➢ Use of statins may be associated with certain tendinopathies and tendon ruptures, especially of the Achilles, quadriceps, and distal biceps tendons.
➢ Tendinopathy usually occurs within the first year of statin use and improves after the drug therapy is stopped.
➢ Systemic conditions with a higher risk of tendon rupture include diabetes, gout, rheumatoid arthritis, and chronic kidney disease.
➢ Certain drugs, such as corticosteroids and fluoroquinolones, have also been implicated in tendon ruptures.
➢ Patients with these systemic conditions who are taking statins in combination with other drugs that increase the risk of tendon injury should be educated about this risk and alternative treatments, including diet and exercise.
Statins inhibit HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A) reductase, an important enzyme in the production of cholesterol. They have increasingly been a mainstay treatment for millions of patients with hyperlipidemia ever since 1987, when lovastatin was introduced1. From 2003 to 2012, the percentage of adults who were forty years of age and older using a statin increased from 18% to 26%. As of 2012, among adults who used any cholesterol-lowering medication, 93% used a statin: 83% of adults taking any cholesterol-lowering medication reported taking only a statin and 10% took both a statin and another drug; the most commonly used statins were simvastatin (42.0%), atorvastatin (20.2%), pravastatin (11.2%), rosuvastatin (8.2%), and lovastatin (7.4%)2.
Tendinopathy, tendinitis, and tendon rupture are increasingly recognized in patients treated with statins3-6. In this article, we review the medical literature on biochemical mechanisms of tendon injury, tendinopathy, and tendon rupture in relation to statins, systemic conditions and drugs that increase the risk of tendon injury, and the prevention of tendon injuries in patients who need statins.
In addition to reducing cholesterol levels and atherosclerosis, statins have beneficial anti-inflammatory effects that are related to decreased by-products of cholesterol synthesis7. Common side effects of statins include myalgias, myopathy, rhabdomyolysis, and elevated liver enzymes (AST [aspartate aminotransferase] and ALT [alanine aminotransferase])6. The prescribing information for Zocor (simvastatin), the second most commonly prescribed medication in America in 20108, noted a higher risk of myopathy or rhabdomyolysis with concomitant use of certain drugs; these include ketoconazole, erythromycin, human immunodeficiency virus (HIV) protease inhibitors, gemfibrozil, and cyclosporine (Table I)9. Furthermore, the prescribing information recommends that the maximum dose of simvastatin should be limited with the use of verapamil, diltiazem, amiodarone, and amlodipine. During controlled clinical studies (2423 patients) and their open extensions with follow-up of about eighteen months, the adverse reactions that most frequently led to drug discontinuation were gastrointestinal disorders (twelve patients [0.5%]), myalgia (two patients [<0.1%]), and arthralgia (two patients [<0.1%]). The most common adverse reactions in these 2423 patients were upper respiratory infections (218 patients [9.0%]), headache (179 patients [7.4%]), abdominal pain (177 patients [7.3%]), constipation (160 patients [6.6%]), and nausea (131 patients [5.4%])6,9.
Mechanisms of Tendon Injury and Rupture
Tendons consist of 80% extracellular matrix protein, primarily type-I collagen, as well as tenoblasts and tenocytes10. Although the exact mechanism of tendon injury from statins is unknown, several theories exist. Perhaps the most important theory is the impact on remodeling by the matrix metalloproteinases (MMPs). Simvastatin has been shown to reduce MMP-9 secretion and messenger RNA (mRNA) levels in a cell culture model of human saphenous vein cells11. Tendon rupture associated with statins has been well documented12-15. A proposed theory is that MMP inhibition interferes with tendon remodeling after microtrauma, with resulting tendinopathy and, in some cases, rupture4. Large and frequently used musculotendinous units that experience high and repetitive mechanical stresses, such as the Achilles tendon, are most susceptible to tendinopathy and rupture.
In a recent study, tenocytes were incubated with varying concentrations of lovastatin, simvastatin, and atorvastatin16. There were no changes in tenocyte viability or morphology, but their ability to migrate was decreased. High concentrations of lovastatin affected the cytoskeleton, decreased levels of mRNA for matrix proteins including type-I and type-III collagen, and increased bone morphogenetic protein 2 (BMP-2) expression. These findings showed that statins decrease tenocyte migration, alter protein expression profiles, and affect the functional network, all of which are potential mechanisms for statin-related tendinopathy16.
Another proposed mechanism for tendon injury involves the drug’s intended effect, namely, inhibition of cholesterol synthesis and subsequent weakening of cell membranes11,17. The cell membranes of tenocytes, the cells primarily responsible for both synthesis and maintenance of the extracellular matrix18, may be compromised, resulting in alterations of the essential structural component of tendons. Tendons and their muscular insertions are vulnerable to this process as they may be hypocellular structures4,19.
Myopathy associated with statins may be related to a decrease in isoprenoids, compounds that are involved in the modification of selenoprotein N and alpha-dystroglycan and beta-dystroglycan, which are abnormal in certain muscle diseases20. Disruption of these biochemical modifications at the myotendinous junction, a site of relative weakness in the musculotendinous unit21, could increase the risk of tendon injury. Tendon rupture often occurs at areas that are weakened by degenerative changes such as hypoxic degenerative tendinopathy, mucoid degeneration, tendolipomatosis, and calcifying tendinopathy, suggesting an area of relative weakness in the overall unit22.
A final possible mechanism for tendon injury relates paradoxically to the beneficial effect of statins on certain cancers23. Statins are thought to activate mechanisms in cancer cells that induce cell death (apoptosis). Apoptosis may also weaken the tendon matrix and make it vulnerable to tendinopathy and rupture.
Marie et al. reported a retrospective review of tendinous complications associated with statins, using a large pharmaceutical surveillance database over a sixteen-year period (1990 to 2005)3. Ninety-six of 115 patients with potential statin-related tendinopathy or rupture were included in this analysis. The prevalence was 2.09%; more men than women reported these symptoms (2.3:1); and the median age was fifty-six years.
Patients taking statins who reported tendon-related tenderness and swelling were usually diagnosed with tendinous complications by physical examination and occasionally by studies such as magnetic resonance imaging (MRI) or ultrasound. Association with statin therapy was determined if symptoms substantially decreased after stopping statin therapy. Marie et al. reviewed the medical history for tendinopathy and concomitant therapy with drugs that increase statin concentration by way of CYP3A4 (cytochrome P450 3A4) inhibition (e.g., cyclosporine and gemfibrozil), combined therapy with a statin and a fibric acid derivative (e.g., ezetimibe), or drugs that cause tendinopathy (e.g., fluoroquinolones and corticosteroids). Nineteen patients were excluded, including those taking drugs associated with tendinopathy. Of ninety-six patients, atorvastatin (thirty-five patients [36.5%]) was the most common drug used, followed by simvastatin (thirty patients [31%]), pravastatin (twenty-one patients [22%]), fluvastatin (five patients [5%]), and rosuvastatin (five patients [5%]). Dosages were within the recommended range in all cases3.
Of the ninety-six affected patients, sixty-three (66%) experienced tendinopathy without rupture. All reported pain, and a majority experienced swelling, stiffness, or difficulty with movement in the involved area. A slight majority of cases (52%) involved the Achilles tendon and also affected were the quadriceps femoris tendon (15%), elbow epicondylar tendon insertions (9.4%), biceps brachii tendon (7.3%), forearm flexor or extensor sheaths (5.2%), and gluteus medius tendon (3.1%). Sports were associated with tendon complications in 15.6% of the patients and tendinopathy occurred on both sides in 41% of the patients.
The median time to onset of tendinous complications after starting statin therapy was eight months for the ninety-six patients with tendinopathy alone or tendinopathy with rupture. Fifty-nine percent of patients experienced symptoms within the first year, and, of those, 80% reported problems within four months. Statin therapy was discontinued in all patients, and substantial symptom improvement was noted after a median time of twenty-three days. Patients also typically received analgesics, immobilization, and/or activity modification. A number of patients (38%) were diagnosed with severe symptoms, and seventeen patients (18%) required hospitalization. Twenty percent were determined to have substantial functional sequelae. Importantly, tendon symptoms recurred in all seven patients for whom statin therapy was reinitiated.
Six other cases5,24 of tendinopathy associated with statins showed findings similar to those in the study by Marie et al.3. Chazerain et al. described four middle-aged patients (three men and one woman) with bilateral hand extensors (one), tibialis anterior (one), and Achilles tendon involvement (two) who were prescribed simvastatin (two cases) or atorvastatin (two cases)5. Symptoms developed one to two months after statins were initiated and abated within that same time frame after discontinuation. Movahed and Samsamsharaiat also reported two similar patients with statin-associated tendinopathy, negative serologic testing, and resolution of symptoms after statin therapy was stopped24.
Statin-Associated Tendon Rupture
The first large study of tendon ruptures with statin use was the review by Marie et al., which identified thirty-three cases of tendon rupture among 4597 statin-associated side effects over sixteen years3. The ruptures developed after statin therapy was begun and improved with discontinuation of the drug therapy. The effect of statins on tendon rupture did not appear to be dose-dependent, as all thirty-three patients were within the recommended dose range.
Beri et al. conducted a case-control study over six years, to assess statin effects in the preceding twelve months in ninety-three cases of tendon rupture compared with 279 controls12. Statin exposure was a significant risk factor (p = 0.04) for tendon rupture in women, with an odds ratio of 3.09 (95% confidence interval [95% CI], 1.04 to 9.75). There was no association with other potential causes in the multivariate analysis, including dose or duration of statin use. Atorvastatin was the most commonly used statin (p = 0.06) by patients with ruptured tendons (fourteen [64%] of twenty-two patients) when compared with controls (twenty-five [38%] of sixty-six patients).
Savvidou and Moreno retrospectively looked at 104 patients who sustained a distal biceps tendon rupture with daily activities (spontaneous) or with strenuous activity (provoked)25. Patients taking statins were 1.81 times (95% CI, 0.56 to 5.84 times; p = 0.320) as likely to sustain a spontaneous tendon rupture. There was a significantly older mean patient age (p = 0.0025) for patients who sustained spontaneous ruptures (52.9 years) compared with patients with provoked ruptures (forty-six years).
Contractor et al. conducted a retrospective evaluation of participants who were sixty-four years of age or younger and were followed for at least a year and found no additional risk of tendon rupture with statin use6. Using a pharmacy database, the authors compared 34,749 patients exposed to statins with 69,498 controls. There were 334 tendon ruptures in the statin group (5.6 per 1000 patient-years) and 870 in the control group (4.7 per 1000 patient-years). No difference was found in the occurrence of tendon ruptures after adjustment for age and sex (incidence rate ratio, 1.13% [95% CI, 0.98 to 1.29]). However, it should be noted that subgroup analysis revealed a significant risk of tendon rupture (p < 0.0001) for patients taking atorvastatin in comparison with controls (incidence rate ratio, 2.4).
Statins may systemically alter cellular structure and function, as suggested by case reports that described bilateral, simultaneous ruptures of the Achilles, quadriceps, and biceps tendons4,13-15,25,26. Interestingly, the bilateral Achilles tendon ruptures occurred in a physically fit, forty-seven-year-old rock climber, suggesting that therapeutic loading exercises like rock climbing may not overcome the predisposition to rupture caused by statins. An alternative possibility is that these individuals with bilateral ruptures had other systemic physiological factors that predisposed them to tendon rupture.
Tendinopathy is one of the most frequent musculoskeletal symptoms evaluated by physicians and is more likely to be encountered in an aging population. In the United States, this population is often prescribed statins to treat hypercholesterolemia and more than thirty million patients take this class of drugs27. Statins stabilize coronary artery plaques and reduce the risk of myocardial infarction, stroke, and death from cardiovascular disease28-30. Statins increase the risk of type-2 diabetes and may reduce the incidence of pancreatitis, but the suggested associations with cataracts, erectile dysfunction, cognition, and chronic obstructive pulmonary disease are still unclear31.
Based on large retrospective series of patients, statins may increase the risk of tendinopathy and tendon rupture, possibly because of their detrimental effects on tendon cell repair and regeneration through inhibition of MMPs3,4,6,12,25. The hypothesis of statin-induced injury is supported by the close temporal relationship of statins to onset of symptoms, improvement after cessation, and recurrence in all seven of seven patients who resumed statins in the study by Marie et al., the study on which many of this review’s conclusions are based3. Patients taking concomitant drugs known to potentiate these effects were also excluded. Tendinous complications, often rated as severe, had a similar prevalence at many drug surveillance centers and there were no dose-dependent effects. Rechallenge with alternative statins was almost always associated with recurrence of tendinopathy, further supporting a likely class effect of statins at the recommended dosages3,5,24. Although atorvastatin was the most common drug associated with tendinopathy and tendon rupture, other statins were also implicated. This could be because atorvastatin is a relatively established drug and is therefore more likely to be in use. A pharmacological mechanism for statin-related tendinopathy is supported by the occurrence of bilateral tendon ruptures due to low stress, which suggests a systemic problem related to statins instead of local trauma.
Clinicians should consider frequent routine musculoskeletal examinations, particularly during the first year of drug administration, and discontinue statin therapy if there are signs of tendinopathy such as tenderness, swelling, stiffness, and bilateral involvement. The association of statin-related tendon injury with increased physical activity, similar to the association observed for drugs like fluoroquinolones, suggests that statin therapy should be stopped before strenuous or prolonged physical exertion such as marathons or triathlons3,32-34. In elderly patients, musculoskeletal degeneration and deconditioning may predispose a patient to statin-related injury35, so one should consider alternative therapies for hyperlipidemias, such as diet and exercise. Practitioners need to find a balance between the substantial cardiovascular benefits of statins and maintaining the patient’s activity level and all of its positive effects, both physiological and psychological35.
If possible, clinicians should avoid concomitant administration of drugs that may potentiate statin-related tendon injury, including CYP3A4 inhibitors (e.g., cyclosporine and gemfibrozil) or drugs known to cause tendinopathy (e.g., fluoroquinolones and corticosteroids). Practitioners should consider avoiding dual therapy involving statins combined with other lipid-lowering compounds such as fibric acid derivatives (e.g., ezetimibe). No patient among the six cases of statin-induced tendinopathy tolerated dual therapy with a statin and adjunctive medications such as ezetimibe, fenofibrate, or gemfibrozil; only one patient became asymptomatic on statin monotherapy, with half the initial dose5,24. Fluoroquinolones such as ciprofloxacin have a black-box warning for risk of tendon-related adverse events, especially in individuals prone to tendon disorders36. Corticosteroids have also been implicated in having an effect on tendon structure and risk of rupture37. In a case-control study with more than 127,000 patients, fluoroquinolone users had a 1.7 times (95% CI, 1.4 to 2.0 times) increased risk of tendon disorders; however, when administered with corticosteroids, the risk of tendon rupture increased 3.1 times (95% CI, 1.5 to 6.3 times) and the risk of Achilles tendon rupture increased 43.2 times (95% CI, 5.5 to 341.1 times)38. Clearly, practitioners should exercise caution when prescribing several agents known to be toxic to tendons. In addition, clinicians should be aware of the higher risk of tendon rupture in the setting of diabetes, gout, rheumatoid arthritis, and chronic kidney disease6. With these systemic conditions, patients taking statins should be educated and carefully monitored.
A recent analysis of cardiovascular risk factors and outcomes yielded data in support of the 2013 American College of Cardiology/American Heart Association guidelines for statin use, which would lead to 12.8 million more adults who would receive these medications39. In view of the side effects of statins, patients should be better educated about the benefits of diet and exercise. A meta-analysis of the Mediterranean diet found a 9% reduction in mortality from cardiovascular disease40. Patients may also be advised about the benefits of the proverbial daily apple, which in a modeling study was compared with a daily statin for cardiovascular risk reduction and was found to be remarkably effective41.
Although not significant, there was a 19% higher incidence of tendon ruptures in the statin group (5.6 with statins compared with 4.7 in controls per 1000 patient-years) in a large case-control study6. Furthermore, in that large retrospective study, Contractor et al. showed that patients taking atorvastatin had a risk of tendon rupture that was more than twice that of controls (incidence rate ratio, 2.4). Some authors have suggested that the prevalence of tendinous complications may be higher in populations currently receiving these drugs (compared with initial drug trials)24,42-44. Larger, randomized, placebo-controlled, post-marketing surveillance trials that analyze differences related to age, sex, concomitant risk factors, the choice of statin, and activity levels are necessary to clarify the relationship of statins to tendinous complications. Given the prevalence of statin use in today’s aging population, orthopaedic surgeons and others who treat musculoskeletal conditions should understand the link between statins and tendon injuries.
Investigation performed at the Department of Orthopaedic Surgery, Warren Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island
Disclosure: There was no source of external funding for this study. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article.
- Copyright © 2016 by The Journal of Bone and Joint Surgery, Incorporated