Background: Osteoporosis is a loss of bone density among aging adults that can cause fractures and disability. Drug-induced osteoporosis is a noteworthy health problem, but many physicians are unaware that many commonly prescribed medications contribute to significant bone loss and fractures. This study investigated the cumulative effects of concurrent polydrug use (≥ 5 medications) on bone mineral density (BMD) with inhibited and induced cytochrome P450 (CYP450) enzyme activity. Methods: This study enrolled 207 middle-aged and elderly male subjects who underwent two dualenergy X-ray absorptiometry (DXA) scans tomeasure lumbar vertebrae BMD between 2012 and 2018 and analyzed their prescribed medicines metabolized via the CYP450 system. Results: The inhibitory group (n = 66) included patients prescribed more drugs that inhibit CYP450 than those that induce CYP450, the inductive group (n = 72) included patients prescribed more medications that induce CYP450 than those that inhibit CYP450, and the reference group (n = 69) included patients administered with the equal number of prescription drugs that inhibit and induce CYP450 or used neither. The results indicated a significant increase in the risk of BMD loss in the inductive group compared to the reference group (OR = 3.63, 95% CI = 1.43-5.84) (p = 0.013). Conclusions: The prescription of drugs that induce CYP450 decreases the BMD in middle-aged and elderly males. A possible mechanism is that more CYP450 inducers in number would accelerate the metabolic rate of vitamin D andwill eventually affect the function of parathyroid hormone in bone remodeling.