Vitamin C in orthopedic practices: Current concepts, novel ideas, and future perspectives
Abstract
Vitamin C (ascorbic acid), is an important antioxidant that has been applied broadly in the field of orthopaedics. Current research on vitamin C examines the molecule's role in bone and tendon physiology, as well as joint replacement and Postoperative pain. Most laboratory and human studies associate the use of vitamin C with improved bone health and tendon healing. Recent literature moderately supports the use of vitamin C to improve functional outcomes, decreased postoperative pain, and prevent complex regional pain syndrome following orthopaedic procedures. The perioperative use of vitamin C in patients undergoing joint replacement surgery and anterior cruciate ligament reconstruction is still under investigation. Overall, there is need for high-quality human trials to confirm whether vitamin C can potentiate the outcomes of orthopaedic procedures and to determine optimal dosage and means of administration to maximize its proposed benefits. The purpose of this review was to summarize the application of vitamin C in orthopaedic practices and to identify potential areas for future study.
1 INTRODUCTION
Vitamin C (ascorbic acid), is an important antioxidant and deficiency of this mineral is most often associated with scurvy.1 Vitamin C is vital to the production of collagen in both bone and connective tissue and it has been associated with improved collagen synthesis and subsequent tendon healing.2-4 It also neutralizes free radicals, which helps to decrease oxidative stress and inflammation.5
Vitamin C has also been used as a supplement in orthopaedic patients.6-8 Vitamin C has been linked to improved bone mineral density as well as decreased risk of bone fracture and osteoporosis.9-11 Furthermore, there is recent evidence to suggest that vitamin C may have a protective role in osteoarthritis.12 From a postoperative recovery perspective, vitamin C has been found to reduce the incidence of complex regional pain syndrome (CRPS) and improve functional outcomes.5, 13 However, some of these conclusions on the therapeutic effect of vitamin C continue to be debated.14
The purpose of this review was to summarize the role of vitamin C in orthopaedic practices and to identify potential areas for future study.
1.1 Perioperative pain management
Postoperative pain exists as a common challenge to orthopaedic surgeons, as it is linked to increased risk of postoperative complications, longer hospital stays, and significant delays in the return to regular function.15 Opioids, such as morphine, may be prescribed to limit postoperative pain in orthopedic patients; however, there are a multitude of side effects associated with their use including but not limited to nausea, vomiting, dizziness, and cardiorespiratory dysfunction.16 Nonsteroidal anti-inflammatory drugs (NSAIDs), may also be used to combat musculoskeletal pain although they too have side effects, such as reflux and stomach ulcers.17 NSAIDs are used withcaution (or not recommended at all) in the immediate postoperative period on orthopaedic patients, due to the possible risk of bleeding.18 Acetaminophen is preferred over NSAIDs or opioids due to its good safety profile, but high doses should be avoided in patients with underlying liver disorders.19, 20 High dose acetaminophen is often part of perioperative pain control regimens in combination with local nerve blocks, opioids or NSAIDS.21, 22
Recently, there have been studies evaluating the role of vitamin C supplementation in the postoperative recovery and the prevention of CRPS.23-25 There is moderate evidence supporting the use of vitamin C following distal radius fracture (DRF) to prevent CRPS, a rare chronic condition characterized by unexplained pain and swelling, hot flashing, and decreased joint mobility.25, 26 Although the analgesic effect on vitamin C has been proven in case series studies, the exact mechanism underlying its antinociceptive effect remains under investigation. It is believed that the analgesic effect of vitamin C is primarily based on its antioxidant properties.27 Vitamin C has been shown to reduce the production of reactive oxygen species (ROS), resulting in the protection of tissues (including the nerves) from oxidative damage. Vitamin C acts as a cofactor in the synthesis of neurotransmitters and peptide hormones, including the biosynthesis of amidated opioid peptides.28 Finally, vitamin C is implicated in the expression of genes and transcription factors that modulate its analgesic effects.28 Further research is necessary to explain the analgesic action of vitamin C in the generation of pain at specific body sites, especially at the postoperative setting.
Malay et al. applied the Hill criteria to existing clinical trials to validate the role of vitamin C supplementation in the prevention of CRPS.25 Of the four clinical studies analyzed in this review, three where conducted in DRF patients and the fourth concerned patients undergoing foot and ankle surgery.25 The authors found that six of the nine Hill criteria were met, suggesting a causal relationship between vitamin C and the preventive effect on CRPS in patients after DRF and foot/ankle surgery.25 Although Malay et al.25 acknowledged the need for more research to identify the mechanism by which vitamin C is able to reduce the incidence of CRPS, they concluded that the AAOS recommendation of vitamin C supplementation to prevent CRPS after DRF has “practical merit.” However, Malay et al.25 acknowledged that the reviewed studies were limited by a potential for selection bias and the possible influence of confounding variables.
In contrast, a randomized controlled trial (RCT) by Ekrol et al.24 on the role of vitamin C postoperative pain following DRF repair found that the administration of vitamin C confers no clinical benefit. The study examined 336 adult patients that were randomized to receive 500 mg of oral vitamin C or a placebo tablet daily for 50 days after the fracture.24 No significant difference in DASH scores (measured preoperatively and at 6 weeks and 1 year postoperatively), the rate of CRPS, or other functional outcomes (wrist and finger motion, grip and pinch strength, and pain) between the DRFs treated with vitamin C and the control were observed.24 In fact, at 6 weeks, the vitamin C group exhibited a higher rate of complications than the control.24 However, Ekrol et al.24 identified a higher patient dropout rate (26%) compared to previous studies as a limitation of their clinical trial.15 Conversely, ameta-analysis by Chen et al. indicated that there was a significant reduction of CRPS with use of vitamin C.15 The authors concluded that there exists “high-level evidence” to support perioperative vitamin C supplementation of 1 g/day for 50 days after DRF to prevent CRPSand that more clinical trials are necessary to increase the level of evidence on vitamin C's effectiveness and determine the optimal dosage.15 Similar to the Malay et al. study, Chen et al.15 cited the potential for selections bias and confounding results as limitations of the examined studies.
Other studies have examined the effect of vitamin C on pain in patients undergoing distal lower extremity and spinal procedures.13, 29 In a RCT by Lee et al.,13 123 adults patients who underwent Posterior Lumbar Interbody Fusion (PLIF) were recruited and assigned to receive 500 mg of daily oral vitamin C or a placebo tablet for 45 days following the procedure.13 The primary outcome measure was pain intensity in the lower back, measured at 1, 3, 6 months and 1 year after surgery using a visual analogue scale (VAS).13 Secondary outcomes included Oswestry Disability Index (ODI), fusion rate, and complications.13 VAS scores, fusion rates, and complications were not significantly different between the two groups over the follow-up period.13 However, the ODI score of the vitamin C group was significantly higher at the third postoperative month than the control.13 Lee et al.13 mentioned that their study was limited by an insufficient sample size, limited follow-up time points, and use of a visual analogue scale over time.
Similarly, Jain et al.29 investigated the connection between vitamin C supplementation and postoperative pain relief following foot and ankle surgery; 60 adult patients with a closed fracture of the foot or ankle were randomly assigned to receive 500 mg of oral vitamin C or a placebo tablet twice daily for 6 weeks following their procedure.29 VAS score, analgesia requirement, and functional outcome were assessed at first, second, sixth week, and 3-month follow-ups.29 The vitamin C group had higher VAS scores at 2 and 6 weeks postoperatively in comparison to the control.29 In addition, the vitamin C group exhibited lower mean amount of analgesia used at the end of 6 weeks, and improved functional outcome at the end of 3 months when compared to the control.29 The Jain et al.29 trial was limited by a small patient population, a short follow-up period, and use of VAS scores, which are a subjective pain measurement.
In comparison to opioids and NSAIDs, vitamin C supplementation is relatively safe and low-cost.21 Some studies have found that high-dose vitamin C (1.5–2 g/day) can cause digestive distress and increased risk of kidney stone formation.22-24 While evidence of its impact of kidney stone formation is conflicting, a tolerable upper limit of 2000 g/day of vitamin C has been set.25, 26 It is believed that supplementation below this threshold represents a low-risk nutritional intervention.30
There is moderate evidence to suggest that vitamin C supplementation plays a beneficial role in postoperative recovery, especially following PLIF and foot/ankle surgery. Limitations aside, the aforementioned clinical trials provide a solid framework for future studies analyzing the effect of 0.5–1 g perioperative vitamin C for 40–50 days on short, mid, and long-term patient outcomes following spinal and lower extremity procedures. Meanwhile, evidence suggesting vitamin C's ability to prevent CRPS following orthopedic procedures is promising but also limited and somewhat conflicting. However, administration of 500–1 gg/day of perioperative vitamin C for 50 days represents a reasonable approach until further higher-level evidence becomes available. Overall, both areas require more prospective clinical trials to provide greater evidence on the effectiveness of vitamin C and determine the optimal dosage and method of administration.
1.2 Bone healing and osteoporosis
Throughout the last decade, the role of vitamin C in bone regeneration has been examined in animal models. Giordano et al. investigated the impact of intraperitoneal vitamin C supplementation on bone healing after rat tibia fracture, and they reported no histological differences between groups A (vitamin C) and B (saline).31 In this study, both groups all had a complete bone union at 6 weeks.31 In another study vitamin C reversed the bone-specific changes caused by ovariectomy in rates, including decreased bone quality and antioxidant capacity.32 Choi et al.9 recently found that vitamin C can inhibit osteoporosis by promoting osteoblast formation and inhibiting osteoclastogenesis via multiple signaling pathways in ovariectomized (OVX) Wistar rats.9 Their results also revealed that vitamin C supplementation led to improved bone mineral density (BMD) and bone volume, a higher number of osteoblasts and osteoclasts, and increased expression of osteoblast differentiation genes in OVX rats.9 Similarly, Zheng et al.33 determined that combined Mg and vitamin C supplementation can attenuate steroid associated osteonecrosis in Sprague-Dawley rats by stimulating osteoblast differentiation, decreasing inflammation, and promoting angiogenesis. The above-mentioned animal studies were all limited by the fact that they were not conducted with human subjects. However, based on the above, vitamin C supplementation may increase bone regeneration and reduce the effect/incidence of degenerative bone conditions, such as osteoporosis, osteoarthritis (OA), and osteonecrosis, although additional human research is needed to confirm these assertions. Table 1 summarizes the laboratory studies that have examined the role of vitamin C in bone regeneration.
| Study (first author, year) | Study design (population, testing groups) | Conclusion |
|---|---|---|
| Giordano et al., 201231 | 30 Male Wistar rats | Intraperitoneal Vitamin C supplementation does not accelerate bone healing. |
| Group A: vitamin C—200 mg intraperitoneally per kg per day of ascorbic acid | ||
| Group B: saline—5 ml per kg per day intraperitoneally once a day | ||
| Chiu et al., 2016a,12 | 80 Male Wistar rats treated w/3 mg monosodium iodoacetate (MIA) to induce osteoarthritis (OA) | Treatment with vitamin C, regardless of dosage, decreased the changes to cartilage following MIA-induced OA. |
| Group A: control | ||
| Group B: 100 μM /kg/day of vitamin C | ||
| Group C: 200 μM /kg/day of vitamin C | ||
| Group D: 300 μM /kg/day of vitamin C | ||
| Segawa et al., 2016b,34 | 80 Female Shionogi rats w/osteogenic disorder and vitamin C deficiency | Vitamin C supplementation improved bone strength in ODS rats. |
| Group A: vitamin C supplemented water (2 mg/ml) daily | ||
| Group B: vitamin C deficient water (0.5 mg/ml) daily | ||
| Group C: vitamin C supplemented water (2 mg/ml) and minodronate daily | ||
| Group D: vitamin C deficient water (0.5 mg/ml) and minodronate daily | ||
| Deyhim et al., 201832 | 42 Female Sprague-Dawley rats | Vitamin C led to increased bone quality and antioxidant capacity in ovariectomized rats |
| Group A: sham ovariectomy | ||
| Group B: ovariectomy | ||
| Group C: ovariectomy + 22 mg oral vitamin C for 60 days following procedure | ||
| Miyakoshi et al., 2019c,35 | 40 Female Shionogi rats w/osteogenic disorder and vitamin C deficiency | TPTD and vitamin C in combination increased cancellous bone strength. |
| Group A: control; vitamin C deficient water (0.5 mg/ml) | ||
| Group B: vitamin C supplemented water (2 mg/ml) | ||
| Group C: vitamin C deficient water (0.5 mg/ml) + teriparatide (TPTD) once/week | ||
| Group D: vitamin C supplemented water (2 mg/ml) + TPTD once/week | ||
| Group D: OVX + vit C free diet + 200 mg vit C daily | ||
| Group E: OVX + vit C free diet + 500 mg vit C daily | ||
| Group F: OVX + vit C free diet + 1000 mg vit C daily | ||
| Choi et al., 2019c,9 | 60 Female Wistar rats | Vitamin C can increase bone regeneration and prevent osteoporosis |
| Group A: sham ovariectomy (OVX) | ||
| Group B: OVX + vit C free diet | ||
| Group C: OVX + normal diet | ||
| Zheng et al., 2020d,33 | 80 Male Sprague-Dawley rats w/induced steroid-associated osteonecrosis (SAON) | Combined Mg and VC supplementation can alleviate SAON in rats |
| Group A: control | ||
| Group B: Mg sulfate solution (50 mg/kg/day Mg ion) | ||
| Group C: sodium ascorbate solution (100 mg/kg/day vitamin C) | ||
| Group D: combination solution (50 mg/kg/day Mg ion + 100 mg/kg/day vitamin C) |
- a Study lasted 2 weeks.
- b Study lasted 4 weeks for half of rats, 8 weeks for the other half.
- c Study lasted 12 weeks.
- d Study lasted 6 weeks.
Recent human studies have examined the link between vitamin C and fracture risk.36-38 A study by Sun et al.36 evaluated the connection between antioxidant intake and risk of hip fracture in the elderly Chinese. The study included 726 subjects with hip fracture as well as 726 control subjects.36 A food frequency questionnaire and face-to-face interviews were conducted to determine various antioxidant intakes, and the authors discovered that there was a significant inverse relationship between dietary intake of vitamin C and risk of hip fracture.36 However, Sun et al. cited recall bias and assumptions made in the calculation of food antioxidant values as possible limitations due to potential dietary changes.36 A similar study byTorbergson et al. determined that low serum concentrations of vitamin C were linked with increased risk of hip fracture in elderly patients, possibly due to its role in bone turnover mechanisms.37 Torbergson et al. recognized that their study was limited by not accounting for patient risk of falling, which could partly explain the difference in hip fracture risk between the two groups.37
Unlike the other two studies, a study by Finck et al.39 specifically examined the effect of vitamin C on hip/spine fracture risk and heel bone ultrasound measurements. The study included over 25,639 patients, 1502 of which had experienced a fracture. The authorsdetermined that dietary vitamin C was significantly linked with higher heel bone ultrasound measures, and that plasma vitamin C concentration was associated with lower fracture risk in men.39 Finck et al. concluded that more research is needed to clarify vitamin C's inconsistent association with bone health factors, pointing to the approximately 3-year gap between diet/plasma measurements and those of the ultrasound as a limitation of the study.39 In a later meta-analysis of 10,807 patients (7908 controls and 2899 cases of hip fracture) a strong statistical correlation of dietary vitamin C and decreased risk of hip fracture was found.38 Specifically, the risk of hip fracture decreased by 5% for every 50 mg/day increase in dietary vitamin C intake.38 However, the authors acknowledged the need for more well-designed RCTs to solidify these conclusions.38
The link between vitamin C and risk of osteoporosis has also been evaluated in human studies.10, 11 Kim et al.10 investigated the connection between dietary vitamin C intake and BMD in postmenopausal women. Their study found that dietary vitamin C intake exhibited a strong positive correlation with BMD and a strong negative correlation with risk of osteoporosis in postmenopausal women, most significantly in subjects with vitamin D deficiency and age 50–59 years or more than 70 years.10 Kim et al.10 mentioned the low incidence of fractures and lack of data on serum vitamin C concentrations as viable limitations. Another research group evaluated the effect of vitamin C intake and physical activity on osteoporosis risk in Korean adults more than 50 years of age.11 The study was comprised of 3047 subjects, and BMD data were used to separate the subjects into two groups: osteoporosis and normal.11 The data showed that higher vitamin C intake was linked to decreased risk of osteoporosis in Korean adults with low levels of physical activity, but no connection was seen between the two in those with high activity levels.11 The inability to infer causality was mentioned as a feasible limitation.11
Finally, one recent trial by Sandukji et al.40 looked at the effect of antioxidants, including vitamin C, on oxidative stress and bone healing following long-bone fixative surgery. The study sample of 55 subjects was separated into 4 groups, and Groups 1 and 2 received the normal postoperative treatment while Groups 3 and 4 received a daily antioxidant tablet (300 µg vitamin A, 10 mg vitamin E, 60 mg vitamin C, and 75 µg selenium) for 1 or 2 weeks.40 The authors found that that both 1- and 2-week postoperative antioxidant supplementation led to a significant decrease in factors associated with oxidative stress compared to the control.40 Sandukji et al.40 added that insufficient sample size and an inability to differentiate the effects of the individual antioxidants represented possible limitations.
Laboratory and human studies generally associate the use of vitamin C with improved bone health, as long-term dietary intake of the antioxidant may help to improve factors such as BMD and decrease risk of fracture, while shorter-term supplementation may attenuatedegenerative bone conditions, such as OA and osteonecrosis. However, additional human trials evaluating vitamin C in isolation are needed to better understand its individual impact on bone health.
1.3 Tendon healing
Tendon injuries affect both active and sedentary populations.41 Common tendon injuries include rupture or inflammation of the biceps, rotator cuff, Achilles, or patellar tendons.8 Collagen is an important component in tendons, where is accounts for almost 75% of dry weight.42 As a result, nutritional and exercise interventions have been proposed as a means of inducing collagen synthesis to strengthen tendons and mitigate injury.3 Several studies have examined the impact of vitamin C supplementation on collagen synthesis and tendon health/healing.4, 43, 44 Vitamin C potentiates tendon healing by increasing the collagen fibril diameter and the number of fibroblasts at the injured site, as well as by promoting local angiogenesis.4 In addition, vitamin C has been shown to reduce peritendinous adhesions in an animal model.45
Animal studies have investigated the effect of vitamin C on healing of the Achilles tendon (AT).43, 44 A study by Omerğlu et al.43 tested the effect of high-dose vitamin C supplementation on AT healing in rats, and they found that vitamin C accelerated tendon healing. A study by Dincel et al.4 sought to determine the effect of high-dose vitamin C or hyaluronic acid (HA) on AT healing in rats, and they discovered that both vitamin C and HA, in isolation but more so in combination, led to higher tendon tensile strength measurements when compared to the control.4 In 2019, Souza et al.44 reported that vitamin C led to faster AT tissue organization, better organization of the collagen network, and improved ultimate tendon functionality compared to the control in rats. Although the beneficial effect of vitamin C on AT healing is generally supported by rat laboratory studies, randomized studies must be conducted on humans before vitamin C can be considered a legitimate nutritional intervention for patients following AT injury. Table 2 presents the findings of laboratory studies examining vitamin C's ability to improve AT healing.
| Study (first author, year) | Study design (population, testing groups) | Conclusion |
|---|---|---|
| Omeroğlu et al., 200943 | 42 Female Wistar rats w/cut Achilles tendons | High-dose vitamin C supplementation accelerated AT healing and increased collagen synthesis |
| Group A: Control | ||
| Group B: 150 mg of vitamin C once every 2 days for 21 days | ||
| Kang et al., 2017a,46 | 28 SMP-30 KO mice with induced Achilles tendonitis | Vitamin C improved the effect of adipose-derived stem cells (ASC) on AT healing |
| Group A: control | ||
| Group B: 1.5 g/L vitamin C in water | ||
| Group C: ASC injection | ||
| Group D: 1.5 g/L vitamin C in water + ASC injection | ||
| Gemalmez et al., 2018b,47 | 16 Male Wistar rats w/cut and sutured Achilles tendons | The trial supplement (mucopolysaccharide, vitamin C, collagen) did not improve collagen synthesis or tendon strength compared to the control |
| Group A: received daily placebo dose (tap water) via gastric gavage | ||
| Group B: received 2.4 mg of trial supplement daily via gastric gavage | ||
| Dincel et al., 2018c,4 | 48 Sprague-Dawley rats w/cut and sutured Achilles tendons | Vitamin C improved AT strength after healing |
| Group A: control | ||
| Group B: high-dose vitamin C intraperitoneally on alternate days | ||
| Group C: 0.075 ml/kg HA once at site of tendon repair | ||
| Souza et al., 2019d,44 | 18 Male Wistar rats w/cut Achilles tendons | Vitamin C led to faster AT healing |
| Group A: control | ||
| Group B: sutured + saline injection (0.9%) once every 2 days | ||
| Group C: sutured + vit C injection (30 mM) once every 2 days | ||
| Oliva et al., 2019e,48 | 24 Male Lewis rats w/cut and sutured Achilles tendons | Vitamin C and T3 accelerated AT healing |
| Group A: 50 μl phosphate-buffered saline (PBS) + 50 μg/ml vit C | ||
| Group B: PBS + 10−7 M T3 | ||
| Group C: PBS + 4 × 106 rBMSCs | ||
| Group D: PBS + Vit C + T3 | ||
| Group E: PBS + rBMSCs + Vit C | ||
| Group F: PBS + rBMSCs + T3 | ||
| Group G: PBS + rBMSCs + T3 + vit C | ||
| Turkmen et al., 2020f,49 | 40 Female Wistar rats w/cut and sutured Achilles tendons | Retendo (mucopolysaccharide, vitamin C, collagen) did not affect AT's ultimate tensile strength |
| Group A: control | ||
| Group B: 1.5 mg Retendo twice daily |
- Abbreviations: PBS, phosphate buffered saline; rBMSCs, rat bone marrow stem cells.
- a Study lasted 30 days.
- b Study lasted 3 weeks.
- c Study lasted 15 days for half, 30 days for half.
- d Study lasted 21 days.
- e Study lasted 30 days.
- f Study lasted 7, 14, 21, 28 days for a quarter of the rats.
Meanwhile, a study by Hung et al.50 sought to determine the effect of vitamin C on the incidence of finger flexor tendon (FFT) adhesion, a complication of FFT repair, in chickens following injury. The 45 chickens were divided into three groups and received a local injection of 50 μl of saline solution, 5 mg/ml vitamin C, or 50 mg/ml vitamin C after FFT injury was induced.50 Both vitamin C groups displayed less FFT adhesion at 6-week postinjury compared to the control.50 Lui et al.51 looked at the effect of tendon-derived stem cells (TSCs) treated with connective tissue growth factor and vitamin C on patellar tendon healing in rats. The study lasted 16 weeks and contained three groups: control, untreated TSCs group, and treated TSCs group.51 According to histology, ultrasound imaging, and biomechanical tests, the treated TSCs group exhibited faster and higher-quality tendon repair than the controls at 8 and 16 weeks.51
Finally, Morikawa et al.52 evaluated the effect of local injection of vitamin C on rotator cuff tendon degeneration in mice. In this 8-week study, mice with induced-rotator cuff degeneration were divided into two groups: the distilled water group and the vitamin C supplemented water group.52 They concluded that the vitamin C group exhibited decreased histologic changes compared with the control, and that vitamin C may prevent oxidative stress-induced rotator cuff degeneration.52
Laboratoryanimal studies principally support the use of vitamin C in isolation and in combination with other interventions, such as stem cells, HA, and magnesium, to improve tendon health/healing. In addition, one study linked the use of vitamin C enriched irrigation saline to better graft healing following anterior cruciate ligament (ACL) reconstruction. However, as mentioned before, high-quality clinical trials withhumans are necessary to justify vitamin C's effectiveness in this arena.I'm unsure what to add to “address local applications/clinical relevance.”
1.4 ACL reconstruction and knee arthroplasty
The ACL is the most commonly injured ligament in the knee, and it has been estimated that over 100,000 ACL reconstructive surgeries are conducted every year in the United States.53 Some studies suggest that ACL patients are at an increased risk of developing OA in the years following reconstruction.54, 55 In fact, OA is a leading cause of pain and disability in the United States, and the knee joint is the most commonly affected site.56 It has been suggested that vitamin C may have an effect on the progression of OA, due to its ability to protect chondrocytes through downstream signaling pathways, however evidence on this mechanism from laboratory studies is currently limited.12 Multiple ROS such as hydrogen peroxide (H2O2), hypochlorite ion, hydroxyl radical and superoxide anion have been implicated in the pathogenesis of OA by increasing the oxidative stress on human cartilage tissue.57 Increased oxidative stress has been associated with chondrocyte dysfunction and cartilage degeneration.57 The highly effective antioxidant properties of vitamin C are mainly responsible for its chondroprotective effect, according to the existing literature.12, 58
Recent studies have examined the role of vitamin C supplementation to potentiate patient outcomes following ACL reconstruction and total knee arthroplasty (TKA).7, 59, 61, 62 Barker et al.62 sought to determine the effect of preoperative vitamin C supplementation on inflammation following ACL reconstruction. A total of 20 patients undergoing ACL surgery were assigned to the antioxidant group, receiving 500 mg vitamin C and 200 IU of vitamin E twice daily, or the matching placebo.62 The study lasted 12 weeks, and the authors discovered that antioxidant supplementation offset decreases in plasma vitamin C concentrations and reduced the increase in a proinflammatory cytokine 90 min after surgery.62 Barker et al.62 also found that antioxidant supplementation led to greater 12-week strength improvement in the injured limb compared to the control, although the difference was not statistically significant. The authors cited insufficiently frequent blood draws following tourniquet removal during surgery as a credible limitation.62 Similar to the studies on AT healing, Cheng et al.63 examined the effect of vitamin C irrigation saline on graft healing in rats following ACL reconstruction. In this 6-week study, 114 rats were separated into four groups to receive 10 ml of either saline solution or vitamin C supplemented saline at doses of 3, 10, or 30 mg/ml.63 All vitamin C groups exhibited decreased inflammatory response Day 1 postoperation, and the 3 mg/ml group benefited from reduced graft deterioration and improved anterior-posterior knee laxity at 6-week postoperation in comparison to the control.63 The authors concluded that irrigation with saline and vitamin C was associated with reduced serum C-reactive protein, and better anterior posterior knee laxity postoperatively, compared to irrigation with saline alone. No study has examined the effect of vitamin C irrigation on the healing of ACL reconstruction graft in humans.
Similarly, some studies have evaluated the role of vitamin C supplementation in the outcomes of patients who undergo knee replacement surgery.7, 59, 61 Behrend et al.7 investigated whether perioperative vitamin C supplementation impacts knee range of motion and risk of arthrofibrosis (AF) following TKA. In this study, 95 patients undergoing TKA were divided into a placebo group, which received a daily placebo pill, and a vitamin C group, which received 100 mg of oral vitamin C daily.7 In both groups, the supplementation started on the day before the procedure and lasted for 50 days. The authors found that vitamin C serum concentration decreased following TKA in the placebo group, but not in the vitamin C group, and that patients that experienced drops greater than 30 μmol/L were more likely to develop AF at 1 year.7 Behrend et al.7 recognized that the study was limited by an insufficient sample size and a lack of measured biomarkers related to inflammation. Meanwhile, Shah et al.59 measured changes in vitamin C and inflammatory cytokine levels in TKA patients. Blood samples were collected from 10 patients pre- and postoperatively.59 The authors witnessed a significant increase in inflammation, but no significant changes in serum vitamin C levels following TKA.59 The small sample size and short study period were acknowledged as limitations.59
Vitamin C's role following TKA and ACL reconstruction is not fully understood and evidence to support its perioperative use in patients undergoing knee joint procedures remains very limited. With more research, vitamin C supplementation has the potential potentiate patient outcomes following ACL reconstruction and decrease the incidence of OA and AF. More human trials are needed to confirm the decline in vitamin C and its suggested benefits after TKA.
2 CONCLUSION
Vitamin C's involvement in molecular pathways related to bone and tendon regeneration represents a relatively new field of musculoskeletal research. Vitamin C supplementation has been associated with improved functional outcomes, decreased postoperative pain, and decreased risk of CRPS development following orthopedic procedures. Overall, there is need for high-quality human trials to confirm whether vitamin C can potentiate the outcomes of orthopaedic procedures and to determine optimal dosages and means of administration to experience its proposed benefits.
ACKNOWLEDGMENTS
The authors would like to acknowledge The Cappo Family Research Fund.
CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.
AUTHOR CONTRIBUTIONS
Bennet Oakes: conception, manuscript preparation; Ioanna K Bolia: manuscript preparation, manuscript review; Alexander E Weber: manuscript review, supervision, administration; Frank A Petrigliano: manuscript review, supervision, administration.
