The Role of Vitamin C in Orthopedic Trauma and Bone Health
Vitamin C is an essential micronutrient with an adult daily recommended intake of 75 mg for women and 90 mg for men. Smokers should consume an additional 35 mg per day because of the increased oxidative stresses from cigarette smoke.
Observational data support the hypothesis that high dietary intake and supplementation with vitamin C may reduce the risk of hip fractures in postmenopausal women.
Results of 2 high-quality trials support use of vitamin C 500 mg daily for 50 days as prophylaxis against complex regional pain syndrome after wrist fracture treated conservatively and operatively. Observational evidence exists for similar treatment after foot and ankle surgery.
The role of vitamin C in preventing osteoarthritis has tremendous potential, though results in animal and human studies are controversial. The heterogeneous results and the lack of prospective trials preclude any recommendation at this time.
Besides promoting bone formation, vitamin C improves the mechanical strength of callus formation. Alcantara-Martos and colleagues31 used an osteogenic disorder Shionogi (ODS) rat model to examine the effects of vitamin C intake on femoral fracture healing. This particular animal model is unable to produce its own vitamin C. The groups with lower serum vitamin C levels demonstrated lower mechanical resistance of the fracture callus to torsional loads 5 weeks after fracture. Moreover, the group that received vitamin C supplementation showed higher histologic grade of callus formation and demonstrated faster healing rates. The authors suggested that subclinical vitamin C deficiency can delay fracture healing and that vitamin C supplementation in nondeficient patients would improve bone healing.
Other research has demonstrated a link between vitamin C and mesenchymal cell differentiation. Mohan and colleagues32 used an sfx mouse model to show that vitamin C deficiency results in decreased bone formation secondary to impaired osteoblast differentiation, diminished bone density, and development of spontaneous fractures. The authors indicated that not only is vitamin C essential for maintenance of differentiated functions of osteoblasts, but deficiency during early active growth may affect peak BMD levels in humans. Additional studies have demonstrated the role of vitamin C in endochondral bone formation through both induction of osteoblast differentiation and modulation of gene expression in hypertrophic chondrocytes.33-36 Chronic vitamin C deficiency has been found to depress osteoblast function and differentiation of chondrocytes.37 More recently, Kim and colleagues38 examined the effect of vitamin C insufficiency in Gulo-deficient mice, which are unable to synthesize ascorbic acid. Ascorbic acid insufficiency over 4 weeks led to decreased plasma levels of osteocalcin and bone formation in vivo as well as significantly diminished metaphyseal trabecular bone. Despite all the evidence demonstrating the importance of vitamin C in bone formation and maintenance, many of the underlying processes in this relationship have yet to be determined.
Bone Mineral Density
Several observational studies have found a positive association between vitamin C intake and BMD in postmenopausal women. In a retrospective, cross-sectional study by Hall and Greendale,39 a positive association was found between vitamin C intake and BMD of the femoral neck in 775 participants in the Postmenopausal Estrogen/Progestin Interventions trial. After calcium intake, physical activity level, smoking, estrogen use, age, and body mass index were adjusted for, each 100-mg increase in dietary vitamin C was associated with a 0.017 g/cm2 increase in BMD. Wang and colleagues40 found a positive association between dietary vitamin C intake and femoral neck BMD in a retrospective analysis of 125 postmenopausal Mexican American women. Other observational studies have reported that decreased intake of vitamin C is associated with osteoporosis41 and increased rates of BMD loss42 and that supplementation with vitamin C may suppress bone resorption in postmenopausal women.43
The results of these studies contrast with the findings of Leveille and colleagues,44 who examined the relationship between dietary vitamin C and hip BMD in 1892 postmenopausal women. Although the authors found that women (age, 55-64 years) using vitamin C supplements for more than 10 years had an average BMD 6.7% higher than that of nonusers, they did not find any association between dietary vitamin C intake and BMD. Moreover, NHANES III also found inconsistent associations between vitamin C and BMD among 13,080 adults surveyed in the United States.45 Although for premenopausal women dietary ascorbic acid was associated with increased BMD, for postmenopausal women with a history of smoking and estrogen replacement, it was actually associated with lower BMD values. For other subgroups in the study, the relationship was also inconsistent or nonlinear.
The exact mechanism by which ascorbic acid contributes to BMD is not fully delineated. However, it likely is related to the known role of vitamin C in collagen formation, bone matrix development, osteoblast differentiation, and its antioxidant effects limiting bone resorption.44,46
Hip Fractures
Besides demonstrating positive effects of vitamin C on bone healing and BMD, epidemiologic studies have found evidence of a protective effect of vitamin C on hip fracture risk. In a study of the Swedish Mammography cohort, 66,651 women (age, 40-76 years) were prospectively followed.47 The authors found that the odds ratio (OR) for hip fractures among smokers with a low intake of vitamin E (median intake, ≤6.2 mg/d) was 3.0 (95% CI, 1.6-5.4) and for vitamin C (median intake, ≤67 mg/d) was 3.0 (95% CI, 1.6-5.6). Moreover, in smokers with a low intake of both vitamins E and C, OR increased to 4.9 (95% CI, 2.2-11.0). In addition, the Utah Study of Nutrition and Bone Health matched 1215 cases of hip fractures in patients who had ever smoked (age, >50 years) with 1349 controls and found that vitamin C intake above 159 mg/d had a significant protective effect on the incidence of hip fracture; however, a graded relationship was not observed.48 Despite the inconsistencies in the NHANES III study regarding the relationship between vitamin C and BMD, Simon and Hudes45 found that serum vitamin C was associated with lower risk for self-reported fracture in postmenopausal women who had ever smoked and had a history of estrogen therapy (OR, 0.51; 95% CI, 0.36-0.70). Finally, Sahni and colleagues49 followed 958 Framingham cohort men and women (mean age, 75 years) over 17 years and found that those in the highest tertile of total vitamin C intake (median, 313 mg/d) had significantly fewer hip fractures and nonvertebral fractures compared with those in the lowest tertile of intake (median, 94 mg/d). Dietary vitamin C intake was not associated with fracture risk in this study.
