Reviewer Pharmaceuticals and Medical Devices Agency, Japan
Background: Bisphosphonate preparations are widely used as the first-line drugs for osteoporosis other than early postmenopausal osteoporosis, and the use in patients with renal impairment is alerted in the "CONTRAINDICATIONS" and "Careful Administration" in the package insert. However, in drug use-results surveys and adverse drug reaction reports, hypocalcaemia occurred when bisphosphonate preparations were administered to patients with renal impairment in Japan.
Objectives: To evaluate the safety of bisphosphonate preparations in patients with renal impairment by comparing the incidence of hypocalcaemia according to the severity of renal impairment in patients with osteoporosis for whom bisphosphonate preparations were prescribed.
Methods: We conducted a longitudinal cohort study using the Medical Information Database NETwork (MID-NET®) in Japan. We identified patients who were prescribed at least one of following six ingredients of bisphosphonate preparations indicated for osteoporosis between January 2009 and March 2019: alendronate sodium hydrate, ibandronate sodium hydrate, etidronate disodium, zoledronic acid hydrate, minodronic acid hydrate, and sodium risedronate hydrate. In patients with a diagnosis of osteoporosis who were newly prescribed bisphosphonate preparations, the incidence of hypocalcaemia during the prescription period was evaluated by renal function categories and estimated hazard ratio and 95% confidential intervals (CIs).
Results: There were 14,551 patients having a new prescription for bisphosphonate preparations. Adjusted hazard ratios (aHRs) for hypocalcaemia compared with the normal group were 1.85 [95%CI 0.75-4.57], 2.30 [95%CI 0.86-6.21], and 22.74 [95%CI 8.37-61.78] in the mild, moderate, and severe groups, respectively. In the subgroup analysis by ingredients, aHRs in each severity group for alendronate sodium hydrate, prescribed to the largest number of patients, were 1.66 [95%CI 0.55-5.00] in the mild group, 2.31 [95%CI 0.70-7.69] in the moderate group, and 16.03 [95%CI 4.68-54.96] in the severe group, showing a similar trend to the overall results. A similar trend was also observed with minodronic acid hydrate and sodium risedronate hydrate. For the other 3 ingredients, no onset of hypocalcaemia was observed in many groups due to the small number of patients.
Conclusions: In this study, the risk of hypocalcaemia was higher in patients with severe renal impairment than in those with normal renal function. Based on the results, the Ministry of Health, Labour and Welfare and the Pharmaceuticals and Medical Devices Agency determined that the revision of Precautions for bisphosphonate preparations indicated for osteoporosis was necessary.
