Could Statin Dose Put Patients At Greater Risk of Osteoporosis?

Benefit or detriment—New study raises potential adverse effects of statin therapy on bone health in patients with comorbid heart disease and osteoporosis. There are other complications necessitating specific considerations when prescribing statins in women at different ages and stages.

with Alexandra Kautzky-Willer MD and Ethel S. Siris MD

Among the many purported benefits of statins is their potential for reducing osteoporosis risk through a variety of effects on bone metabolism.1Of particular note, findings from a large population study of more than 350,000 adults who were taking statins suggest that the dose prescribed may be a key factor in the prospect of achieving a beneficial effect on osteoporosis and bone health.

Leutner and colleagues from the Medical University of Vienna in Austria showed that at low daily doses (eg, 10 mg or less), statins appeared to be associated with slower onset of osteoporosis.2Conversely, treatment with high dose (eg, over 40 mg/day) statins may have a detrimental effect, as seen with higher rates of osteoporosis in individuals receiving high intensity treatment group.

Older women beware: Taking high dose statins may causes an increase in bone loss,.

Methodology to Assess Intensity of Statin Treatment on Bone Density

While the study was not designed to show causation, the results offer a strong warning that the effect of statins on bone health appear to be dose-dependent.2

  • The retrospective study used a health claims database from nearly eight million Austrians (about 97% of the population).
  • 353,502 adults had prescription claims indicating statin treatment for at least one year (175,506 men and 177,996 women).
  • Of these, a diagnosis of osteoporosis was found in 1,765 of the men and in 9,936 of the women  

Looking at the patterns associated with statin use, osteoporosis was found to be under-represented in those individuals who were receiving low dose statin (10 mg or less per day of lovastatin, pravastatin, simvastatin, or rosuvastatin). At the same time, high daily statin therapy (> 40 mg for simvastatin or > 20 mg for atorvastatin and rosuvastatin) was related to over-representation of osteoporosis in the study population.

A diagnosis of osteoporosis was more prevalent in subjects of any age treated with statins, compared with control subjects not treated with statins (OR: 3.62, 95% CI 3.55 to 3.69, P < 0.01). Odds ratios for women were significantly higher than in those of the men.2

Mechanisms of Bone Remodeling and Resorption in Patients Treated for CVD

Given that the bone remodeling balance typically shifts with age,.4this process—while occurring in both sexes— is accelerated in postmenopausal women as their estrogen levels drop, while in men who maintain a healthy level of free testosterone, manage to have higher BMD levels.5,6

This led the researchers to explore the possibility that statins may impact patients with the comorbid health conditions—osteoporosis in older adults with cardiovascular risk factors.

To elucidate the potential for statin to exacerbate bone loss in a high-risk cohort, the investigators repeated the statistical analysis excluding people with several comorbidities, including arthritis, cardiovascular disease, stroke, diabetes, renal failure, overweight and obesity, nicotine dependence, and diseases involving corticosteroid treatment (eg, asthma).2 "The exclusion of these patients does not change the results qualitatively," they reported.

"We were surprised that controlling for possible confounding factors typically related to statin therapy and osteoporosis—including diabetes or cardiovascular disease—did not change our results qualitatively," senior author Alexandra Kautzky-Willer, MD, head of the Gender Medicine Unit in the Division of Endocrinology and Metabolism at the Medical University of Vienna, Austria.

"Nevertheless, these results support our findings and point out that further research should be done in order to investigate the exact pathophysiological mechanism of this possible relationship," Prof. Kautzky-Willer told EndocrineWeb.

Exploring the Potential for Statins to Affect Bone Metabolism

Statins are known to be effective in lowering hyperlipidemia given their action in blocking the enzyme HMG-CoA reductase, thereby reducing the body's ability to synthesize cholesterol. However, the ability to exert an impact on bone metabolism was recognized about 20 years ago in animal studies,7and more recent investigations have furthered our understanding that statins have both antiresorptive and anabolic influences on bone, affecting bone cell proliferation, differentiation, protection of osteoblasts, and reducing osteoclast formation.5,8

"One has to keep in mind that cholesterol is the basic substance for the synthesis of sex hormones," said Prof. Kautzky-Willer. "Statins have been shown to lower estrogen and testosterone concentrations, and in higher dosages, the possible inhibiting effect of statins on sex hormones could overrule the osteoprotective effect. Similarly, due to the osteoprotective effect of estrogens, the decline in sex hormones in post-menopausal women is an important and major risk factor for osteoporosis."  

Previous studies present "rather heterogenous results" on the question of whether statins help decrease fracture risk, said Leutner et al. Observational studies in humans have demonstrated lower fracture risk or greater bone mineral density (BMD) levels among statin users compared with non-users, but conflicting findings have been presented, as well.9,10

In hoping to find a more definitive response, data reported in a recent meta-analysis indicated that statin treatment had "a tendency toward a positive effect" on the reduction of fracture risk and marked improvement of BMD in statin-treated patients.8

Strong Possibility of Adverse Clinical Impact of High Dose Statins on Bone Health

The key conclusion offered by the Austrian researchers is that the potential influence of statin dosage on osteoporosis risk is real and maybe significant.

While a causal relationship between statin use and bone remodeling cannot yet be confirmed, the authors advise clinicians to individualize therapy and carefully monitor women on statins who are at risk for osteoporosis or under treatment for bone loss.

Clinical practice guidelines on the use of cholesterol-lowering therapies to prevent adverse cardiovascular outcomes set plasma low-density lipoprotein (LDL-cholesterol) from the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) suggest initiating treatment at levels as low as 70 mg/dL among high-risk populations. 11

"While the new guidelines propose even lower targets because of the need for reduction of cardiovascular risk in high-risk patients, we propose that monitoring of high-risk patients—particularly postmenopausal female patients under high-dosage statin therapy," Prof. Kautzky-Willer said. "This offers a more individualized approach to therapy to prevent or treat osteoporosis [in vulnerable patients] while still offering protection from cardiovascular events."

Patients with medical conditions requiring treatment with statins, are likely to exhibit other risk factors for osteoporosis, such as low levels of physical activity,  which offers greater rationale for individualizing care, according to the study authors.

Manage Risks of Cardiovascular Disease and Osteoporosis Individually

Ethel S. Siris, MD, Madeline C. Stabile Professor of Medicine and director of the Toni Stabile Osteoporosis Center at Columbia University Medical Center in New York City, agreed with the study authors that clinicians "should not jump to conclusions" based on these preliminary observational findings.

"From a purely practical point of view, in terms of patient care, you should give a statin if there's an indication to do so. And if you're worried that the patient may have risk factors for osteoporosis, you get a bone density test. If there's evidence of a problem, you monitor it or you manage it." Dr. Siris told EndocrineWeb.

She offered clinicians similarly practical advice regarding statin dosage— to use the lowest dose possible to reach target lipid levels and to increase the statin level as needed. "As I'm sure the Austrian investigators would agree, there is not enough information in the current study to confirm a detrimental effect of higher statin doses on bone formation or bone resorption. Thus, this study should not be misinterpreted to suggest that patients with osteoporosis or risk factors should avoid taking high-dose statins," she concluded.

Among other limitations of the study was the inability to confirm a diagnosis of osteoporosis among the population using bone densitometry data, and the inability to confirm the patient's current statin dose. "We are currently planning a prospective study to investigate the relationship between different statin dosages and osteoporosis” to gain a more definitive picture of a dose-response effect with comorbid osteoporosis and CVD, Professor Kautzky-Willer said.

Older Patients Not Likely to Gain Sufficient Benefit from Statins

And More Reasons to Hesitate Before Prescribing Statin Therapy

The most comprehensive, collaboratively-derived multisociety guidance for clinicians facing patients at risk for cardiovascular disease (CVD) is to advocate for a step-wise approach, reserving the most aggressive therapy for those at highest risk for repeat CVD events.12  

For patients over 75 years who do not have confirmed atherosclerotic cardiovascular disease, it appears they do not gain sufficient risk reduction from statin therapy;13 this is the conclusion of a study appearing in Lancet. While the authors pointed to a positive trend in health benefits, the data were not statistically significant. In fact, their findings suggest that older individuals have a greater likelihood of dying from cancer, than cardiovascular-related events.

While the need to prescribe statin therapy is well established in women who reach the menopausal transition, there are well founded reasons to more closely consider the sex-specific CVD challenges confronting younger women, too,14 according to Roger S. Blumenthal, MD, FACC, FAHA, Kenneth Jay Pollin Professor of Cardiology and director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease who raised these added concerns during a presentation at the Cardiometabolic Health Congress in Chicago, Illinois. 

Women who have undergone induced menopause (before age 40) or have experienced pregnancy-related conditions such as gestational diabetes, preeclampsia, hypertension, and premature deliveries, are at increased risk for cardiovascular disease, and may benefit from statin therapy, he said.

Yet, any woman who is prescribed a statin, should be advised to use a reliable method of contraception to avoid pregnancy, and then when a desire to become pregnant arises, she should be advised to discontinue statin therapy for about 2 months to minimize any adverse effects during pregnancy.12

In the end, it all comes down to personalizing treatment approaches to meet individual risk profile, according to Dr. Blumenthal who was a member of the writing committee for the 2018 ACC/AHA Guideline on the Management of Blood Cholesterol.

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