Elsevier

Atherosclerosis

Volume 215, Issue 1, March 2011, Pages 23-29
Atherosclerosis

Review
The relationship of vitamin D deficiency to statin myopathy

https://doi.org/10.1016/j.atherosclerosis.2010.11.039Get rights and content

Abstract

Objective

Our goal was to examine the interaction between vitamin D and statins and the possible role of vitamin D deficiency in statin myopathy.

Background

The vitamin D receptor is present in skeletal muscle and vitamin D deficiency can cause myopathy. Statins (3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors) are generally well tolerated, but have been associated with a spectrum of skeletal muscle complaints, ranging from myalgia and asymptomatic mild elevations of creatine kinase (CK) to rhabdomyolysis. There has been recent interest in the possible interaction between statin myopathy and vitamin D deficiency. We performed a systematic medical literature review to examine this possible relationship.

Methods

We identified English language articles relating statins, vitamin D and statin myopathy via a PubMed search through July 2010. Articles pertinent to the topic were reviewed in detail.

Results/conclusions

Our review suggests that some but not all statins increase 25(OH) D levels. Two cross sectional studies have associated vitamin D deficiency with statin-associated myalgias, and suggested that that increasing vitamin D levels can reverse the myalgia. Nevertheless, given the quality and paucity of studies examining this possibility, additional studies are needed to examine the potential role of vitamin D deficiency in statin myopathy. It is presently premature to recommend vitamin D supplementation as treatment for statin associated muscle complaints in the absence of low vitamin D levels although such supplementation could be tried in patients with deficient or reduced vitamin D levels.

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

References (102)

  • H.A. Bischoff-Ferrari et al.

    Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes

    Am J Clin Nutr

    (2006)
  • J.H. Lee et al.

    Vitamin D deficiency an important, common, and easily treatable cardiovascular risk factor?

    J Am Coll Cardiol

    (2008)
  • A.E. Riek et al.

    Vitamin D regulates macrophage cholesterol metabolism in diabetes

    J Steroid Biochem Mol Biol

    (2010)
  • L.A. Carlson et al.

    Effect of different doses of vitamin D on serum cholesterol and triglyceride levels in healthy men

    Atherosclerosis

    (1970)
  • M. Tuppurainen et al.

    Does vitamin D3 have negative effects on serum levels of lipids? A follow-up study with a sequential combination of estradiol valerate and cyproterone acetate and/or vitamin D3

    Maturitas

    (1995)
  • S.N. Rajpathak et al.

    Effect of 5 y of calcium plus vitamin D supplementation on change in circulating lipids: results from the Women's Health Initiative

    Am J Clin Nutr

    (2010)
  • G.C. Major et al.

    Supplementation with calcium + vitamin D enhances the beneficial effect of weight loss on plasma lipid and lipoprotein concentrations

    Am J Clin Nutr

    (2007)
  • M.A. Denke et al.

    Short-term dietary calcium fortification increases fecal saturated fat content and reduces serum lipids in men

    J Nutr

    (1993)
  • B. Ditscheid et al.

    Cholesterol metabolism is affected by calcium phosphate supplementation in humans

    J Nutr

    (2005)
  • R. Defay et al.

    DNA synthesis and 3-hydroxy-3-methylglutarylCoA reductase activity in PHA-stimulated human lymphocytes: a comparative study of the inhibitory effects of some oxyterols with special reference to side chain hydroxylated derivatives

    Biochem Biophys Res Commun

    (1982)
  • J.F. Aloia et al.

    Statins and vitamin D

    Am J Cardiol

    (2007)
  • A.S. Dobs et al.

    Effects of pravastatin, a new HMG-CoA reductase inhibitor, on vitamin D synthesis in man

    Metabolism

    (1991)
  • J.L. Pérez-Castrillón et al.

    Effects of Atorvastatin on vitamin D levels in patients with acute ischemic heart disease

    Am J Cardiol

    (2007)
  • A.R. De Boland et al.

    Non-genomic signal transduction pathway of vitamin D in muscle

    Cell Signal

    (1994)
  • S. Ebashi et al.

    Calcium ion and muscle contraction

    Prog Biophys Mol Biol

    (1968)
  • R. Boland et al.

    Avian muscle cells as targets for the secosteroid hormone 1,25-dihydroxy-vitamin D3

    Mol Cell Endocrinol

    (1995)
  • L. Drittanti et al.

    Modulation of DNA synthesis in cultured muscle cells by 1,25-dihydroxyvitamin D-3

    Biochim Biophys Acta

    (1989)
  • G.D. Schott et al.

    Muscle weakness in osteomalacia

    Lancet

    (1976)
  • R.U. Simpson et al.

    Identification of 1,25-dihydroxyvitamin D3 receptors and activities in muscle

    J Biol Chem

    (1985)
  • J.S. Rodman et al.

    Changes in the kinetics of muscle contraction in vitamin D depleted rats

    Kidney Int

    (1978)
  • L. Ceglia

    Vitamin D and skeletal muscle tissue and function

    Mol Aspects Med

    (2008)
  • L. Schubert et al.

    Hypophosphatemia is responsible for skeletal muscle weakness of vitamin D deficiency

    Arch Biochem Biophys

    (2010)
  • D.D. Boltan et al.

    Fatal and widespread skeletal myopathy confirmed morphologically years after initiation of simvastatin therapy

    Am J Cardiol

    (2007)
  • W. Ahmed et al.

    Low serum 25 (OH) vitamin D levels (<32 ng/mL) are associated with reversible myositis-myalgia in statin-treated patients

    Transl Res

    (2009)
  • M. Mitka

    Researchers worry about myopathy risk for patients taking high-dose simvastatin

    JAMA

    (2009)
  • P.J. Neuvonen et al.

    Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance

    Clin Pharmacol Ther

    (2006)
  • T.R. Joy et al.

    Narrative review: statin-related myopathy

    Ann Intern Med

    (2009)
  • D. Williams et al.

    Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors

    Clin Pharmacokinet

    (2002)
  • P.D. Thompson et al.

    Statin-associated myopathy

    JAMA

    (2003)
  • A. Draeger et al.

    Statin therapy induces ultrastructural damage in skeletal muscle in patients without myalgia

    J Pathol

    (2006)
  • C.F. Schaars et al.

    Effects of ubiquinone (coenzyme Q10) on myopathy in statin users

    Curr Opin Lipidol

    (2008)
  • P.S. Phillips et al.

    Statin myopathy as a metabolic muscle disease

    Expert Rev Cardiovasc Ther

    (2008)
  • H. Päivä et al.

    High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial

    Clin Pharmacol Ther

    (2005)
  • M.L. Urso et al.

    Changes in ubiquitin proteasome pathway gene expression in skeletal muscle with exercise and statins

    Arterioscler Thromb Vasc Biol

    (2005)
  • S. Guis et al.

    In vivo and in vitro characterization of skeletal muscle metabolism in patients with statin-induced adverse effects

    Arthritis Rheum

    (2006)
  • T.J. Wang et al.

    Vitamin D deficiency and risk of cardiovascular disease

    Circulation

    (2008)
  • L. Wang et al.

    Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events

    Ann Intern Med

    (2010)
  • A.A. Ginde et al.

    Prospective study of serum 25-hydroxyvitamin D level, cardiovascular disease mortality, and all-cause mortality in older U.S. adults

    J Am Geriatr Soc

    (2009)
  • A.W. Norman

    Receptors for 1,25(OH)2D3: past, present, and future

    J Bone Miner Res

    (1998)
  • O. Engelsen et al.

    Daily duration of vitamin D synthesis in human skin with relation to latitude, total ozone, altitude, ground cover, aerosols and cloud thickness

    Photochem Photobiol

    (2005)
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