Funayama H, Ohsako M, Monma Y, Mayanagi H, Sugawara S, Endo Y
Department of Molecular Regulation, Graduate School of Dentistry, Tohoku University, Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
Calcif Tissue Int. 2005 Jun;76(6):448-57. doi: 10.1007/s00223-004-0180-3. Epub 2005 May 19.
Among the bisphosphonates (BPs), the aminobisphosphonates (aminoBPs) have much stronger bone-resorption-inhibitory activities (BRIAs) than nonaminobisphosphonates (nonaminoBPs). However, aminoBPs have inflammatory effects. We previously reported that in mice: (i) all aminoBPs tested (10-40 micromol/kg) induced various inflammatory reactions (including induction of histidine decarboxylase), whereas clodronate (a non-aminoBP) (10-160 micromol/kg) inhibited these reactions; and (ii) a clear sclerotic line (tentatively called the BP line) was detectable in the tibia by radiography a few weeks after a single injection of either alendronate (a typical aminoBP) (1.6 micromol/kg) or clodronate (160 micromol/kg), and this BP-line formation (a marker for the BRIAs of BPs) was not reduced in mice given both alendronate and clodronate. In this study, using this murine model, we compared clodronate, etidronate (another typical non-aminoBP), alendronate, etidronate + alendronate, and clodronate + alendronate in terms of their inflammatory effects and/or BP-line formation. For BP-line formation, 480 micromol/kg etidronate was needed (single injection). At 160 micromol/kg, etidronate inhibited the histidine decarboxylase induction, but not the other inflammatory reactions induced by alendronate. However, etidronate (unlike clodronate) also inhibited alendronate-induced BP-line formation (even at 40 micromol/kg). Etidronate (160 micromol/kg) also inhibited the physicochemical changes in the tibia induced by six, weekly injections of alendronate. Therefore, depending on the dose, etidronate can inhibit alendronate's inflammatory actions and its BRIA. These results, together with those reported previously, suggest that a strategy utilizing clodronate (but not etidronate) plus an aminoBP might prevent or reduce the inflammatory side effects induced by aminoBPs while preserving their powerful BRIAs. We discuss the mechanisms underlying the antagonism between aminoBPs and non-aminoBPs.
在双膦酸盐（BPs）中，氨基双膦酸盐（aminoBPs）比非氨基双膦酸盐（nonaminoBPs）具有更强的骨吸收抑制活性（BRIAs）。然而，氨基双膦酸盐具有炎症效应。我们之前报道过，在小鼠中：（i）所有测试的氨基双膦酸盐（10 - 40微摩尔/千克）都会诱导各种炎症反应（包括组氨酸脱羧酶的诱导），而氯膦酸盐（一种非氨基双膦酸盐）（10 - 160微摩尔/千克）则会抑制这些反应；（ii）在单次注射阿仑膦酸钠（一种典型的氨基双膦酸盐）（1.6微摩尔/千克）或氯膦酸盐（160微摩尔/千克）几周后，通过X射线摄影可在胫骨中检测到一条清晰的硬化线（暂称为BP线），并且在同时给予阿仑膦酸钠和氯膦酸盐的小鼠中，这种BP线的形成（BPs骨吸收抑制活性的一个标志物）并未减少。在本研究中，使用该小鼠模型，我们比较了氯膦酸盐、依替膦酸盐（另一种典型的非氨基双膦酸盐）、阿仑膦酸钠、依替膦酸盐 + 阿仑膦酸钠以及氯膦酸盐 + 阿仑膦酸钠在炎症效应和/或BP线形成方面的差异。对于BP线的形成，需要480微摩尔/千克的依替膦酸盐（单次注射）。在160微摩尔/千克时，依替膦酸盐抑制组氨酸脱羧酶的诱导，但不抑制阿仑膦酸钠诱导的其他炎症反应。然而，依替膦酸盐（与氯膦酸盐不同）也抑制阿仑膦酸钠诱导的BP线形成（即使在40微摩尔/千克时）。依替膦酸盐（160微摩尔/千克）还抑制了每周注射六次阿仑膦酸钠所诱导的胫骨物理化学变化。因此，根据剂量不同，依替膦酸盐可以抑制阿仑膦酸钠的炎症作用及其骨吸收抑制活性。这些结果与之前报道的结果一起表明，一种利用氯膦酸盐（而非依替膦酸盐）加氨基双膦酸盐的策略可能会预防或减少氨基双膦酸盐诱导的炎症副作用，同时保留其强大的骨吸收抑制活性。我们讨论了氨基双膦酸盐和非氨基双膦酸盐之间拮抗作用的潜在机制。
