Using multivariable Mendelian randomization to estimate the causal effect of bone mineral density on osteoarthritis risk, independently of body mass index

April Hartley, Eleanor Sanderson, Raquel Granell, Lavinia Paternoster, Jie Zheng, George Davey Smith, Lorraine Southam, Konstantinos Hatzikotoulas, Cindy G. Boer, Joyce Van Meurs, Eleftheria Zeggini, Celia L. Gregson, Jon H. Tobias, Lilja Stefánsdóttir, Yanfei Zhang, Rodrigo Coutinho De Almeida, Tian T. Wu, Maris Teder-Laving, Anne Heidi Skogholt, Chikashi TeraoEleni Zengini, George Alexiadis, Andrei Barysenka, Gyda Bjornsdottir, Maiken E. Gabrielsen, Arthur Gilly, Thorvaldur Ingvarsson, Marianne B. Johnsen, Helgi Jonsson, Margreet G. Kloppenburg, Almut Luetge, Reedik Mägi, Massimo Mangino, Rob R.G.H.H. Nelissen, Manu Shivakumar, Julia Steinberg, Hiroshi Takuwa, Laurent Thomas, Margo Tuerlings, George Babis, Jason Pui Yin Cheung, Dino Samartzis, Steve A. Lietman, P. Eline Slagboom, Kari Stefansson, André G. Uitterlinden, Bendik Winsvold, John Anker Zwart, Pak Chung Sham, Gudmar Thorleifsson, Tom R. Gaunt, Andrew P. Morris, Ana M. Valdes, Aspasia Tsezou, Kathryn S.E. Cheah, Shiro Ikegawa, Kristian Hveem, Tõnu Esko, J. Mark Wilkinson, Ingrid Meulenbelt, Ming Ta Michael Lee, Unnur Styrkársdóttir

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


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.

Original languageEnglish
Pages (from-to)1254-1267
Number of pages14
JournalInternational Journal of Epidemiology
Issue number4
StatePublished - 1 Aug 2022
Externally publishedYes


  • Mendelian randomization
  • Osteoarthritis
  • UK Biobank
  • body mass index
  • bone mineral density


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