Reconsidering the Widespread Use of Active Vitamin D Analogues for Osteoporosis in Japan: A Call for Evidence-Based Prescription Practices

In Japan, active vitamin D has been widely prescribed for osteoporosis due to its regulatory approval, in contrast to international practice where it is not considered standard therapy. However, growing evidence indicates that these agents offer limited efficacy in fracture prevention and may pose significant risks. Mechanistically, active vitamin D increases both serum calcium and phosphate, which, in the absence of bone-forming signals such as growth, fracture healing, or high mechanical loading, may promote ectopic calcification rather than bone strengthening. Osteoporosis, particularly in low-turnover states common in aging or immobilization, is poorly responsive to active vitamin D, as calcium incorporation into bone is physiologically limited. Clinical trials have shown little benefit of vitamin D supplementation in individuals without deficiency, and adverse outcomes such as hypercalcemia, nephrolithiasis, kidney impairment, and vascular calcification have been documented, including a recent case series in patients with severe motor and intellectual disabilities. Despite these concerns, Japanese guidelines continue to list active vitamin D as an effective option, diverging from the recommendations of the European Society for Clinical and Economic Aspects of Osteoporosis and the United States Endocrine Society, which reflect nuanced, evidence-graded recommendations rather than explicit discouragement in primary osteoporosis. The persistence of widespread prescribing in Japan likely reflects historical practices, regulatory frameworks, and economic incentives. Given the aging population and high prevalence of osteoporosis, reconsideration of this approach is warranted. Prescribing should be restricted to clear endocrine indications such as hypoparathyroidism or chronic kidney disease-related secondary hyperparathyroidism. Aligning national practice with international standards, while promoting nutritional vitamin D and other evidence-based therapies, could reduce unnecessary harm and improve healthcare efficiency.