Low serum 25 (OH) vitamin D levels (,32 ng/mL) areassociated with reversible myositis-myalgia instatin-treated patients

WAQAS AHMED, NASEER KHAN, CHARLES J. GLUECK, SUMAN PANDEY, PING WANG,NAILA GOLDENBERG, MUHAMMAD UPPAL, and SURAJ KHANAL

CINCINNATI, OHIO

From the Cholesterol Center, Jewish

Ohio.

Supported in part by the Lipoprote

Research Funds of the Jewish Hosp

Submitted for publication Octobe

November 5, 2008; accepted for pu

Reprint requests: Charles J. Glueck

ing, 3200 Burnet Ave, Cincinnati

healthall.com.

1931-5244/$ – see front matter

� 2009 Mosby, Inc. All rights rese

doi:10.1016/j.trsl.2008.11.002

Our specific aims were to determine whether low serum 25 (OH) vitamin D (D2 1 D3)(,32 ng/mL) was associated with myalgia in statin-treated patients and whether themyalgia could be reversed by vitamin D supplementation while continuing statins.After excluding subjects who took corticosteroids or supplemental vitamin D, serum25 (OH) D was measured in 621 statin-treated patients, which consisted of 128 pa-tients with myalgia at entry and 493 asymptomatic patients. The 128 myalgic patientshad lower mean 6 standard deviation (SD) serum vitamin D than the 493 asymptom-atic patients (28.6 6 13.2 vs 34.2 6 13.8 ng/mL, P , 0.0001), but they did not differ(p . 0.05) by age, body mass index (BMI), type 2 diabetes, or creatine kinase levels.By analysis of variance, which was adjusted for race, sex, and age, the least squaremean (6 standard error [SE]) serum vitamin D was lower in the 128 patients with my-algia than in the 493 asymptomatic patients (28.7 6 1.2 vs 34.3 6 0.6 ng/mL,P , 0.0001). Serum 25 (OH) D was low in 82 of 128 (64%) patients with myalgia versus214 of 493 (43%) asymptomatic patients (c2 5 17.4, P , 0.0001). Of the 82 vitamin-D–deficient, myalgic patients, while continuing statins, 38 were given vitamin D(50,000 units/week for 12 weeks), with a resultant increase in serum vitamin D from20.4 6 7.3 to 48.2 6 17.9 ng/mL (P , 0.0001) and resolution of myalgia in 35 (92%).We speculate that symptomatic myalgia in statin-treated patients with concurrentvitamin D deficiency may reflect a reversible interaction between vitamin D defi-ciency and statins on skeletal muscle. (Translational Research 2009;153:11–16)

Abbreviations: BMI ¼ body mass index; CK ¼ creatine kinase

V itamin D deficiency or insufficiency1 is be-

coming more widespread in diverse clinical

populations in variegated settings and environ-

ments.2-4 Low serum 25 (OH) vitamin D levels have

been associated with myositis.5 Erkal et al5 reported

Hospital of Cincinnati, Cincinnati,

in Research Fund and the Medical

ital of Cincinnati.

r 15, 2008; revision submitted

blication November 7, 2008.

, Cholesterol Center, ABC Build-

, OH 45229; e-mail: glueckch@

rved.

a strong correlation between low serum 25 (OH) D

levels and higher rates and longer duration of general-

ized bone pain and/or muscle aches and pains (often

diagnosed as fibromyalgia). Bischoff-Ferrarri al6 have

reported that vitamin D may improve muscle strength

through a highly specific nuclear receptor in muscle tis-

sue. Lips7 reported that muscle cells contain vitamin D

receptors and noted that serum 25 (OH) D is related to

physical performance. Hypovitaminosis D is highly

prevalent in adults with type 2 diabetes.8

Mild clinical muscle problems (myositis-myalgia) are

common in subjects treated with statins.9 In a retrospec-

tive analysis of members of a health maintenance orga-

nization, which included 10,247 patients with diabetes

and 21,978 patients without diabetes, Nichols and

Koro9 employed National Heart, Lung, and Blood Insti-

tute categories for clinical muscle problems: myalgia,

mild myositis, severe myositis, and rhabdomyolysis. A

11

AT A GLANCE COMMENTARY

Background

Low serum 25 (OH) vitamin D has been associated

with myositis. Myositis is common in statin-

treated subjects to promote statin intolerance.

Translational Significance

The current report revealed that patients with

statin-induced myalgias had lower serum vitamin

D levels than statin-treated patients without myal-

gias. Low serum 25 (OH) vitamin D (D2 1 D3)

(,32 ng/mL) is associated with myalgia in sta-

tin-treated patients; while continuing statins, this

myalgia can largely be reversed by vitamin D sup-

plementation that normalizes serum vitamin D

levels. We speculate that vitamin D deficiency

reversibly augments statin-induced myalgias.

Translational Research12 Ahmed et al January 2009

greater proportion of statin initiators versus matched

controls experienced ‘‘myopathic events,’’ 7.9% versus

5.5% in diabetics and 9.0% versus 3.7% in the nondia-

betic cohorts.9 Nichols and Koro9 reported that 95% of

statin-associated events were myalgia-mild myositis.

Although uncommon, severe myositis, which is also

called myopathy with creatine kinase (CK) more than

10 times the laboratory upper normal limit, is signifi-

cantly associated with statin monotherapy (relative

risk 5 2.8; 95% confidence interval,1.3–5.9).10 In

subjects on statin monotherapy, myopathy rates with

CK levels more than 10 times the laboratory upper limit

have been reported to be 33 per 100,000 person years,

with a mean time to event of 2 years.10

Our specific aims were to determine whether low

serum 25 (OH) vitamin D (D2 1 D3) (,32 ng/mL)

was associated with myalgia in statin-treated patients

and whether the myalgia could be reversed by vitamin

D supplementation while continuing statins.

MATERIALS AND METHODS

Study design: patients. The study conformed to the

ethical guidelines of the Jewish Hospital Institutional

Review Board for human research.

From May 2007 to May 2008, in the temporal order of

their referral to our outpatient Cholesterol Center for

diagnosis and therapy of hyperlipidemia, serum 25

(OH) vitamin D (D2 1 D3) was measured in 687 sta-

tin-treated patients, 140 of whom had myositis-myalgia

at study entry and 547 patients were asymptomatic. After

excluding subjects who were taking corticosteroids or

supplemental vitamin D, or who had comorbidities that

would result in muscle or bone pain (fibromyalgia,

arthritis, peripheral vascular disease, and sensory neu-

ropathy), we studied 621 statin-treated patients, of

whom 128 had symptomatic myositis-myalgia and 493

were asymptomatic at study entry.

At the initial visit, after an overnight fast, blood was

drawn for a total of 25 (OH) vitamin D levels (D2 1

D3), quantitated by 2-dimensional liquid chromatogra-

phy with tandem mass spectrometry detection after pro-

tein precipitation.11 The laboratory lower normal limit

for total 25 (OH) vitamin D was 32 ng/mL.11 Additional

measures included plasma cholesterol, triglyceride, and

high-density lipoprotein cholesterol, along with CK,

glucose, and insulin testing, as well as renal, thyroid,

and liver function tests.

At the initial and follow-up visits, a detailed history

was obtained for statin, prescription drug, and supple-

mental vitamin use. Patients were instructed not to take

supplemental vitamins, and, where initial serum vitamin

D was low, and when myalgia was present, were given

a prescription to take 50,000 units of vitamin D (ergocal-

ciferol) once per week for 12 weeks. Most patients were

continued during follow-up on the same statins that they

had been taking at study entry.

At the initial visit and at every follow-up visit, patients

were interviewed by the principal investigators, who em-

ployed National Heart, Lung, and Blood Institute cate-

gories for clinical muscle problems: myalgia, mild

myositis, severe myositis, and rhabdomyolysis.9 The dis-

tinction between myalgia and nonmyalgic groups is neces-

sarily imprecise; it is based entirely on subjective reports.9

In the current study, at entry, we characterized the most

severe myositis-myalgias as those that had caused

patients to discontinue more than 3 different statins.

In all, 38 statin-treated patients with myalgia and low se-

rum vitamin D at study entry had follow-up visits for 3

months on statins plus vitamin D (50,000 units/week for

12 weeks). We prospectively assessed changes in their

myositis-myalgia symptoms and serum vitamin D levels.

Adherence to the weekly vitamin D (50,000 units/

week) was reviewed by the investigators at each

follow-up visit (1 and 3 months after study entry).

Statistical analyses. All statistical analyses were per-

formed using SAS (version 9.1; SAS Institute, Inc.,

Cary, NC). Sample size calculations were based on

population studies of serum vitamin D12 and assessments

of optimal13 serum vitamin D levels, using an estimate of

mean 6 standard deviation (SD) serum vitamin D of 28

6 10 ng/mL for statin-using patients with myositis-

myalgia, and 35 6 10 ng/mL for asymptomatic statin-

using patients. With alpha 5 0.05 and power 5 0.8, 34

statin-using patients with myositis-myalgia and 34

asymptomatic statin-using patients would be required

to detect differences in serum 25 (OH) vitamin D levels.

Fig 1. Characterization of cohort and of vitamin D supplementation.

Translational ResearchVolume 153, Number 1 Ahmed et al 13

Comparisons of categorical variables were performed

by X2 tests, the Fisher exact tests, or Mantel-Haenszel X2

tests. Comparisons of numerical variables were done

using nonparametric Wilcoxon tests. An analysis of

variance was used to compare least square mean serum

vitamin D in patients with and without entry myositis-

myalgia, after covariance adjusting for age, sex, and

race. Changes in serum vitamin D after 3 months of

supplementation with vitamin D (50,000 units/week)

in 38 symptomatic statin users with low serum vitamin

D at entry were compared using nonparametric-paired

Wilcoxon tests.

Fig 2. Distributions of serum 25 OH vitamin D in 128 statin-treated

patients with myalgia at study entry and in 493 statin-treated asymp-

tomatic patients.

RESULTS

We studied 621 statin-treated patients, which

consisted of 128 patients with myalgia at study entry

and 493 asymptomatic patients. These patients were

categorized by low serum 25 OH D (,32 ng/mL), and

subsequent treatment with vitamin D supplementation

in 38 myalgic, vitamin-D–deficient patients while con-

tinuing statin therapy (Figs 1 and 2, Tables I–III). All

621 patients had normal thyroid-stimulating hormone

and thyroxine.14

The 128 symptomatic and 493 asymptomatic statin-

taking patients did not differ (P . 0.1) at study entry

by age, body mass index (BMI), type 2 diabetes mellitus,

or high CK, but more nonwhites (12% vs 5%, P 5 .012)

and women (59% vs 44%, P 5 0.0025) were present in

the symptomatic than in the asymptomatic group

(Table I). Of the 128 symptomatic statin-taking patients,

3 had developed myositis-myalgia that caused discontin-

uation of more than 3 statins prior to referral to our center.

At study entry, the distribution of serum vitamin D

was shifted to lower levels in the 128 patients with

myalgia versus the 493 asymptomatic patients (Fig 2).

The mean serum vitamin D was lower in the 128 patients

with myalgia than in the 493 asymptomatic patients

(28.6 6 13.2 vs 34.2 6 13.8 ng/mL, P , 0.0001; Fig

1, Table II). By analysis of variance, which was adjusted

for race, sex, and age, the least square mean 6 standard

error (SE) serum vitamin D was lower in the myalgia

group than in the asymptomatic group (28.7 6 1.2 vs

Tab

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(n5

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22

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Translational Research14 Ahmed et al January 2009

34.3 6 0.6 ng/mL; P , 0.0001; Table II). When the

serum vitamin D distribution was examined categori-

cally, the myalgia group was overrepresented in the

lower end of the distribution, and the asymptomatic

group was overrepresented in the upper end of the distri-

bution (Mantel-Haenszel c2 5 16.9, P , 0.0001; Table

II). In all, 64% of the 128 patients with myalgia had low

vitamin D versus 43% of the 493 asymptomatic patients

(c2 5 17.4; P , 0.0001; Table I).

Vitamin D supplementation was given only to patients

who had myalgia symptoms and vitamin D levels less

than 32 ng/mL, and it was not given to the 46 symptom-

atic patients who had normal entry serum vitamin D

levels (Fig 1). Of the 82 myalgic, vitamin-D–deficient

patients, 38 received 50,000 units vitamin D per week

for 12 weeks, 8 had just started vitamin D therapy, 22

had only 1 visit without follow-up, and 14 were currently

untreated (Fig 1). The 38 patients did not differ (P .

0.05) from the 44 patients by entry vitamin D levels

(20.4 6 7.3 vs 21.1 6 7.0 ng/mL), by age (60 6 12 vs

58 6 12 years), by CK (165 6 153 vs 125 6 98

IU/L), or by BMI (31.1 6 5.8 vs 31.1 6 10.6 kg/m2).

The 38- and 44-patient groups also did not differ by

sex (45% male vs 41% male), but they did differ by

race, with more nonwhite patients in vitamin D treatment

group (29% vs 5%, P 5 0.0026).

After 3 months follow-up on vitamin D in the 38

myalgic, vitamin-D–deficient, statin-treated patients,

mean 6 SD serum vitamin D increased from 20.4 6

7.3 to 48.2 6 17.9 ng/mL (P , 0.0001), and 35 patients

(92%) had become free of myalgia (Table III).

In the 38 symptomatic statin-treated patients with low

entry vitamin D who subsequently received vitamin D

supplementation, the most frequently used statins were

rosuvastatin at entry and continued (n 5 10), atorvastatin

at entry then switched to rosuvastatin (n 5 7), atorvasta-

tin at entry and then continued (n 5 4), and pravastatin at

entry and then continued (n 5 2).

By investigator interview, adherence to the weekly

regimen of 50,000 units of vitamin D per week was excel-

lent, with no patients recording missed doses. No side ef-

fects attributable to the vitamin D therapy were reported.

DISCUSSION

The current report revealed that patients with statin-in-

duced myalgias had lower serum vitamin D levels than

statin-treated patients without myalgias. Low serum 25

(OH) vitamin D (D2 1 D3) is associated with myalgia

in statin-treated patients and, while continuing statins,

this myalgia can largely be reversed by vitamin D sup-

plementation which normalizes serum vitamin D levels.

We speculate that vitamin D deficiency reversibly

augments statin-induced myalgias.

Tab

leII

.D

istr

ibu

tio

no

fse

rum

vita

min

Dle

ve

lsin

621

hyp

erc

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493

asy

mp

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(ng

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20

20

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32

32

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40

40

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60

60

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80

$8

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(n5

128)

28.6

613.2

28.7

61.2

7(5

.4%

)28

(21.9

%)

47

(36.7

%)

19

(14.8

%)

25

(19.5

%)

1(0

.8%

)1

(0.8

%)

Asy

mp

tom

atic

(n5

493)

34.2

613.8

34.3

60.6

12

(2.4

%)

58

(11.8

%)

144

(29.2

%)

116

(23.5

%)

145

(29.4

%)

16

(3.3

%)

2(0

.4%

)W

ilcoxo

nte

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NO

VA

P,

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001

P,

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001

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25

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en

de

r,a

nd

ag

e.

Translational ResearchVolume 153, Number 1 Ahmed et al 15

In the current study, the symptomatic (myositis-myal-

gia) and asymptomatic groups did not differ in variables

that can affect serum 25 (OH) vitamin D levels, which

include age, BMI,15 type 2 diabetes,8 and by selection,

exogenous vitamin D, or corticosteroid use.16 More

women (59% vs 44%) and more nonwhites (12% vs

5%) were in the myalgia group than in the asymptomatic

group. Statin-treated females seem to have more myop-

athy than males.17 This result perhaps is related to lower

female exposure to sun, which results in more common

vitamin D deficiency.18 African Americans are much

more likely than Caucasians to have vitamin D defi-

ciency,19,20 which is related to decreased efficacy of

vitamin D production by darker pigmented skin. Low se-

rum vitamin D levels are very common; in this study,

lower levels are found in 43% of 493 asymptomatic

patients. This result provides a broad base for potential

interactions with commonly used statins to facilitate

development of myositis-myalgia.

In the current report, vitamin D supplementation that

normalized serum vitamin D levels was concurrently asso-

ciated with resolution of myalgias in 35 of 38 (92%) statin-

treated patients with myalgia and low pretreatment serum

vitamin D levels. We speculate that statins and vitamin D

deficiency interact additively or synergistically on the

muscle to produce myalgia that is reversible by vitamin

D supplementation, while continuing statin therapy.

Low 25 (OH) vitamin D levels have been associated

with myositis-myalgia5,6 and reduced muscle func-

tion.21-23 A case report of reversible muscle weakness

in a patient with vitamin D deficiency has been pub-

lished.24 The association of vitamin D deficiency, statin

use, and myopathy has been commented on in a case re-

port.25 Vitamin D may improve muscle strength through

a highly specific nuclear receptor in muscle tissue.6,7 In

healthy elderly subjects, 25 (OH) vitamin D levels are

related to physical performance.26

The pathoetiology of statin-induced myalgia-myopa-

thy is not well understood, but common polymorphic

variants within SLCO1B1 on chromosome 12 are

strongly associated with an increased risk of statin-in-

duced myopathy,17 perhaps by increasing statin blood

levels. Although 95% of statin-associated clinical events

involve myalgia or mild myositis,9 myalgic symptoms

are often enough to cause the patients to stop statin ther-

apy.27 We speculate that symptomatic myositis-myalgia

in statin-treated patients may reflect a potentially revers-

ible interaction in muscle between 25 (OH) vitamin D

deficiency and statins, which individually are commonly

associated with mild myositis-myalgia.9,10,27

A limitation of our and other studies of myositis-

myalgia lies in reliance on patients’ subjective reports

of muscle symptoms. Our study was also limited by

not having a matched, blinded, vitamin-D–deficient

Table III. Thirty-eight statin-taking patients with entry myositis-myalgia and low serum vitamin D (,32 ng/mL)

who were given vitamin D supplementation therapy (50,000 units/week) for 3 months

At follow-up n Entry serum vitamin D (ng/mL) Follow-up serum vitamin D (ng/mL) P (paired Wilcoxon)

Asymptomatic 35 20.4 6 7.3 48.1 6 17.1 ,0.0001Myalgia 3 20.0 6 8.2 49.0 6 30.4All 38 20.4 6 7.3 48.2 6 17.9 ,0.0001

Translational Research16 Ahmed et al January 2009

control group with previous myositis-myalgia on statins,

continuing statins, given a vitamin D placebo, and by the

absence of a second matched, blinded, vitamin-D–

deficient control group with previous myositis-myalgia

on statins, given a statin placebo, and vitamin D treat-

ment. The lack of blinding in the current study is an

important issue, especially in the context of subjective

reports of symptomatic myositis-myalgia. Future double

blind, placebo-controlled studies of statin-taking

patients with low serum vitamin D and symptomatic

myositis-myalgia will be needed to confirm our current

observations, which suggest that in vitamin-D–deficient,

statin-taking patients with myalgia, vitamin D supple-

mentation that normalizes serum vitamin D is associated

with resolution of myalgia in 92% of patients.

Speculations. Symptomatic myositis-myalgia in sta-

tin-treated patients may reflect a potentially reversible

additive or synergistic interaction in muscle between

25 (OH) vitamin D deficiency and statins, which individ-

ually are commonly associated with mild myositis-myal-

gia.9,10,27 Normalization of low serum 25 (OH) D by oral

vitamin D largely reverses myositis-myalgia, which

otherwise might cause statin intolerance.27

REFERENCES

1. Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem

with health consequences. Am J Clin Nutr 2008;87:1080S–6.

2. Mark S, Gray-Donald K, Delvin EE, et al. Low vitamin D status in

a representative sample of youth from Quebec, Canada. Clin Chem

2008;54:1283–9.

3. Goswami R, Mishra SK, Kochupillai N. Prevalence & potential

significance of vitamin D deficiency in Asian Indians. Indian

J Med Res 2008;127:229–38.

4. Alsafwah S, Laguardia SP, Nelson MD, et al. Hypovitaminosis D

in African Americans residing in Memphis, Tennessee with and

without heart failure. Am J Med Sci 2008;335:292–7.

5. Erkal MZ, Wilde J, Bilgin Y, et al. High prevalence of vitamin D

deficiency, secondary hyperparathyroidism and generalized bone

pain in Turkish immigrants in Germany: identification of risk fac-

tors. Osteoporos Int 2006;17:1133–40.

6. Bischoff-Ferrari HA, Dietrich T, Orav EJ, et al. Higher 25-hydroxy

vitamin D concentrations are associated with better lower-extrem-

ity function in both active and inactive persons aged . or 560 y.

Am J Clin Nutr 2004;80:752–8.

7. Lips P. Vitamin D physiology. Prog Biophys Mol Biol 2006;92:

4–8.

8. Targher G, Bertolini L, Padovani R, et al. Serum 25-hydroxyvitamin

D3 concentrations and carotid artery intima-media thickness among

type 2 diabetic patients. Clin Endocrinol (Oxf) 2006;65:593–7.

9. Nichols GA, Koro CE. Does statin therapy initiation increase the

risk for myopathy? An observational study of 32,225 diabetic

and nondiabetic patients. Clin Ther 2007;29:1761–70.

10. McClure DL, Valuck RJ, Glanz M, Murphy JR, Hokanson JE. Sta-

tin and statin-fibrate use was significantly associated with in-

creased myositis risk in a managed care population. J Clin

Epidemiol 2007;60:812–8.

11. Tsugawa N, Suhara Y, Kamao M, Okano T. Determination of 25-

hydroxyvitamin D in human plasma using high-performance liq-

uid chromatography—tandem mass spectrometry. Anal Chem

2005;77:3001–7.

12. Ford ES, Ajani UA, McGuire LC, Liu S. Concentrations of serum

vitamin D and the metabolic syndrome among U.S. adults. Diabe-

tes Care 2005;28:1228–30.

13. Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T,

Dawson-Hughes B. Estimation of optimal serum concentrations

of 25-hydroxyvitamin D for multiple health outcomes. Am J

Clin Nutr 2006;84:18–28.

14. Thompson PD, Clarkson P, Karas RH. Statin-associated myopa-

thy. JAMA 2003;289:1681–90.

15. Ybarra J, Sanchez-Hernandez J, Perez A. Hypovitaminosis D and

morbid obesity. Nurs Clin North Am 2007;42:19–27, v.

16. Sentongo TA, Semaeo EJ, Stettler N, Piccoli DA, Stallings VA,

Zemel BS. Vitamin D status in children, adolescents, and young

adults with Crohn disease. Am J Clin Nutr 2002;76:1077–81.

17. Link E, Parish S, Armitage J, et al. SLCO1B1 variants and statin-

induced myopathy–a genomewide study. N Engl J Med 2008;359:

789–99.

18. Fuleihan GE, Deeb M. Hypovitaminosis D in a sunny country.

N Engl J Med 1999;340:1840–1.

19. Nesby-O’Dell S, Scanlon KS, Cogswell ME, et al. Hypovitaminosis

D prevalence and determinants among African American and white

women of reproductive age: third National Health and Nutrition

Examination Survey, 1988-1994. Am J Clin Nutr 2002;76:187–92.

20. Hannan MT, Litman HJ, Araujo AB, et al. Serum 25-hydroxyvita-

min D and bone mineral density in a racially and ethnically diverse

group of men. J Clin Endocrinol Metab 2008;93:40–6.

21. Zittermann A. Vitamin D in preventive medicine: are we ignoring

the evidence? Br J Nutr 2003;89:552–72.

22. Pfeifer M, Begerow B, Minne HW. Vitamin D and muscle func-

tion. Osteoporos Int 2002;13:187–94.

23. Shinchuk LM, Holick MF. Vitamin d and rehabilitation: improv-

ing functional outcomes. Nutr Clin Pract 2007;22:297–304.

24. Ziambaras K, Dagogo-Jack S. Reversible muscle weakness in pa-

tients with vitamin D deficiency. West J Med 1997;167:435–9.

25. Goldstein MR. Myopathy, statins, and vitamin D deficiency. Am J

Cardiol 2007;100:1328.

26. Bunout D, Barrera G, Leiva L, et al. Effects of vitamin D supplemen-

tation and exercise training on physical performance in Chilean vita-

min D deficient elderly subjects. Exp Gerontol 2006;41:746–52.

27. Glueck CJ, Aregawi D, Agloria M, et al. Rosuvastatin 5 and 10

mg/d: a pilot study of the effects in hypercholesterolemic adults

unable to tolerate other statins and reach LDL cholesterol goals

with nonstatin lipid-lowering therapies. Clin Ther 2006;28:

933–42.