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17cebo or treatment with 200, 500, or 1500 mg of vitaminC daily for a period of 50 days. The prevalence ofCRPS type I was 10.1% in the placebo group and 2.4%in the vitamin C group (p.002). Patients were diag-

ichigan, 1500 East Medical Center Drive, 2912 Taubman Center, Ann Arbor, MI 48109; e-mail:urvas@med.umich.edu.

63-5023/09/34A09-0026$36.00/0i:10.1016/j.jhsa.2009.08.013

36 Published by Elsevier, Inc. on behalf of the ASSH.of the DistApurva S. Shah, MD, M

Peter J. L. Je

HERE HAS BEEN considerable debate regardingthe effect of vitamin C on the prevention ofcomplex regional pain syndrome (CRPS) in the

ting of distal radius fractures.13 Vitamin C, alsoown as ascorbic acid, is a water-soluble organic com-und first identified in 1932. Although humans areable to synthesize vitamin C, it is an essential micro-trient in many enzymatic and chemical pathways.tamin C acts as a cofactor for 8 different enzymest are involved in collagen hydroxylation, carnitine

d norepinephrine biosynthesis, amidation of peptidermones, and tyrosine metabolism.4 In addition, vita-n C acts as a powerful chemical reducing agent, ortioxidant.4Vitamin C is found in a large number of vegetablesd fruits (Table 1).5 The precise amount of vitamin Ca specific vegetable or fruit varies based on servinge, season, transport, shelf time, storage, and cookingctices. If an individual consumes 5 standard servingsvegetables and fruit in a day, daily vitamin C intakell range from 210 to 280 mg.4Complex regional pain syndrome, also known asex sympathetic dystrophy or algodystrophy, occursquently after fracture of the distal radius. Althoughorted incidence varies from one study to another, theidence has been reported to be as high as 25% to% in prospective investigations.6,7 CRPS is charac-ized by unexplained pain and swelling, vasomotortability, and loss of joint mobility. The pathophysi-gy of CRPS remains poorly understood.Two landmark, randomized, controlled trials by Zol-ger et al. demonstrated that vitamin C reduces the

omtheDepartment ofOrthopaedic Surgery, University ofMichiganHospitals, AnnArbor,MI.

ceived for publicationAugust 12, 2009; accepted in revised formAugust 20, 2009.

o benefits in any form have been received or will be received related directly or indirectly to theRadiussh K. Verma, MD,n, MD

idence of CRPS in the setting of distal radius frac-es.1,2 In the most recent trial, 416 patients with 427

ABLE 1. Food Sources of Vitamin C

ood Source (Preparation, Portion Size)VitaminC (mg) Calories

ruitsCantaloupe (raw, medium) 47 51Guava (raw, cup) 188 56Kiwi (raw, 1 medium) 70 46Mango (raw, cup) 23 54Orange (raw, 1 medium) 70 62Papaya (raw, medium) 47 30Pineapple (raw, cup) 28 37Strawberries (raw, cup) 49 27

egetablesBroccoli (cooked, cup) 37 26Broccoli (raw, cup) 39 15Brussels sprouts (cooked, cup) 48 28Cauliflower (cooked, cup) 28 17Edible pod peas (cooked, cup) 38 34Green pepper (sweet, cooked, cup) 51 19Green pepper (sweet, raw, cup) 60 15Kale (cooked, cup) 27 18Kohlrabi (cooked, cup) 45 24Red sweet pepper (cooked, cup) 116 19Red sweet pepper (raw, cup) 142 20Sweet potato (canned, cup) 34 116

uicesGrapefruit juice ( cup) 5070 7186Orange juice ( cup) 6193 7984Tomato juice ( cup) 33 31Vegetable juice cocktail ( cup) 50 34

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ORAL VITAMIN C AFTER DISTAL RADIUS FRACTURE 1737

InBriefVeldman et al. were present at the hand or wrist:explained diffuse pain, difference of skin color rela-e to the contralateral side, diffuse edema, differenceskin temperature relative to the contralateral side, andited active range of motion.8 A beneficial doseponse was observed; however, the effect reached ateau at a dose of 500 mg

r day. A statistically signif-nt difference was not ob-

rved between the placeboup and the 200-mg group,

ggesting that typical di-ry intake alone may be

sufficient in the preven-n of CRPS. Independent

vestigation of the role oftamin C in the prevention

CRPS would significantly add to the existingerature.Concerns have been raised regarding the methodol-y of the 2 trials conducted by Zollinger et al.3,9,10e issue is the confounding effect of cast com-

aints. Patients with early cast complaints were farore likely to develop CRPS (relative risk, 5.35).2wever, the primary concern revolves around the

agnosis of CRPS. Although the 2 trials used theagnostic criteria suggested by Veldman et al.,8ere are alternative sets of criteria published in theerature. The lack of consistency among these setscriteria indicates that the exact nature of CRPS

mains uncertain, and its diagnosis imprecise. Ow-g to a lack of precision in the diagnosis of CRPS,llinger et al. acknowledged that whereas vitamin Celiorates the Veldman signs and symptoms, it mayt prevent CRPS.2In addition, there is a lack of clarity regarding the

echanism by which vitamin C acts to decrease theidence of CRPS.3 Toxic oxygen radicals are thoughtbe involved in the pathogenesis of CRPS,11 and theiroduction in neutrophils is reduced in the presence ofamin C.12 The role of vitamin C has been studied iner inflammatory processes. In the setting of burns,amin C serves as a scavenger of free oxygen radicals.addition, there are data supporting vitamin Cs role asantioxidant in limiting skeletal muscle injury causedischemic reperfusion injury or compartment syn-

ome.13,14 One can infer that there may be a similarysiologic basis for vitamin C in the prevention ofPS.Beyond its role in the prevention of CRPS, vitamin Cintegral to collagen formation and bone synthesis.

EDUCATIONAL OBJECT Describe the mechanism of actions

State the role of Vitamin C in the pr

List the appropriate dose of daily Vi

Define the role of Vitamin C after di

Earn up to 2 hours of CME credit perarticles and take an online test. To payvisit http://www.assh.org/professionJHS Vol A, Noveial effect from vitamin C supplementation during thecture healing process.1518 In addition to acceleratingfracture healing process,15,16 vitamin C supplemen-

ion improves the mechanical resistance of the devel-ing fracture callus.18 Free oxygen radicals impaircture healing and are produced naturally by the inflam-

matory process surroundinga fracture. The antioxidantproperties of vitamin Cneutralize the adverse ef-fects of free oxygen radi-cals.17 The effect of vita-min C on fracture healinghas not been studied thor-oughly in humans. Onestudy demonstrated thatconservatively treated tib-

l shaft fractures healed 3 weeks earlier when supple-ented with vitamin C.19 However, the study suf-red from a high attrition rate and an inability tontrol for multiple confounding variables. Overall,e literature analyzing the effects of vitamin C one fracture healing process in humans is inadequatemake any absolute recommendations on its use.Although controversy exists regarding the value of

escribing vitamin C to patients with distal radiusctures, there appears to be limited downside with itse. Adverse effects of vitamin C are dose-dependentd occur at doses well above the recommended dailyowance of 60 mg daily. Generally, adverse side ef-ts can be avoided with doses below 1000 mg daily in

althy people.4 When several grams of vitamin C areen at once, diarrhea and abdominal bloating are the

ost frequent side effects. In addition, renal calculin precipitate as a result of the ingestion of excesstamin C. Oxalic acid is produced and renallycreted during vitamin C metabolism. In patientsth underlying hyperoxaluria, oxalate excretion iscelerated with vitamin C doses above 1000 mgily and can contribute to formation of renallculi. Similarly, hyperuricosuria can occur withrge doses of vitamin C, also leading to formationrenal calculi. In patients requiring dialysis, hy-roxalemia can occur with doses as low as 500g daily. Therefore, these patients should limitily intake to 200 mg.Based on the existing literature, patients with distalius fractures should be treated with vitamin C toit the risk of developing CRPS. Specifically, a daily

se of 500 mg for a period of 50 days is recom-ended. Dietary intake alone is insufficient. There may

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be an incidental benefit of reduced time to fracturehealing, although this potential benefit merits furtherclinical investigation. The disadvantages of treatmentwith vitamin C are trivial given its low cost and limitedside effect profile with doses less than 1000 mg daily.The use of vitamin C does not obviate the need forcareful splinting and casting, which also has a role inthe development of CRPS.

REFERENCES1. Zollinger PE, Tuinebreijer WE, Kreis RW, Breederveld RS. Effect

of vitamin C on frequency of reflex sympathetic dystrophy in wristfractures: a randomised trial. Lancet 1999;354:20252028.

2. Zollinger PE, Tuinebreijer WE, Breederveld RS, Kreis RW. Canvitamin C prevent complex regional pain syndrome in patients withwrist fractures? A randomized, controlled, multicenter dose-responsestudy. J Bone Joint Surg 2007;89A:14241431.

3. Amadio PC. Vitamin C reduced the incidence of reflex sympatheticdystrophy after wrist fracture. J Bone Joint Surg 2000;82A:873.

4. Levine M, Rumsey SC, Daruwala R, Park JB, Wang Y. Criteria andrecommendations for vitamin C intake. JAMA 1999;281:14151423.

5. U.S. Department of Health and Human Services, U.S. Department ofAgriculture. Dietary guidelines for americans 2005. Washington,DC: U.S. Department of Health and Human Services, U.S. Depart-ment of Agriculture, 2005:65.

6. Atkins RM, Duckworth T, Kanis JA. Algodystrophy following Col-les fracture. J Hand Surg 1989;14B:161164.

7. Atkins RM, Duckworth T, Kanis JA. Features of algodystrophy afterColles fracture. J Bone Joint Surg 1990;72B:105110.

8. Veldman PH, Reynen HM, Arntz IE, Goris RJ. Signs and symptoms

9.

drome in patients with wrist fractures? J Bone Joint Surg 2007;89A:2550 2551.

10. Rogers BA, Ricketts DM. Can vitamin C prevent complex regionalpain syndrome in patients with wrist fractures? J Bone Joint Surg2008;90A:447448.

11. Goris RJ, Dongen LM, Winters HA. Are toxic oxygen radicalsinvolved in the pathogenesis of reflex sympathetic dystrophy? FreeRadic Res Commun 1987;3:1318.

12. Herbaczynska-Cedro K, Wartanowicz M, Panczenko-Kresowska B,Cedro K, Kosiewicz-Wasek B, Wasek W. Inhibitory effect of vita-mins C and E on the oxygen free radical production in humanpolymorphonuclear leucocytes. Eur J Clin Invest 1994;24:316319.

13. Kearns SR, Moneley D, Murray P, Kelly C, Daly AF. Oral vitaminC attenuates acute ischaemia-reperfusion injury in skeletal muscle.J Bone Joint Surg 2001;83B:12021206.

14. Kearns SR, Daly AF, Sheehan K, Murray P, Kelly C, Bouchier-Hayes D. Oral vitamin C reduces the injury to skeletal muscle causedby compartment syndrome. J Bone Joint Surg 2004;86B:906911.

15. Yilmaz C, Erdemli E, Selek H, Kinik H, Arikan M, Erdemli B. Thecontribution of vitamin C to healing of experimental fractures. ArchOrthop Trauma Surg 2001;121:426428.

16. Sariszen B, Durak K, Diner G, Bilgen OF. The effects of vitaminsE and C on fracture healing in rats. J Int Med Res 2002;30:309313.

17. Duygulu F, Yakan B, Karaoglu S, Kutlubay R, Karahan OI, OzturkA. The effect of zymosan and the protective effect of variousantioxidants on fracture healing in rats. Arch Orthop Trauma Surg2007;127:493501.

18. Alcantara-Martos T, Delgado-Martinez AD, Vega MV, CarrascalMT, Munuera-Martinez L. Effect of vitamin C on fracture healing inelderly Osteogenic Disorder Shionogi rats. J Bone Joint Surg 2007;89B:402407.

19. Jamdar J, Rao B, Netke S, Roomi MW, Ivanov V, Niedzwiecki A, etal. Reduction in tibial shaft fracture healing time with essential

1738 ORAL VITAMIN C AFTER DISTAL RADIUS FRACTURE

InBriefof reflex sympathetic dystrophy: prospective study of 829 patients.Lancet 1993;342:10121016.Frlke JP. Can vitamin C prevent complex regional pain syn-JHS Vol A, Novenutrient supplementation containing ascorbic acid, lysine, and pro-line. J Altern Complement Med 2004;10:915916.mber

Use of Oral Vitamin C After Fractures of the Distal RadiusREFERENCES