Inflammatory and Necrotic Effects of Minodronate, a Nitrogen-Containing Bisphosphonate, in Mice

Abstract

Diseases involving enhanced bone-resorption (e.g., osteoporosis) are widely treated with bisphosphonates (BPs). BPs are of two types: the nitrogen-containing BPs (N-BPs) and the non-nitrogen-containing BPs (non-N-BPs). N-BPs have much stronger anti-bone-resorptive effects than non-N-BPs, and N-BPs can exert inflammatory and necrotic effects, including osteonecrosis of jawbones. Minodronate, an N-BP, was approved in 2009 in Japan for osteoporosis. Its anti-bone-resorptive effect is comparable to that of zoledronate, the N-BP with the strongest anti-bone-resorptive effect and the highest risk of side effects yet reported. Unlike other N-BPs, minodronate has an analgesic effect, and no serious side effects have been documented. Here, to examine whether minodronate lacks inflammatory and/or necrotic effects, we used mice (since the N-BPs tested so far induce such effects in mice with potencies that parallel those reported in humans). To facilitate comparison with previous studies, we gave a single systemic (intraperitoneal) or local (ear pinna) injection of minodronate (or another N-BP). We measured the systemic responses (weight of thoracic exudate, number of inflammatory cells in the peritoneal cavity, and spleen weight) or local responses (area of inflamed skin and incidence of necrosis). Anti-bone-resorptive effects were evaluated by X-ray analysis of tibias following intraperitoneal injection. Minodronate's anti-bone-resorptive effect and its inflammatory and necrotic effects were as great as, or greater than those of zoledronate. Moreover, in cultured human periodontal ligament cells, the cytotoxicity of minodronate was significantly greater than that of zoledronate. These results suggest that caution may be needed with minodronate in clinical use, as with other N-BPs.

Antiresorptive Agents are More Effective in Preventing Titanium Particle‐Induced Calvarial Osteolysis in Ovariectomized Mice Than Anabolic Agents in Short‐Term Administration

“…The method of TPTD administration is consistent with other in vivo studies using mouse models . Local administration is also common in studies evaluating the inflammatory effect of bisphosphonate drugs and prevention effect of ZOL on particle‐induced osteolysis . There are also many studies comparing the effect of single dose ZOL and consecutive administration of TPTD on bone structure, osteoporotic fracture healing and the prevention of disuse osteopenia in small animal models .…”

Phosphonocarboxylates Can Protect Mice against the Inflammatory and Necrotic Side Effects of Nitrogen-Containing Bisphosphonates by Inhibiting Their Entry into Cells <i>via</i> Phosphate Transporters

“…Minodronate's anti-bone-resorptive effect and inflammatory/necrotic effects in mice are similar to, or greater than, those of zoledronate. 19) As shown in Fig. 3, minodronate and zoledronate induced inflammatory/necrotic effects at 2 mM, while alendronate did so at 32 mM.…”

Underlying Mechanisms and Therapeutic Strategies for Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ)

“…28) Later, we found in various experiments that Eti and Clo inhibit not only the inflammation but also the necrosis induced by N-BPs, and that the inhibitory effect of Clo is more potent than that of Eti. [7][8][9][10]14,15,27,55,56) For example, although Zol (one of the most potent anti-bone-resorptive N-BPs) induces severe inflammation and necrosis in mouse ear-pinnas, such effects of 2 mM Zol are completely prevented by 8 mM Eti 14) and those induced by 4 mM Zol are completely prevented by 4 mM Clo.…”

“…These conclusions were supported by experiments using other N-BPs, too. 9,10,15) In brief, our view is that N-BPs enter cells via SLC20 and/or SLC34 phosphate transporters, and the non-N-BPs Eti and Clo inhibit this transport and thus reduce or prevent the inflammatory/necrotic effects of N-BPs (Fig. 5).…”