J Bone Miner Res. 2019 Dec 10. doi: 10.1002/jbmr.3937. [Epub ahead of print]
Vascular endothelial growth factor (VEGF) is important for bone formation and has been associated with osteoporosis in humans. Therefore, we conducted a two-sample Mendelian randomization study to test whether genetically decreased circulating VEGF was associated with decreased bone mineral density (BMD) and increased risk of fracture. Summary statistics from a genome-wide association study (GWAS) meta-analysis of circulating VEGF level (N = 16,112) were used to identify 10 genetic variants explaining up to 52% of the variance in circulating VEGF levels. GWAS meta-analyses on dual X-ray absorptiometry-derived BMD of forearm, lumbar spine, and femoral neck (N = up to 32,735), and BMD estimated from heel calcaneus ultrasound (eBMD) (N = 426,824) were used to assess the effect of genetically lowered circulating VEGF levels on BMD. A GWAS meta-analysis including a total of 76,549 cases and 470,164 controls was used to assess the effect of genetically lowered circulating VEGF levels on risk of fracture. A natural log-transformed pg/mL decrease in circulating VEGF levels was not associated with a decrease in forearm BMD (0.02 standard deviations (SD), 95% CI: [-0.024, 0.064], p = 0.38), lumbar spine BMD (-0.005 SD, 95% CI: [-0.03, 0.019], p = 0.67), femoral neck BMD (0.004 SD, 95% CI: [-0.017, 0.026], p = 0.68), eBMD (-0.006 SD, 95% CI: [-0.012, -0.001], p = 0.031) or risk of fracture (odds ratio: 0.99, 95% CI: [0.98, 1.0], p = 0.37) in inverse-variance weighted Mendelian randomization analyses. Sensitivity analyses did not provide evidence that our results were influenced by pleiotropy. Genetically lowered circulating VEGF was not associated with a decrease in BMD or increased risk of fracture, suggesting that efforts to influence circulating VEGF level are unlikely to have beneficial effects on osteoporosis outcomes and that previous observational associations of circulating VEGF with BMD were influenced by confounding or reverse causation.