The SINTER study: A Recall-by-Genotype design with multidimensional musculoskeletal phenotyping across internal-medicine outpatient clinics

Bone mineral density (BMD) measured by DXA remains the clinical standard for diagnosing osteoporosis, but fails to capture the heterogeneity of skeletal fragility, particularly in patients with chronic diseases. We hereby describe the design of the EraSmus medIcal CeNTer skEletal fRagility (SINTER) Study, which integrates polygenic scores for BMD (PGS _BMD ) with a multidimensional phenotyping approach in diverse outpatient clinics, as a methodological framework for musculoskeletal research. The study aims at assessing the additional value of combining genetic information with comprehensive musculoskeletal phenotyping to better elucidate the mechanisms of skeletal fragility in chronic conditions. SINTER is an observational, cross-sectional Recall-by-Genotype ( RbG ) study drawn in two stages: (1) genotyping 5,650 patients from nine internal medicine clinics; (2) recalling 1,500 patients from the extremes of the PGS _BMD distribution for multidimensional musculoskeletal phenotyping together with 400 patients with a rare condition (mastocytosis). Phenotyping includes imaging (DXA, EOSEdge, pQCT), macro- and tissue-level skeletal properties (ultrasound, reference point indentation), functional assessments (mechanography, handgrip), lifestyle and systemic exposures (diet, physical activity), and patient perceptions obtained via in-depth interview and questionnaires. The study design is unique in combining a RbG framework with multidimensional phenotyping in outpatient-clinics, enabling systematic evaluation of genetic and disease-specific contributors to skeletal fragility. SINTER establishes a methodological template for RbG designs in clinical musculoskeletal research while helping elucidate the mechanisms of skeletal fragility.