The Role of Vitamin C in Orthopedic Trauma and Bone Health

L-ascorbic acid, more commonly know as vitamin C, is an essential micronutrient used in numerous metabolic pathways. It functions physiologically as a water-soluble antioxidant by virtue of its high reducing power, playing a key role in the function of leukocytes, protein metabolism, and production of neurotransmitters.^1-3 Vitamin C also contributes to musculoskeletal health through biosynthesis of carnitine and collagen⁴ and enhancement of intestinal absorption of dietary iron⁵ from plants and vegetables. Unlike most animals, humans are unable to synthesize this essential vitamin and therefore require intake from natural dietary sources or supplements.⁶ The ability of vitamin C to prevent or treat disease has been an area of research interest since the vitamin was identified and isolated by Szent-Györgyi in the 1930s.^7-16 Research in orthopedic surgery has focused on the effects of vitamin C on fracture healing, its potential use in preventing complex regional pain syndrome (CRPS), and its role in the pathophysiology of osteoarthritis. In this article, we review the basics of vitamin C metabolism and summarize the evidence surrounding the role of vitamin C supplementation in orthopedics.

Sources and Metabolism

Vitamin C is found naturally in many fruits and vegetables (Table 1) and is a common fortification in cereals, juices, and multivitamins. Daily recommended intake (Table 2) depends on age and smoking status. Absorption occurs in the distal small intestine, with blood plasma vitamin C concentrations reflecting dietary intake. Pharmacokinetic studies have shown that vitamin C concentrations are tightly regulated through absorption, tissue accumulation, and renal resorption, with plasma concentrations rarely exceeding 100 μmol/L without additional supplementation.¹⁷ Although the usual dietary doses of 100 mg/d (adult) are almost completely absorbed, producing a plasma concentration of 60 μmol/L, higher intake results in an increasingly smaller fraction absorbed.^1,18 Intake of more than 1000 mg/d results in less than 50% absorption¹⁹ (unmetabolized vitamin C is excreted in stool and urine¹). Even at higher doses, vitamin C has low toxicity³; the most common complaints are diarrhea, nausea, and abdominal cramps caused by the osmotic effect of unabsorbed vitamin C in the gastrointestinal tract.¹

Vitamin C Deficiency

The relationship between vitamin C deficiency and the development of scurvy has been documented for centuries. Symptoms are described in the ancient Egyptian, Greek, and Roman literature.²⁰ Ascorbic acid is essential for normal collagen function, as it is a required cofactor for enzymatic transfer of hydroxyl groups to select proline and lysine residues during procollagen formation. Hydroxylysine contributes to the intermolecular cross-links in collagen, and hydroxyproline stabilizes the triple-helix structure of collagen.²¹ Insufficient vitamin C during this process results in collagen that is non-cross-linked, nonhelical, structurally unstable, and weak.²¹ Clinical manifestations of scurvy stem from an underlying impairment of collagen production causing a systemic decrease in connective tissue integrity, capillary fragility, poor wound healing, fatigue, myalgias, arthritis, and even death.²² Vitamin C deficiency has also been implicated as a cause of diffuse bleeding in surgical patients with normal coagulation parameters secondary to capillary fragility.²³ In the United States, the 2003–2004 National Health and Nutrition Examination Survey (NHANES) measured serum vitamin C concentrations in 7277 noninstitutionalized patients 6 years old or older.²⁴ Age-adjusted incidence of subnormal serum vitamin C levels (<28 μmol/L) was 19.6%, and incidence of frank vitamin C deficiency (<11.4 μmol/L) was 7.1%. Reported rates of vitamin C deficiency in hospitalized patients are much higher, with 47% to 60% having subnormal values (<28 μmol/L) and 17% to 19% being vitamin C–deficient (<11.4 μmol/L).^22,25 Identified risk factors for hypovitaminosis C include advanced age, obesity, low socioeconomic status, unemployment, male sex, and concomitant alcohol and tobacco consumption.^22,24,25

Fracture Healing and Prevention

The effects of vitamin C deficiency on bone healing have been studied with animal models as early as the 1940s.^26,27 Early experiments using guinea pigs demonstrated failure of bone graft incorporation, delayed collagen maturation, and decreased collagen and callus formation in scorbutic animals compared with controls that received vitamin C supplementation.^26,27 Based on his work with guinea pigs, Bourne²⁶ reported in 1942 that vitamin C deficiency significantly inhibited the reparative process in damaged bone and that patients with fractures should receive vitamin C supplementation. Building on this early research, Yilmaz and colleagues²⁸ found faster histologic healing for tibia fractures in a rat model for animals that received a single injection of vitamin C 0.5 mg/kg compared with a nonscorbutic control group, and Sarisözen and colleagues²⁹ showed significantly accelerated histologic bone formation and mineralization at the fracture site for rats that received vitamin C supplementation. Moreover, Kipp and colleagues³⁰ found that scorbutic guinea pigs had lower bone mineral density (BMD), decreased bone mineral content, and impaired collagen synthesis of articular cartilage and tendons compared with nondeficient controls.