resorptive agents. Unfortunately, in spite of their undisputed efficacy, these drugs can cause a dangerous side effect called osteonecrosis of the jaw (ONJ). Researchers have been exploring different ways to reverse ONJ by encouraging the activity of osteoclasts in the jaw, which could help heal the bone damage. Previous reports have shown that high levels of magnesium can favor the development of osteoclasts promoted by vitamin D3, and this effect is even stronger in the presence of a BP named zoledronate. In this study, we found that magnesium also favors osteoclast formation in the presence of a more important osteoclastogenic factor called RANKL. This observation suggests that magnesium could help treating ONJ even when this condition is provoked by a distinct anti-resorptive agent named denosumab, which is a monoclonal antibody-neutralizing RANKL.

Bisphosphonates (BPs) are drugs used to cure metabolic diseases like osteoporosis and oncological conditions, such as multiple myeloma and bone metastases. The pharmacological activity of these compounds is mediated by their capacity to induce a systemic osteoclast depletion, finally resulting in reduced bone resorption. In spite of their efficacy, the clinical application of BPs is sometimes associated with a frightening side effect known as osteonecrosis of the jaw (ONJ). In principle, a therapeutic approach able to elicit the local re-activation of osteoclast production could counteract the onset of ONJ and promote the healing of its lesions. Using a vitamin D3-dependent model of osteoclast differentiation, it has been previously demonstrated that when used at supra-physiological concentrations, magnesium strongly favors the process under consideration, and its effect is furtherly enhanced by the presence of a BP called zoledronate. Here, we show that similar results can be obtained in a RANKL-dependent model of osteoclast differentiation, suggesting that a topical therapy based on magnesium may be also suitable for ONJ determined by denosumab in light of the ability of this monoclonal antibody to target RANKL.