Response to comments by Clockaerts and colleagues

Daniel L. Riddle, Professor,

Other Contributors:

March 26, 2013

Dear Editor,

We thank Clockaerts and colleagues for their thoughtful commentary on our paper and will address a number of their comments. They expressed concern regarding lack of verification of our data related to statin use, duration of use, and dosage, and indicated these data were based on self- report. While we acknowledged in our paper[1] that we did not have dosage data, the verification was that participants brought their medications with them during yearly follow-up visits and we were able to confirm that statins were prescribed for these patients. This approach was not as valid as a pill count but, in our view, is more rigorous than self-report.

Clockaerts and colleagues accounted for duration of statin use by examining effects for those with 1-119 days, 120-364 days and 365 days or greater of statin use at 50% or more of the recommended daily dosage. Our approach was to use the yearly follow-up visit prescription data indicating 0, 1, 2, 3 or 4 years of statin use to examine the effects on changes in OA structural progression, pain and function. While we did not have dosage data, we believe that our approach reasonably accounted for differing durations of statin usage in our sample. In the end, an assumption of compliance was made in both studies[1,2] that medications were taken as prescribed.

In our opinion, neither our study[1] nor the work of Clockaerts et al[2] provides convincing evidence of a subgroup(s) who might be most responsive to OA-related benefits, if any, of statins. Clockaerts and colleagues suggested it is more plausible that statins could be useful in the early as compared to later stages of OA. They went on to recommend studies of statin use in persons with Kellgren and Lawrence (KL) scores of 0 at baseline. While we did not conduct subgroup analyses, we had 684 persons in our sample who had a baseline KL grade of 0 on one knee and 1,286 who had a baseline grade of 0 or 1 in at least 1 knee. If an association between statin use or duration of use and OA disease progression existed for patients with either no or very mild disease of at least one knee, the random intercept analyses in the structural equation models would have detected these relationships. No associations were found. When describing their analyses for persons with and without KL scores of 0, Clockaerts and colleagues reported that "when we used those separate definitions of incidence and progression, we found similar results."p645 It is not clear to us why Clockaerts and colleagues suggest statins may be more effective DMOADS for persons with either no or mild OA.

Clockaerts et al correctly indicated that we did not report the occurrence of muscle pain in our sample. They also suggested that muscle pain is an important side effect of statins and should be taken into account when considering pain scores for OA; the implication would be that, if statins caused muscle pain, then statin-related muscle pain might interfere with knee OA pain and function measures. On further reflection, this appears unlikely. First, our pain measure asked the participant to "rate the pain that you've had in your right/left knee during the past 7 days," requesting a focal pain report, not a more generalized pain assessment. Second, Clockaerts et al cite the work of Armitage who summarized potential adverse musculoskeletal effects of statin use including myopathy (defined as muscle symptoms accompanied by muscle enzyme elevation 10-fold-or-higher above the upper limit of normal) or myalgia (muscle symptoms with enzyme elevation up to 10-fold) [3]. Armitage indicated myopathy is a rare event particularly for standard doses, about 11 per 100,000 person-years of follow-up. Given that we had approximately 3,000 person-years of statin use in our study, we suspect myopathy influences were minimal (less than one represented in our panel). Regarding myalgia risk, Armitage reviewed several randomized trials that failed to support the assertion that statins cause myalgia or muscle cramps. For example, in one trial, the frequency of unexplained muscle pain or weakness was 32.9% in simvastatin-treated subjects and 33.2% in placebo-treated subjects[4]. Symptoms of myalgia are frequent among patients in the age ranges commonly needing cholesterol-lowering therapy, but the causal relationship of statins to myalgia is unsupported.

Thus, given the focused pain questions, the very low anticipated frequency of true myopathy and absence of evidence that statins are causally associated with myalgia, we suspect that any misreporting of muscle symptoms as knee OA pain and reduced function would likely have occurred in both statin-treated and statin-untreated groups about equally.

We agree that additional study is needed and we fully endorse the recommendation by Clockaerts and colleagues that future studies of the potentially protective effects of statins on OA incidence and progression should be targeted toward sub-groups who are most likely to benefit. Unfortunately, our study does not assist in identifying a subgroup whose osteoarthritis may be more likely to respond favorably to statins.

References

1. Riddle DL, Moxley G, Dumenci L. Associations between statin use and changes in pain, function and structural progression: a longitudinal study of persons with knee osteoarthritis. Ann Rheum Dis. 2013;72:196-203.

2. Clockaerts S, Van Osch GJ, Bastiaansen-Jenniskens YM, et al. Statin use is associated with reduced incidence and progression of knee osteoarthritis in the Rotterdam study. Ann Rheum Dis 2012;71:642-647.

3. Armitage J. The safety of statins in clinical practice. Lancet 2007;370:1781-1790.

4. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-22.

Conflict of Interest:

We have no competing interests. This "response" is submitted in response to the comments by Clockaerts and colleagues who were responding to our paper published in ARD (Riddle et al. Associations Between Statin Use and Changes in Pain, Function and Structural Progression: A Longitudinal Study of Persons with Knee Osteoarthritis. ARD. 2013 Feb;72(2):196-203.

Conflict of Interest

None declared