UNLABELLED: This retrospective cohort study analysed a total of 344 patients from the OSTEOMED registry with matched baseline and follow-up DXA data, finding that comorbidities such as nephrolithiasis, hypertension or coronary heart disease may influence the response to prescribed anti-osteoporotic treatment. PURPOSE: To determine: 1) comorbidities associated with reduced bone mineral density (BMD), T-score and Z-score at the lumbar spine (L1 to L4 vertebrae), femoral neck and total hip; and 2) the role of multimorbidity (≥ 2 comorbidities) in reduced BMD, T-score and Z-score at the lumbar spine, femoral neck and total hip. METHODS: Retrospective cohort study analyzing patients [319 females (92.73%), 25 males (7.27%), age 62.13 ± 10.46 years] from the OSTEOMED registry with matched baseline and follow-up dual-energy X-ray absorptiometry (DXA) data. Patients' sex, age, body mass index (BMI), comorbidities and treatments were collected from their medical records after they had given written informed consent. RESULTS: Considering a least significant change (LSC) of 4.2%, neither comorbidity nor multimorbidity was statistically significantly associated with a reduction in BMD in any of the bone regions studied. However, binary logistic regression analyses adjusted for sex, age, BMI and treatments showed that nephrolithiasis (p = 0.044) and coronary heart disease (p = 0.026) were statistically significantly associated with a reduction in total hip T-score and that hypertension (p = 0.049) and coronary heart disease (p = 0.01) were statistically significantly associated with a reduction in total hip Z-score. CONCLUSION: Despite comorbidity and multimorbidity, patients with osteoporosis are mostly well protected by anti-osteoporotic treatment in daily clinical practice. However, nephrolithiasis, hypertension, and coronary heart disease can influence the response to prescribed anti-osteoporotic treatment, especially at the total hip level.