Do High-Dose Statins Increase the Risk for Osteoporosis?

Nancy A. Melville

October 14, 2019

The protective effect of statin therapy on bone health that has been demonstrated in some studies may be dose-related, and although low doses are associated with a reduced risk for osteoporosis, high doses were linked to an increased risk of the bone disease in new research.

"To the best of our knowledge, this is the first study which shows that it is important to consider the different kinds of substances and dosages when investigating the relationship of osteoporosis and statin therapy," say Michael Leutner, MD, of the Clinical Division of Endocrinology and Metabolism, Unit of Gender Medicine, Medical University of Vienna, Austria, and colleagues in an article published online in the Annals of the Rheumatic Diseases.

"The results were surprising for us," senior author Alexandra Kautzky-Willer, Dr Med, also of the Medical University of Vienna, told Medscape Medical News.

"We propose that monitoring high-risk patients, that is, postmenopausal female patients under high-dosage statin therapy, might be useful in order to offer an individual therapy to prevent or treat osteoporosis," she said.

Asked to comment, Ching-Lung Cheung, PhD, assistant professor in the Department of Pharmacology and Pharmacy and investigator with the Center for Genomic Sciences at the University of Hong Kong, said key caveats to consider in the study include the role of high cholesterol, which prompts the need for higher doses of statins.

"Elevated serum low-density lipoprotein (LDL) cholesterol is associated with reduced bone mineral density (BMD); thus, it is possible that those patients receiving high-dose statins had a lower baseline BMD compared to those receiving low-dose statins, which confound the observed association," Cheung, who is also involved in research on the relationship between statins and bone health, told Medscape Medical News.

Large Study in Austrian Population

For the large population study, Leutner and colleagues reviewed data on all Austrians younger than 90 years, nearly 8 million, from January 2006 to December 2007.

They identified 353,502 patients who had been taking one of the seven statins available at the time for at least 1 year, including simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin and rosuvastatin. The patients were approximately evenly divided among males and females.

Among them, 11,701 patients, including 1765 males and 9936 females, were diagnosed with osteoporosis, according to International Classification of Diseases, 10th Revision (ICD10) codes.

They were compared with a control group of about 7.5 million patients who were not treated with statins. About 3.5 million were male and 4 million were female. Among them, 68,699 were diagnosed with osteoporosis, including 10,410 males and 58,289 females.

Overall, treatment with statins was associated with more than threefold greater odds of having osteoporosis compared to nonstatin use among control persons (odds ratio [OR], 3.62; P < .01).

However, low-dose statin therapy (0 – 10 mg/day) was associated with a lower risk for osteoporosis.

The effects were similar for the different drugs, including lovastatin (OR, 0.39; P < .05), pravastatin (OR, 0.68; P < .01), simvastatin (OR, 0.70; P < .01), and rosuvastatin (OR, 0.69; P < .01).

However, risk for osteoporosis increased among those taking higher doses of statins, defined as doses exceeding 40 mg for simvastatin (OR, 1.64; P < .01) and exceeding 20 mg for atorvastatin (OR, 1.78; P < .01) and rosuvastatin (OR, 2.04; P < .01), compared to control persons.

The study controlled for other prescribed drugs and for comorbidities that included diabetes and diseases typically treated with corticosteroids that are known risk factors for the development of osteoporosis.

Could Higher Doses of Statins Affect Sex Hormones?

Kautzky-Willer explained, "In mouse models and in vitro, statins have been shown to enhance bone formation ― for example, by increasing the expression of bone morphogenic protein (BMP-2), which is an osteoprotective protein. However, statin dosages were insufficiently considered in existing studies.

"In lower dosages of statins, this osteoprotective effect of BMP-2 could be a major reason for the lower rates of diagnosed osteoporosis," she said.

However, estrogen, which plays a crucial role in the maintenance of BMD, is derived from cholesterol.

Therefore, the strong cholesterol-lowering effects of stains at high doses could also lower estrogen and have an effect on the bones similar to that of menopause, which is a leading cause of osteoporosis.

"Our hypothesis is that in higher dosages of statins, the possible inhibiting effect of statins on sex hormones could overrule the osteoprotective effect," Kautzky-Willer said.

Likewise, statin use has been associated with reduced levels of testosterone in some research. One study showed that higher levels of non–sex hormone–binding globulin-bound testosterone were associated with a decrease in BMD in Korean men.

"Taken together, these findings suggest a connection between sex hormone levels and statins in the pathogenesis of osteoporosis," the Austrian authors conclude.

Whether Statins Affect Levels of Sex Hormones Requires Further Study

Cheung and some of his colleagues focused on the roles of LDL cholesterol and statins in bone health in research reported as a poster at last month's annual meeting of the American Society for Bone and Mineral Research.

Using a US cohort from NHANES III (n = 3638) and another from the Hong Kong Osteoporosis Study (n = 1128), they found that reductions in LDL cholesterol were significantly associated with increases in femoral neck and lumbar spine BMD.

Furthermore, statins' LDL cholesterol–lowering proxies were associated with increased total body BMD.

These findings "suggest that statin use was associated with increased BMD," Cheung said.

In further commenting on the Austrian study, Cheung agreed that the potential effect of high-dose statins on sex hormones is noteworthy.

"This is an interesting hypothesis," he said. "Although the authors mention a few studies showing a significant association between statins and sex hormones, there [are also] a few studies showing null association of statins with sex hormones.

"Thus, whether statins use affects sex hormone requires further study," he commented.

Cheung also underscored the fact that the use of ICD codes to define osteoporosis is a "major limitation" of the Austrian study.

"The authors should validate the accuracy of the coding, as this is extremely important in a pharmacoepidemiology study, especially [because] BMD is not routinely measured. [Therefore,] accuracy of the coding of osteoporosis is doubtful," he said.

The study received funding from the Vienna Science and Technology Fund. The authors and Cheung have disclosed no relevant financial relationships.

Ann Rheum Dis. Published online September 26, 2019. Abstract

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