Osteoporosis is a systemic skeletal disease characterized by reduced bone mineral density (BMD) and increased fracture risk; it poses a significant global health challenge. The multifactorial pathogenesis of osteoporosis involves complex interactions between genetic factors and vitamin D metabolism, particularly involving key genes such as the vitamin D receptor (VDR), CYP27B1 and CYP24A1. Polymorphisms in these genes, including FokI, BsmI, TaqI and ApaI in the VDR gene, have been associated with variations in BMD, fracture susceptibility and differential responses to vitamin D supplementation, underscoring the importance of personalized medicine. Genome-wide association studies (GWAS) have identified over 500 loci, including WNT16, ESR1 and SOST, linked to osteoporosis-related traits, underlining the disease's polygenic nature and the impact of gene-environment interactions, including dietary vitamin D intake, sun exposure and gene variations. Despite these advancements, translating genetic insights into clinical practice remains challenging, especially due to the variability in genetic determinants and limited access to genotype assessment such as gene sequencing. This review advocates for precision medicine approaches to osteoporosis management. By addressing the gaps in the studies on osteoporosis aetiology, integrating genetic screening into routine diagnosis and care and promoting collaborative efforts in genomics, nutrition and public health, the global burden of osteoporosis can be significantly reduced. This approach offers a promising pathway to improve patient outcomes and advance personalized medicine strategies for osteoporosis as a debilitating condition.