The relationship between genetic bone mineral density and spinal stenosis: a Mendelian randomization and cohort study

Abstract

To evaluate whether genetic liability to higher bone mineral density (BMD) is associated with spinal stenosis and primary lumbar decompression surgery. We integrated two-sample Mendelian randomization (MR), multivariable MR, MRlap, reverse MR, and longitudinal UK Biobank analyses. The primary exposure was UK Biobank heel estimated BMD (eBMD); lumbar spine and total body DXA BMD were evaluated as sensitivity exposures. The primary outcome was FinnGen R12 spinal stenosis (26,090 cases; 353,224 controls), and decompression GWAS summary statistics were generated in UK Biobank (1,215 cases; 155,913 controls). Multivariable MR adjusted for body mass index and height. Cox models included 157,128 European-ancestry UK Biobank participants with valid baseline heel eBMD. Genetically proxied higher heel eBMD was associated with stenosis before (OR = 1.097, 95% CI: 1.01–1.191, p = 0.028) and after (OR = 1.09, 95% CI: 1.010–1.175, p = 0.026) MR-PRESSO outlier removal. The final instruments included 462 independent SNPs with mean F-statistic 46.3. Associations persisted after adjustment for BMI and height. Lumbar spine BMD showed stronger associations with stenosis (IVW OR = 1.23, 95% CI: 1.14–1.33, p < 0.001), but reverse MR also associated stenosis liability with higher lumbar BMD, suggesting local remodeling or disease-site contamination. Heel eBMD was not associated with decompression in MRlap, and lumbar BMD was similarly non-significant. Observationally, baseline heel eBMD was modestly associated with incident stenosis (HR = 1.04, 95% CI: 1.00-1.09, p = 0.037), but not decompression. Higher genetically proxied BMD was associated with lumbar stenosis but not decompression. Findings support skeletal remodeling biology as a contributor to stenosis susceptibility while highlighting surgery as a downstream clinical endpoint.