Leutner M, Matzhold C, Bellach L, et al. Diagnosis of osteoporosis in statin-treated patients is dose-dependent. Ann Rheum Dis. 2019 Sep 26. pii: annrheumdis-2019-215714. doi: 10.1136/annrheumdis-2019-215714. (Original study)

OBJECTIVE: Whether HMG-CoA-reductase inhibition, the main mechanism of statins, plays a role in the pathogenesis of osteoporosis, is not entirely known so far. Consequently, this study was set out to investigate the relationship of different kinds and dosages of statins with osteoporosis, hypothesising that the inhibition of the synthesis of cholesterol could influence sex-hormones and therefore the diagnosis of osteoporosis.

METHODS: Medical claims data of all Austrians from 2006 to 2007 was used to identify all patients treated with statins to compute their daily defined dose averages of six different types of statins. We applied multiple logistic regression to analyse the dose-dependent risks of being diagnosed with osteoporosis for each statin individually.

RESULTS: In the general study population, statin treatment was associated with an overrepresentation of diagnosed osteoporosis compared with controls (OR: 3.62, 95% CI 3.55 to 3.69, p<0.01). There was a highly non-trivial dependence of statin dosage with the ORs of osteoporosis. Osteoporosis was underrepresented in low-dose statin treatment (0-10 mg per day), including lovastatin (OR: 0.39, CI 0.18 to 0.84, p<0.05), pravastatin (OR: 0.68, 95% CI 0.52 to 0.89, p<0.01), simvastatin (OR: 0.70, 95% CI 0.56 to 0.86, p<0.01) and rosuvastatin (OR: 0.69, 95% CI 0.55 to 0.87, p<0.01). However, the exceeding of the 40 mg threshold for simvastatin (OR: 1.64, 95% CI 1.31 to 2.07, p<0.01), and the exceeding of a 20 mg threshold for atorvastatin (OR: 1.78, 95% CI 1.41 to 2.23, p<0.01) and for rosuvastatin (OR: 2.04, 95% CI 1.31 to 3.18, p<0.01) was related to an overrepresentation of osteoporosis.

CONCLUSION: Our results show that the diagnosis of osteoporosis in statin-treated patients is dose-dependent. Thus, osteoporosis is underrepresented in low-dose and overrepresented in high-dose statin treatment, demonstrating the importance of future studies' taking dose-dependency into account when investigating the relationship between statins and osteoporosis.

Discipline Area Score
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Internal Medicine 6 / 7
Endocrine 6 / 7
Cardiology 5 / 7
Comments from MORE raters

Endocrine rater

This is interesting information. It should not preclude clinicians from using statins in appropriate patients. It should alert them, however, to use the lowest dose that achieves the desired LDL targets. Also the study adds high dose statins as a risk factor for osteoporosis which should lead to more screening with DXA scans, especially in younger patients.

Internal Medicine rater

Despite limitations, the association seems quite clear, and the dose-dependancy is a clue pointing to causal inference.
Comments from EvidenceAlerts subscribers

Dr. Felix Wicke (10/22/2019 9:25 AM)

There are multiple confounders not controlled for in this study (e.g., body-weight, physical activity, health-care seeking behavior, or drugs like corticoids). Furthermore, it is susceptible to confounding by indication. Evidence from RCTs shows that statins do not affect fracture risk (at least not relevantly, https://www.ncbi.nlm.nih.gov/pubmed/11229669). The observation is most likely an artifact.

Dr. Stephen Roedde (10/15/2019 7:13 AM)

The association and dose-dependency may both be due to higher risk (statin-dose) patients being less active, with other potential confounding variables not controlled for (autoimmune conditions and prednisone use for example). Although diabetes (via metformin use) was controlled for, other risk factors were not. I remain unconvinced of a causal relation.