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Abstract：
BACKGROUND: In the post-marketing stage, cases of hypocalcemia associated with bisphosphonate preparations (BPs) have been reported in patients with decreased kidney function, despite warning against use of BPs in such patients in the package insert (PI) of Japan. The purpose of this study was to investigate the safety of BPs in patients with decreased kidney function.
METHODS: The cohort study was conducted in patients with osteoporosis and newly prescribed bisphosphonate utilizing real-world data from MID-NET® in Japan. The adjusted hazard ratios (aHRs) for hypocalcemia (a corrected serum Ca level < 8.00 mg/dL) relative to the normal group were calculated in each decreased kidney function group (mild, moderate or severe group).
RESULTS: A total of 14,551 patients were included in the analysis, comprising 2,601 (17.88%) with normal (eGFR ≥ 90 mL/min/1.73m2), 7,613 (52.32%) with mild (60 ≤ eGFR < 90 mL/min/1.73m2), 3,919 (26.93%) with moderate (30 ≤ eGFR < 60 mL/min/1.73m2), and 418 (2.87%) with severe kidney function (eGFR < 30 mL/min/1.73m2). The aHRs (95% confidence interval) for hypocalcemia were 1.85 (0.75-4.57), 2.30 (0.86-6.21), and 22.74 (8.37-61.78) in the mild, moderate, and severe groups, respectively. The increased risk of hypocalcemia depending on kidney function was also observed even when calculating the aHR for each specific BP such as alendronate sodium hydrate, minodronic acid hydrate, and sodium risedronate hydrate. Furthermore, similar results were obtained in the sensitivity analysis by altering the outcome definition to a 20% or more reduction in corrected serum Ca level from the baseline, as well as when focusing on patients with more than one laboratory test result per 30 days during the follow-up period.
CONCLUSIONS: These findings suggest that the risk of hypocalcemia during BP prescription is higher in patients with decreased kidney function, particularly those with severely decreased kidney function. The quantitative real-world evidence on the safety risk of BPs obtained in this study has led to the PI revision describing a relationship between hypocalcemia risk and decreased kidney function as a regulatory action in Japan and will contribute to promoting the proper use of BPs with appropriate risk management in clinical practice.
METHODS: The cohort study was conducted in patients with osteoporosis and newly prescribed bisphosphonate utilizing real-world data from MID-NET® in Japan. The adjusted hazard ratios (aHRs) for hypocalcemia (a corrected serum Ca level < 8.00 mg/dL) relative to the normal group were calculated in each decreased kidney function group (mild, moderate or severe group).
RESULTS: A total of 14,551 patients were included in the analysis, comprising 2,601 (17.88%) with normal (eGFR ≥ 90 mL/min/1.73m2), 7,613 (52.32%) with mild (60 ≤ eGFR < 90 mL/min/1.73m2), 3,919 (26.93%) with moderate (30 ≤ eGFR < 60 mL/min/1.73m2), and 418 (2.87%) with severe kidney function (eGFR < 30 mL/min/1.73m2). The aHRs (95% confidence interval) for hypocalcemia were 1.85 (0.75-4.57), 2.30 (0.86-6.21), and 22.74 (8.37-61.78) in the mild, moderate, and severe groups, respectively. The increased risk of hypocalcemia depending on kidney function was also observed even when calculating the aHR for each specific BP such as alendronate sodium hydrate, minodronic acid hydrate, and sodium risedronate hydrate. Furthermore, similar results were obtained in the sensitivity analysis by altering the outcome definition to a 20% or more reduction in corrected serum Ca level from the baseline, as well as when focusing on patients with more than one laboratory test result per 30 days during the follow-up period.
CONCLUSIONS: These findings suggest that the risk of hypocalcemia during BP prescription is higher in patients with decreased kidney function, particularly those with severely decreased kidney function. The quantitative real-world evidence on the safety risk of BPs obtained in this study has led to the PI revision describing a relationship between hypocalcemia risk and decreased kidney function as a regulatory action in Japan and will contribute to promoting the proper use of BPs with appropriate risk management in clinical practice.
摘要：
背景：在上市后阶段，在肾功能下降的患者中，已经报道了与双膦酸盐制剂（BPs）相关的低钙血症病例，尽管在日本的包装说明书（PI）中警告此类患者不要使用BP。目的探讨肾功能下降患者BPs的安全性。
方法：队列研究是利用日本MID-NET®的实际数据，对骨质疏松症和新处方的双膦酸盐患者进行的。在每个肾功能下降组（轻度，中度或重度组)。
结果：共有14,551名患者被纳入分析，包括2,601（17.88%），正常（eGFR≥90mL/min/1.73m2），7,613（52.32%），轻度（60≤eGFR<90mL/min/1.73m2），3,919（26.93％），中度（30≤eGFR<60mL/min/1.73m2），和418（2.87％）严重肾功能（eGFR<30mL/min/1.73m2）。低钙血症的aHR（95％置信区间）为1.85（0.75-4.57），2.30（0.86-6.21），温和的22.74（8.37-61.78），中度,和严重的群体，分别。甚至在计算每种特定BP的aHR时，如阿仑膦酸钠水合物，米诺膦酸水合物，和利塞膦酸钠水合物。此外，在敏感性分析中，通过将结果定义更改为校正后的血清Ca水平从基线降低20%或更多，获得了类似的结果。以及在随访期间每30天关注一次以上实验室检查结果的患者。
结论：这些研究结果表明，肾功能下降的患者在BP处方期间发生低钙血症的风险更高，尤其是肾功能严重下降的患者。在这项研究中获得的BPs安全风险的定量现实世界证据导致PI修订，描述了低钙血症风险与肾功能下降之间的关系，作为日本的监管行动，并将有助于促进BPs的正确使用在临床实践中进行适当的风险管理。
方法：队列研究是利用日本MID-NET®的实际数据，对骨质疏松症和新处方的双膦酸盐患者进行的。在每个肾功能下降组（轻度，中度或重度组)。
结果：共有14,551名患者被纳入分析，包括2,601（17.88%），正常（eGFR≥90mL/min/1.73m2），7,613（52.32%），轻度（60≤eGFR<90mL/min/1.73m2），3,919（26.93％），中度（30≤eGFR<60mL/min/1.73m2），和418（2.87％）严重肾功能（eGFR<30mL/min/1.73m2）。低钙血症的aHR（95％置信区间）为1.85（0.75-4.57），2.30（0.86-6.21），温和的22.74（8.37-61.78），中度,和严重的群体，分别。甚至在计算每种特定BP的aHR时，如阿仑膦酸钠水合物，米诺膦酸水合物，和利塞膦酸钠水合物。此外，在敏感性分析中，通过将结果定义更改为校正后的血清Ca水平从基线降低20%或更多，获得了类似的结果。以及在随访期间每30天关注一次以上实验室检查结果的患者。
结论：这些研究结果表明，肾功能下降的患者在BP处方期间发生低钙血症的风险更高，尤其是肾功能严重下降的患者。在这项研究中获得的BPs安全风险的定量现实世界证据导致PI修订，描述了低钙血症风险与肾功能下降之间的关系，作为日本的监管行动，并将有助于促进BPs的正确使用在临床实践中进行适当的风险管理。
