Nitrogen-containing bisphosphonates (NBPs) exhibit powerful anti-bone-resorptive effects (ABREs) via inhibition of farnesyl pyrophosphate synthase during cholesterol biosynthesis. Clinical applications have disclosed an unexpected side effect, namely osteonecrosis of jaw bones, and although thousands of cases have been documented in the last few years the mechanism remains unclear. Since NBPs accumulate in bone-hydroxyapatite, more jaw bone osteonecrosis cases may come to light if NBPs continue to be used as they are being used now. We have previously reported that in mice, systemic (intraperitoneal) injection of clodronate (a non-NBP) prevents the inflammatory effects of NBPs. Here, we examined in mice the local necrotic actions of various NBPs and the anti-necrotic effects of clodronate. A single subcutaneous injection of an NBP into the ear pinna induced necrosis at the injection site (relative potencies of necrotic actions of NBPs: zoledronate >> pamidronate ≥ alendronate > risedronate), while non-NBPs lacked this effect. Clodronate, when injected together with an NBP, reduced or prevented the necrosis induced by that NBP, but not its ABRE. Clodronate reduced the amount of each NBP retained within tissues. These results, together with those of previous studies, suggest that (i) clodronate inhibits the inflammatory and necrotic actions of NBPs by inhibiting their incorporation into cells related to inflammation and/or necrosis, (ii) clodronate could be useful as a combination drug with NBPs for preventing their necrotic actions while retaining their ABREs and (iii) clodronate could also be useful as a substitution drug for NBPs in patients at risk of osteonecrosis of jaw bones.

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We present a new analysis of Rossi X-Ray Timing Explorer observations of the 2002 outburst of the transient X-ray nova 4U 1543-47. We focus on observations in the high/soft state, and attempt to measure the "spin" of the black hole by simultaneously fitting the thermal disk continuum and by modeling the broadened iron k-shell emission lines and additional blurred reflection features. Previous works have found that use of these methods individually returns contradictory values for the dimensionless spin parameter a * = cJ/GM 2 . We find that when used in conjunction with each other, a moderate spin is obtained (a * = 0.43 +0.22 −0.31 ) that is actually consistent with both other values within errors. We discuss limitations of our analysis, systematic uncertainties, and implications of this measurement, and compare our result to those previously claimed for 4U 1543-47.

Bisphosphonates (BPs) are pyrophosphate analogs. They are widely used against enhanced boneresorption in various diseases. Nitrogen-containing BPs (N-BPs) exhibit strong anti-bone-resorptive effects but have inflammatory and necrotic side effects. The non-nitrogen-containing BPs (non-N-BPs) etidronate and clodronate lack such side effects, but their anti-bone-resorptive effects are weak. In mice, etidronate and clodronate reduce the inflammatory/necrotic effects of N-BPs, even those of zoledronate, the N-BP with the strongest anti-bone-resorptive effect yet reported and the highest risk of inflammation/necrosis. Here, to explore the mechanisms underlying this protection, we used a mouse model in which a single reagent or a mixture of two reagents was injected subcutaneously into ear-pinnas. These reagents included zoledronate, four non-N-BPs, pyrophosphate, and inhibitors of various organic-anion-transporters. Pyrophosphate and two of the four non-N-BPs (not etidronate or clodronate) had inflammatory/necrotic effects. These effects were reduced by etidronate and clodronate, but not by phosphonoformate, an inhibitor of two of the three known phosphate-transporter families. Phosphonoformate reduced the inflammatory/necrotic effects of zoledronate, but not those of pyrophosphate or of non-N-BPs. Conversely, pyrophosphate, at non-inflammatory/necrotic concentrations, reduced the inflammatory/necrotic effects of non-N-BPs, but not those of zoledronate. The efficacies of the protective effects against the inflammatory/ necrotic effects of zoledronate were clodronate > etidronate > phosphonoformate. These findings suggest that (i) the N-BP zoledronate may enter soft-tissue cells via phosphonoformate-inhibitable phosphatetransporters, (ii) other phosphate-transporters may carry pyrophosphate and inflammatory/necrotic non-N-BPs into such cells, and (iii) etidronate and clodronate inhibit all these transporters, and they ameliorate the side effects of zoledronate by inhibiting phosphonoformate-inhibitable phosphatetransporters.