Revival of nitrogen-containing bisphosphonate-induced inhibition of osteoclastogenesis and osteoclast function by water-soluble microfibrous borate glass.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious skeletal complication associated with the long-term oral or intravenous use of nitrogen-containing bisphosphonates (N-BPs). Here, we investigated the effects of an ionic cocktail prepared from water-soluble microfibrous borate glass on neutralizing the inhibitory effects of two heterocyclic N-BPs, risedronate or zoledronic acid, on osteoclastogenesis, apoptosis of differentiated osteoclasts and osteoclast function. Cell growth and proliferation assays were first performed on RAW 264.7 cells to optimize the concentrations of the ionic cocktail and N-BPs to be used for static cell culture. The pre-osteoclasts were then stimulated with RANKL to differentiate into osteoclasts. The effects of the ionic cocktail and N-BPs on osteoclast differentiation, apoptosis and function were subsequently examined using 3 series of experiments conducted at the gene, protein, morphological and functional levels. After concentration optimization, the ionic cocktail was found to partially reverse N-BP-induced inhibition of osteoclastogenesis, stimulation of osteoclasts apoptosis and reduction of osteoclast resorptive activity. Ultrastructural examination of osteoclasts that had been exposed to either N-BP identified classical features of late apoptosis and secondary necrosis, while osteoclasts exposed simultaneously to the concentration-optimized ionic cocktail and N-BPs exhibited only signs of early apoptosis that were possibly reversible. Taken together, the results of the 4 series of experiments indicate that the ionic cocktail produced from dissolution of borate glass dressings has the potential to rescue the adverse effects of heterocyclic N-BPs on osteoclast differentiation and function. These results warrant further confirmation using dynamic cell culture and small animal BRONJ models. STATEMENT OF SIGNIFICANCE: Long-term oral and intravenous use of nitrogen-containing bisphosphonates (N-BPs) may result in bisphosphonate-related osteonecrosis of the jaw (BRONJ) due to the suppression of normal bone turnover. There is no effective treatment for such a complication to date. This work reported the use of an ionic cocktail derived from water-soluble microfibrous borate glass to revert heterocyclic N-BP-induced inhibition of osteoclastogenesis, stimulation of osteoclasts apoptosis and reduction of osteoclasts resorption in static cell culture condition. This ionic cocktail may have the potential to be further developed into a new adjunctive treatment for BRONJ.

A mechanistic study of the interaction of water-soluble borate glass with apatite-bound heterocyclic nitrogen-containing bisphosphonates.

Long-term oral and intravenous use of nitrogen-containing bisphosphonates (N-BPs) is associated with osteonecrosis of the jaw. Although N-BPs bind strongly to bone surfaces via non-covalent bonds, it is possible for extrinsic ions to dissociate bound N-BPs from mineralized bone by competitive desorption. Here, we investigate the effects and mechanism of using an ionic cocktail derived from borate bioactive glass for sequestration of heterocyclic N-BPs bound to apatite. By employing solid-state and solution-state analytical techniques, we confirmed that sequestration of N-BPs from bisphosphonate-bound apatite occurs in the presence of the borate-containing ionic cocktail. Simulations by density functional theory computations indicate that magnesium cation and borate anion are well within the extent of the risedronate or zoledronate anion to form precipitate complexes. The sequestration mechanism is due to the borate anion competing with bisphosphonates for similar electron-deficient sites on the apatite surface for binding. Thus, application of the borate-containing ionic cocktail represents a new topical lavage approach for removing apatite-bound heterocyclic N-BPs from exposed necrotic bone in bisphosphonate-related osteonecrosis of the jaw. STATEMENT OF SIGNIFICANCE: Long-term oral consumption and injections of nitrogen-containing bisphosphonates (N-BPs) may result in death of the jaw bone when there is traumatic injury to the bone tissues. To date, there is no effective treatment for such a condition. This work reported the use of an ionic cocktail derived from water-soluble borate glass microfibers to displace the most potent type of N-BPs that are bound strongly to the mineral component on bone surfaces. The mechanism responsible for such an effect has been identified to be cation-mediated complexation of borate anions with negatively-charged N-BPs, allowing them to be released from the mineral surface. This borate-containing cocktail may be developed into a novel topical rinse for removing mineral-bound N-BPs from exposed dead bone.

Microfibrous borate bioactive glass dressing sequesters bone-bound bisphosphonate in the presence of simulated body fluid.

Ion exchange occurs between borate bioactive glass and simulated body fluid. Borate bioactive glass dressings may be used for managing bisphosphonate-related osteonecrosis of the jaw through the formation of a complex incorporating leached calcium and borate ions and sequestered bone-bound bisphosphonates.