ビスホスホネート製剤と急性期反応について

An update on bisphosphonates and trends in drug therapy for osteoporosis. Acute phase reaction following bisphosphonates.

　経口ビスホスホネート製剤は，Monthly製剤や注射製剤が使用できるようになりアドヒアランスが向上している。一方でこれらの製剤は初回投与時に筋肉痛，骨痛，関節痛や発熱，全身倦怠感などのインフルエンザ様症状を呈する急性期反応を起こすことがある。急性期反応は一過性で通常治療を必要としないが，解熱鎮痛剤の使用により速やかに症状は消失する。ビタミンDの不足により急性期反応が起こりやすいことが報告されており，ビタミンDの充足ならびに併用は急性期反応の予防に役立つ可能性がある。急性期反応によりアドヒアランスが低下することがないように，患者には投与前に十分な説明と情報提供が必要である。

　Bisphosphonates are effective in decreasing bone resorption, the incidence of fragility fracure, and pain from bone metastases. Although relatively well tolerated, the initial dose（s）of intravenous or oral monthly aminobisphosphonates can be associated with an acute phase response, a nonspecific physiologic reaction associated with increased levels of inflammatory cytokines, fever, and flu like symptoms including fatigue, nausea, and myalgia within 3 days of dosing and lasting 7 days or less. 　Nitrogen-BPs（N-BPs）inhibit osteoclast function by acting as potent inhibitors of the enzyme　farnesyl diphosphate（FPP）synthase in the mevalonate biosynthetic pathway. Following an intravenous infusion or oral monthly BPs, transient uptake of N-BP into peripheral blood monocytes results in intracellular accumulation of isopentenyl diphosphate（IPP）due to FPP synthase inhibition. Recognition of IPP by γδT cells triggers their activation and expansion, resulting in the release of pro-inflammatory cytokines that cause the flulike symptoms of the acute phase reaction. 　There is trial evidence that its severity can be reduced by more than half with coadministration of acetaminophen, so the short-term use of these drugs to lessen the APR is advisable in patients receiving their first dosing of N-BPs. 　Levels of 25（OH）D were negatively correlated with the incidence and severity of APR. Vitamin D reduces the intensity of musculoskeletal pain after dosing of N-BPs for postmenopausal osteoporosis. 　APR has minimal impact on long-term adherence to therapy. It is less common in subjects who have previously used bisphosphonates. Information of APR to a patient is important before administration.