Genetic Influences and Targeted Treatments in Osteoporosis: A Systematic Review

Cureus. 2025 Jul 7;17(7):e87436. doi: 10.7759/cureus.87436. eCollection 2025 Jul.

ABSTRACT

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 COL1A1, COL1A2, and WNT1, whereas multifactorial osteoporosis, particularly postmenopausal, was associated with variants in LRP5, SOST, VDR, 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.

PMID:40772209 | PMC:PMC12327379 | DOI:10.7759/cureus.87436