PCSK9 inhibitors and osteoporosis: mendelian randomization and meta-analysis

• Published in: BMC musculoskeletal disorders Vol. 25; no. 1; pp. 548 - 9
• Main Authors: Chen, Ding-Qiang, Xu, Wen-Bin, Xiao, Ke-Yi, Que, Zhi-Qiang, Feng, Jin-Yi, Sun, Nai-Kun, Cai, Di-Xin, Rui, Gang
• Format: Journal Article
• Language: English
• Published: England BioMed Central 16.07.2024; BMC
• Subjects: Cardiovascular disease; Cardiovascular diseases; Cholesterol; Clinical trials; Coronary artery disease; Datasets; Fractures; Genome-wide association studies; Genome-Wide Association Study; Heart diseases; HMGCR; Humans; Hydroxymethylglutaryl CoA Reductases - genetics; Hydroxymethylglutaryl-CoA reductase; Hyperlipidemia; Kexin; Lipids; Lipoproteins; Mendelian randomization; Mendelian Randomization Analysis; Meta-analysis; Metabolism; Older people; Osteoporosis; Osteoporosis - chemically induced; Osteoporosis - epidemiology; Osteoporosis - genetics; Pathogenesis; PCSK9; PCSK9 Inhibitors; Polymorphism, Single Nucleotide; Proprotein Convertase 9 - genetics; Proprotein Convertase 9 - metabolism; Proprotein convertases; Sensitivity analysis; Side effects; Single-nucleotide polymorphism; Statins; Subtilisin; Osteoporosis; PCSK9; HMGCR; Mendelian randomization
• ISSN: 1471-2474; 1471-2474
• DOI: 10.1186/s12891-024-07674-w

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent an effective strategy for reducing cardiovascular disease risk. Yet, PCSK9's impact on osteoporosis remains unclear. Hence, we employed Mendelian randomization (MR) analysis for examining PCSK9 inhibitor effects on osteoporosis. Single nucleotide polymorphisms (SNPs) for 3-hydroxy-3-methylglutaryl cofactor A reductase (HMGCR) and PCSK9 were gathered from available online databases for European pedigrees. Four osteoporosis-related genome-wide association studies (GWAS) data served as the main outcomes, and coronary artery disease (CAD) as a positive control for drug-targeted MR analyses. The results of MR analyses examined by sensitivity analyses were incorporated into a meta-analysis for examining causality between PCSK9 and HMGCR inhibitors and osteoporosis. The meta-analysis involving a total of 1,263,102 subjects, showed that PCSK9 inhibitors can increase osteoporosis risk (P < 0.05, I , 39%). However, HMGCR inhibitors are not associated with osteoporosis risk. Additionally, a replication of the analysis was conducted with another exposure-related GWAS dataset, which led to similar conclusions. PCSK9 inhibitors increase osteoporosis risk. However, HMGCR inhibitors are unremarkably linked to osteoporosis.