High dose statins can increase osteoporosis risk finds Annals of the Rheumatic Diseases study

Austria: A higher dose of statins, the cholesterol-lowering drug, could increase the risk of osteoporosis, a recent study published in the Annals of the Rheumatic Diseases journal has found. However, at low doses statins provide protection against bone resorption.

According to the study, whether statins decrease or increase the risk of osteoporosis is dependent on their dosage. At low doses, statins provide protection against bone resorption. However, the higher the dosage of statins greater is the risk of osteoporosis. In short, osteoporosis is underrepresented in low-dose and overrepresented in high-dose statin treatment. Findings are based on an analysis of millions of patient data by the Complexity Science Hub Vienna show.

Osteoporosis is one of the most commonly occurring metabolic bone disorders. It is characterized by decreased bone mineral density (BMD) in which bones become weak and brittle. This increases the bone fragility making it susceptible to fracture.

Statins are cholesterol-lowering drugs that help protect the heart and brain by preventing artery plaques — buildups of cholesterol, calcium and other substances in blood vessels — from blocking blood flow and causing a heart attack or stroke. They are among the most prescribed drugs worldwide.

Whether HMG-CoA-reductase inhibition, the main mechanism of statins, plays a role in the pathogenesis of osteoporosis, is not entirely known so far. Michael Leutner, the Clinical Department of Endocrinology and Metabolism at the Medical University of Vienna (MedUni), and colleagues conducted the study 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.

"Statins inhibit the synthesis of cholesterol from the liver. This lowers blood cholesterol. However, cholesterol is crucially important for many processes in the body," explains Leutner. "Among other things, it is a basic building block for the production of sex hormones such as estradiol and testosterone."

For the investigation, the researchers used Big Data. They obtained access to the health data of more than 7.9 million Austrians between 2006 and 2007. From this big data set the patients who regularly took statins for at least one year were filtered out. The researchers also calculated the daily dosage of satins and formed different dosage groups. In a further step, the interdisciplinary team filtered out osteoporosis diagnoses.

Key findings of the study include:

• Statin treatment was associated with an overrepresentation of diagnosed osteoporosis compared with controls.


• 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, pravastatin, simvastatin and rosuvastatin.


• The exceeding of the 40 mg threshold for simvastatin and the exceeding of a 20 mg threshold for atorvastatin and for rosuvastatin was related to an overrepresentation of osteoporosis.

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"We know that low concentrations of sex hormones—especially the drop in estrogen levels during menopause—are the main cause for the increase of osteoporosis in women," explains Alexandra Kautzky-Willer, an expert in gender medicine and endocrinology, and head of the MedUni team. "There is a similar relationship between bone density and testosterone. We were interested in whether the inhibition of cholesterol production by statins has an effect on bone formation and whether there could be a dose-response relationship."

"In the lower dose groups, there were fewer osteoporosis cases than expected," Kautzky-Willer points out. At doses up to 10 milligrams of the statins lovastatin, pravastatin, simvastatin or rosuvastatin, the scientists found fewer osteoporosis diagnoses compared to patients without statin therapy. "With doses of 20 milligrams and more, however, the tide seems to turn. We found more osteoporosis cases in patients treated with simvastatin, atorvastatin and rosuvastatin than expected," explains Kautzky-Willer. The higher the dosage, the stronger the effect.

"In earlier joint studies we saw how helpful large data sets can be to examine open medical questions," says Peter Klimek, leader of the data analysis team at the Complexity Science Hub Vienna and at the Medical University of Vienna. "The combination of medical expertise with our knowledge in big data analysis makes completely new insights possible." According to Klimek, the newly discovered correlation between statin therapy and osteoporosis risk should now be investigated in clinical studies.

"With such results, we are coming closer to truly personalized and individualized medicine," maintains Kautzky-Willer. "We can now advise high-risk osteoporosis patients undergoing statin therapy to have their bone metabolism regularly monitored."

"We propose that monitoring high-risk patients, that is, postmenopausal female patients under high-dosage statin therapy, might be useful in order to offer individual therapy to prevent or treat osteoporosis. Thus, larger and prospective studies with a focus on dosages of statins should be conducted in order to clarify the relationship with osteoporosis," concluded the authors.

To read the study in detail follow the link: http://dx.doi.org/10.1136/annrheumdis-2019-215714