ReviewThe relationship of vitamin D deficiency to statin myopathy
Introduction
Statins or 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are associated with a spectrum of skeletal muscle complaints, ranging from myalgia and asymptomatic elevations of creatine kinase (CK) to frank rhabdomyolysis. Risk factors for statin-associated muscle complaints include genetic predisposition [1], high-dose statin treatment [2], advanced age, hypothyroidism, hepatobiliary disease, renal disease and the concomitant administration of drugs that interfere with statin metabolism [3], [4], especially gemfibrozil [5]. The exact mechanism of statin-induced myopathy is not clear, but suggested mechanisms include decreased sarcolemmal [6], or sarcoplasmic reticular cholesterol [7], decreased production of ubiuquinone or coenzyme Q10 [8], [9], decreased production of prenylated proteins [6], changes in fat metabolism [10], increased skeletal muscle uptake of cholesterol [11] or phytosterols [12], failure to catabolize damaged muscle protein via the ubiquitin pathway [13], disruption of calcium metabolism [14], inhibition of selenoprotein synthesis [15], mitochondrial dysfunction [16] and activation of mild inherited myopathies [1].
A recent case report [96], case series [95] and crossectional studies [99], [101] have linked vitamin D insufficiency and statin myalgia suggesting vitamin D as possible therapy for statin myalgia. This possible relationship may be especially important because vitamin D deficiency has been identified as a possible risk factor for atherosclerotic cardiovascular disease, a topic summarized elsewhere [17], [18], [19]. We performed a systematic review of the evidence linking statin myopathy and vitamin D to examine the scientific evidence for the hypothesis that vitamin D may contribute to statin myopathy.
Section snippets
Methods
We searched PubMed for English language articles examining the relationship between statins, vitamin D and statin myalgia using the search words: statins, myopathy, muscle, skeletal muscle, HMG-CoA reductase inhibitors, lipids, vitamin D, and vitamin D deficiency alone and in combination. Articles published through July 2010 were reviewed and those articles pertinent to statin myopathy and vitamin D were examined in detail. In addition, we searched the reference citations of all identified
Overview of vitamin D metabolism
Bioactive vitamin D or calcitriol (1,25-(OH)2D3) is a steroid hormone [20] that has an important role in regulating body levels of calcium and phosphorus and in bone mineralization. Even though the human body can synthesize vitamin D in skin from sun exposure, it is still considered a vitamin since many people despite living in geographical locations with adequate sunlight exposure do not make enough vitamin D and require an exogenous source. Season, geographic latitude, time of day, cloud
Effects of vitamin D on serum lipids
Vitamin D deficiency may be a novel risk factor for atherosclerotic cardiovascular disease [17], [34], [35]. Numerous potential mechanisms have been proposed for this vitamin D effect including an effect on the atherosclerotic process in diabetics [36], [37], but vitamin D appears to have little or no effect on serum lipid levels [38], [39], [40]. For example, 10–20 mcg (400–800 Units) of vitamin D3 provided daily for 1 year to 173 subjects of Pakistani origin with low vitamin D status living in
Effect of vitamin D levels on the lipid response to statins
Vitamin D status may affect lipid changes during statin therapy, and some have suggested that adequate Vitamin D levels >30 nmol/L may be required for atorvastatin to reduce lipid levels [50]. Among 63 patients with acute myocardial infarction treated with low (10–20 mg) or high dose (40–80 mg) atorvastatin, there was no reduction in total cholesterol (173 ± 47 mg/dl vs. 164 ± 51 mg/dl), triglycerides (151 ± 49 mg/dl vs. 177 ± 94 mg/dl), or LDL cholesterol (111 ± 48 mg/dl vs. 92 45 ± mg/dl) at 12 months in
Effect of statins on vitamin D levels
As noted above vitamin D is produced endogenously from cholesterol via 7-DHC. Statins reduce both cholesterol and 7-DHC production, and would be expected to reduce both cholesterol and vitamin D production. While some studies suggest that statins increase serum 25(OH) D levels [62], [63], there are also studies which suggest that statins do not affect vitamin D levels [47], [57], [58] (Table 1). The mechanism by which statins might increase vitamin D levels is not clear. Inhibition of HMG–CoA
Molecular actions of vitamin D in muscle
Molecular mechanisms of vitamin D action on muscle tissue include genomic and non-genomic effects [65] via a receptor present in muscle cells. Genomic effects are initiated by binding of 1,25(OH)2D3 to its nuclear receptor, which results in changes in gene transcription of mRNA and subsequent protein synthesis. Non-genomic effects of vitamin D are rapid and mediated through a cell surface receptor.
The genomic pathway affects muscle calcium uptake, phosphate transport across cell membranes, and
Vitamin D and muscle function
Vitamin D deficiency can cause skeletal muscle myopathy of varying clinical severity [76]. The first associations between vitamin D and muscle function were made from observations of muscle weakness in children with rickets as well as adults with osteomalacia [77]. A functional role for vitamin D in muscle was appreciated more with the discovery of vitamin D receptors in skeletal muscle tissue [78]. Vitamin D deficiency has been known to cause proximal [79] muscle weakness [80], hypotonia [81],
Vitamin D deficiency and statin myopathy
Some patients are unable to tolerate the statin doses required to achieve their target lipid levels because of musculoskeletal complaints. Myalgia, the most common statin related complaint, may affect 10% of patients on statins [93]. Several clinical anecdotes [35], [94], case reports [95], [96], and two crossectional studies [99], [101] have linked vitamin D deficiency with statin myopathy.
A case of fatal skeletal myopathy attributed to simvastatin was noted to have low vitamin D levels on lab
Conclusion
Both statins and vitamin D affect skeletal muscle metabolism and function. There is preliminary data to suggest that vitamin D deficiency is associated with increased statin-associated skeletal muscle complaints, but no definitive evidence that vitamin D contributes to statin myalgia or is effective in its treatment. Vitamin D supplementation reduced myalgic symptoms in some statin-treated patients although a placebo effect cannot be excluded. Consequently, it is reasonable to determine vitamin
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