Genetic Influences and Targeted Treatments in Osteoporosis: A Systematic Review.

Osteoporosis is a chronic skeletal disorder marked by reduced bone mineral density (BMD) and increased fracture risk, posing a substantial global health burden. Traditionally considered multifactorial, growing evidence highlights a significant genetic contribution across both early-onset monogenic and adult-onset polygenic forms. Understanding the molecular and genetic architecture of osteoporosis is crucial for guiding targeted diagnostics and developing personalised therapeutic strategies. This review aimed to: (1) identify and summarise genetic mutations and polymorphisms associated with osteoporosis, classifying them into monogenic and multifactorial causes; (2) distinguish between syndromic and non-syndromic forms of genetically influenced osteoporosis; (3) evaluate how specific genetic variations influence the risk, onset, and severity of osteoporosis, particularly in postmenopausal populations; (4) examine current anti-resorptive and anabolic treatments in the context of genetic backgrounds; and (5) identify gaps in knowledge to guide future research into genetics-based screening and individualised treatment. A comprehensive literature search was conducted across PubMed, Embase, CINAHL, and the Cochrane Library for studies published between 2000 and 2025. Medical Subject Headings (MeSH) and free-text keywords were used to retrieve peer-reviewed articles, clinical trials, genetic association studies, and systematic reviews. Eligible studies explored genetic variants, bone signalling pathways (e.g., WNT/β-catenin, Notch), or pharmacological therapies in relation to BMD, fracture incidence, or osteogenesis. Data were extracted and thematically analysed under the following three core domains: genetic and molecular mechanisms, osteogenesis and bone remodelling, and treatment responses linked to genetic profiles. The review identified a wide spectrum of genetic contributors to osteoporosis. Monogenic forms, often syndromic, were linked to mutations in genes such as , , and , whereas multifactorial osteoporosis, particularly postmenopausal, was associated with variants in , , , and other GWAS-identified loci. The interplay between these variants and osteogenic signalling cascades was found to influence bone homeostasis. Treatments were categorised as anti-resorptive (e.g., bisphosphonates, denosumab) or anabolic (e.g., parathyroid hormone analogues, romosozumab), with genetic factors influencing efficacy. The evidence suggests a future need for personalised therapeutic strategies based on genetic profiling. There remains a need for further large-scale studies to validate genotype-phenotype correlations and treatment responses across diverse populations. Further exploration into pharmacogenomics, microRNA regulation, and gene-targeted interventions is required. Advancing osteoporosis care will depend on integrating genetic insights into clinical practice to enable earlier diagnosis, individualised treatment, and improved patient outcomes.