Relationship between high-dose statin therapy and risk of osteoporosis confirmed in mouse models

Using several million medical records, a research group from MedUni Vienna and the Complexity Science Hub (CSH) showed that there was a correlation between the dosage of statins and the diagnosis of osteoporosis as early as 2019. This finding has now been confirmed in a preclinical study, which was recently published in the journal Biomedicine and Pharmacotherapy.

Statins are among the most frequently prescribed drugs. The higher the dosage, the greater the risk of osteoporosis: this was the key finding from the previous Big Data analysis in 2019. This finding has now been confirmed in preclinical studies. "This is the first time that the link between a high dose of statins and osteoporosis has been demonstrated in an animal model," says Alexandra Kautzky-Willer and Michael Leutner from the University Internal Medicine III Department, Division of Endocrinology and Metabolism, at MedUni Vienna.

In 2019, in a Big Data analysis the research team found that high doses of statins were associated with an increased risk of bone loss (osteoporosis), whereas low doses were actually associated with a lower risk of osteoporosis. At that time, a health database of more than 7.9 million Austrians was reviewed. 353,502 Austrians were taking statins at the time, and 11,701 of them were diagnosed with osteoporosis. A corresponding correlation was also confirmed by the Big Data analysis in the current study, in which patients on high-dose statin therapy were four to six times more likely to be diagnosed with osteoporosis.

In the current study, the researchers also used a detailed 3D imaging technique in collaboration with bone specialist Peter Pietschmann to examine bone quality in mice and found that long-term high-dose statin therapy had adverse effects on bone in both male and female ovariectomized mice. Both the trabecular and cortical regions of the femur showed significantly lower bone volume in the mice that had received high-dose statin therapy. "Adverse effects of high-dose simvastatin therapy were also reflected in the cortical thickness of the femur and in the L4 vertebral body," said Michael Leutner, lead author of the study. Clemens Fürnsinn, who was primarily responsible for conducting the mouse experiments, emphasized their significance as evidence of a direct causal relationship between statin use and loss of bone quality.

The new findings have implications for future treatments. "Our findings inevitably raise concerns about osteoporosis as a possible side effect of high statin dosing and call for monitoring of bone metabolism in such patients," said Alexandra Kautzky-Willer. "Currently, based on our 2019 results and mouse models, we are investigating the relationship between cholesterol-lowering drugs and osteoporosis in a collaborative translational project that includes a clinical trial, mouse models, and Big Data analyses to gain more information about this relationship," Leutner explained.

Treatment of high cholesterol levels is a top priority
According to Leutner and Kautzky-Willer, treating elevated cholesterol levels should be a top priority because they are closely linked to cardiovascular disease and, consequently, mortality. "However, it remains to be demonstrated whether newer non-statin cholesterol-lowering drugs (such as PCSK9 inhibitors - the newer and most effective drugs for treating high cholesterol with proven cardiovascular benefits) have better effects on bone metabolism in humans. If this is the case, treatment should be tailored to the individual," maintained Leutner and Kautzky-Willer.

When high doses of statins are used, bone metabolism should be closely monitored, especially in high-risk patients, such as postmenopausal women, the study authors advise. "Calcium and vitamin D levels should also be monitored regularly in patients on high-dose statin therapy," explained the lead author of the study, Michael Leutner.
Peter Klimek, co-author of the study and leader of the data analysis team, also pointed out that these new findings demonstrate the importance of a multidisciplinary approach to biomedical research. From a Big Data perspective, the results show that it is possible to gain concrete scientific insight into any new adverse effects for some of the most commonly prescribed drugs.

Publication: Biomedicine and Pharmacotherapy
Simvastatin therapy in higher dosages deteriorates bone quality: consistent evidence from population-wide patient data and interventional mouse studies;
Leutner Michael, Butylina Maria, Matzhold Caspar, Klimek Peter, Cuhaj Carina, Bellach Luise, Baumgartner-Parzer Sabina, Reiter Birgit, Preindl Karin, Kautzky Alexander, Stimpfl Thomas, Thurner Stefan, Pietschmann Peter, Fürnsinn Clemens, Kautzky-Willer Alexandra