Using multivariable Mendelian randomization to estimate the causal effect of bone mineral density on osteoarthritis risk, independently of body mass index
Authors: Hartley April , Sanderson Eleanor , Granell Raquel , Paternoster Lavinia , Zheng Jie , Smith George Davey , Southam Lorraine , Hatzikotoulas Konstantinos , Boer Cindy G , van Meurs Joyce , Zeggini Eleftheria ,   The Genetics of Osteoarthritis Consortium, Stefánsdóttir Lilja , Zhang Yanfei , de Almeida Rodrigo Coutinho , Wu Tian T , Zheng Jie , Teder-Laving Maris , Skogholt Anne-Heidi , Terao Chikashi , Zengini Eleni , Alexiadis George , Barysenka Andrei , Bjornsdottir Gyda , Gabrielsen Maiken E , Gilly Arthur , Ingvarsson Thorvaldur , Johnsen Marianne B , Jonsson Helgi , Kloppenburg Margreet G , Luetge Almut , Mägi Reedik , Mangino Massimo , Nelissen Rob R G H H , Shivakumar Manu , Steinberg Julia , Takuwa Hiroshi , Thomas Laurent , Tuerlings Margo , Babis George , Cheung Jason Pui Yin , Samartzis Dino , Lietman Steve A , Slagboom P Eline , Stefansson Kari , Uitterlinden André G , Winsvold Bendik , Zwart John-Anker , Sham Pak Chung , Thorleifsson Gudmar , Gaunt Tom R , Morris Andrew P , Valdes Ana M , Tsezou Aspasia , Cheah Kathryn S E , Ikegawa Shiro , Hveem Kristian , Esko Tõnu , Wilkinson J Mark , Meulenbelt Ingrid , Lee Ming Ta Michael , Styrkársdóttir Unnur , Gregson Celia L , Tobias Jon H 
Published: November 2021

Abstract

Objectives
Observational analyses suggest that high bone mineral density (BMD) is a risk factor for osteoarthritis (OA); it is unclear whether this represents a causal effect or shared aetiology and whether these relationships are body mass index (BMI)-independent. We performed bidirectional Mendelian randomization (MR) to uncover the causal pathways between BMD, BMI and OA.

Methods
One-sample (1S)MR estimates were generated by two-stage least-squares regression. Unweighted allele scores instrumented each exposure. Two-sample (2S)MR estimates were generated using inverse-variance weighted random-effects meta-analysis. Multivariable MR (MVMR), including BMD and BMI instruments in the same model, determined the BMI-independent causal pathway from BMD to OA. Latent causal variable (LCV) analysis, using weight-adjusted femoral neck (FN)–BMD and hip/knee OA summary statistics, determined whether genetic correlation explained the causal effect of BMD on OA.

Results
1SMR provided strong evidence for a causal effect of BMD estimated from heel ultrasound (eBMD) on hip and knee OA {odds ratio [OR]hip = 1.28 [95% confidence interval (CI) = 1.05, 1.57], p = 0.02, ORknee = 1.40 [95% CI = 1.20, 1.63], p = 3 × 10–5, OR per standard deviation [SD] increase}. 2SMR effect sizes were consistent in direction. Results suggested that the causal pathways between eBMD and OA were bidirectional (βhip = 1.10 [95% CI = 0.36, 1.84], p = 0.003, βknee = 4.16 [95% CI = 2.74, 5.57], p = 8 × 10–9, β = SD increase per doubling in risk). MVMR identified a BMI-independent causal pathway between eBMD and hip/knee OA. LCV suggested that genetic correlation (i.e. shared genetic aetiology) did not fully explain the causal effects of BMD on hip/knee OA.

Conclusions
These results provide evidence for a BMI-independent causal effect of eBMD on OA. Despite evidence of bidirectional effects, the effect of BMD on OA did not appear to be fully explained by shared genetic aetiology, suggesting a direct action of bone on joint deterioration.