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Objectives: To determine the relationship between serum 25- hydroxyvitamin D [25(OH)D] levels and the likelihood of post- operative complications and fracture ...

ORIGINAL ARTICLE

Do 25-Hydroxyvitamin D Levels Correlate With Fracture Complications? Blake M. Bodendorfer, MD,* James L. Cook, DVM, PhD,† Daniel S. Robertson, MD,‡ Gregory J. Della Rocca, MD, PhD,† David A. Volgas, MD,† James P. Stannard, MD,† and Brett D. Crist, MD†

Objectives: To determine the relationship between serum 25-

Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

hydroxyvitamin D [25(OH)D] levels and the likelihood of postoperative complications and fracture reoperation rate in orthopaedic trauma patients receiving vitamin D and calcium supplementation.

(J Orthop Trauma 2016;30:e312–e317)

Design: Retrospective case series. Setting: Level I trauma center, Midwestern United States. Patients: All orthopaedic trauma patients—18 years or older—over a 20-month period were included with available initial and repeat 25 (OH)D serum levels. In total, 201 patients met inclusion criteria.

Intervention: All patients received 1000 IU of vitamin D3 and 1500 mg of calcium daily. Vitamin D deficient and insufficient patients also received 50,000 IU of ergocalciferol (vitamin D2) weekly until 25(OH)D levels normalized or fractures healed.

Main Outcome Measurements: fracture complications and 25 (OH)D levels.

Results: Fifteen patients experienced postoperative healing complications. There was no significant difference between initial (P = 0.92) or repeat (P = 0.91) 25(OH)D levels between patients with and without fracture healing complications. Twenty-eight patients required repeat orthopaedic surgery. There was no significant difference between initial (P = 0.62) or repeat (P = 0.18) 25(OH)D levels between patients who did or did not require repeat orthopaedic surgery. There was no significant difference between initial (P = 0.66) or repeat (P = 0.89) 25(OH)D levels between patients who did or did not require nonorthopaedic surgery. Conclusions: Serum 25(OH)D levels did not significantly affect the likelihood of fracture healing complications requiring surgery or any nonorthopaedic injury-related surgery. Key Words: vitamin D deficiency, musculoskeletal trauma, fracture healing Accepted for publication May 26, 2016. From the *Department of Orthopaedic Surgery, MedStar Georgetown University Hospital, Washington, DC; †Department of Orthopaedic Surgery, University of Missouri, School of Medicine, Columbia, MO; and ‡Department of Orthopedics, Mid-Atlantic Permanente Medical Group, Largo, MD. The authors report no conflict of interest. Reprints: Brett D. Crist, MD, Department of Orthopaedic Surgery, University of Missouri, One Hospital Drive, N119, Columbia, MO 65212 (e-mail: [email protected]). Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/BOT.0000000000000639

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INTRODUCTION Vitamin D regulates several areas of human physiology including cardiac, immune, digestive, and musculoskeletal systems.1 Vitamin D deficiency is associated with secondary hyperparathyroidism, increased bone turnover and bone loss, and mineralization defects.2 Low vitamin D levels are associated with hip fractures3–5 and nonunions.6–9 The American Geriatrics Society and the National Osteoporosis Foundation currently recommend that older adults maintain a minimum serum 25-hydroxyvitamin D [25(OH)D] concentration of 30 ng/mL to reduce the incidence of fractures.10,11 However, there is significant debate in the literature regarding vitamin D supplementation for fracture prevention. Some trials suggest a dose-dependent benefit,12–17 others suggest benefit with the addition of calcium,18,19 others suggest benefit in only institutionalized patients,20–22 others have shown no significant benefit,23–26 and 1 trial even suggested high-dose supplementation was harmful.27 Orthopaedic surgeons frequently prescribe combined calcium and vitamin D supplementation to patients with fractures to promote fracture healing; however, this supplementation is based on limited data to suggest its efficacy.28–35 In this study, we retrospectively reviewed patients with 25(OH)D levels available over a 20-month period. Approximately 77% of them had either vitamin D deficiency or insufficiency as defined by Hollis et al.36,37 Because of this and the associated health implications, our center implemented a supplementation protocol for patients during the fracture-healing period as previously described.38 The purpose of this study was to determine the relationship between serum 25(OH)D levels and the likelihood of postoperative complications requiring operative management for fracturerelated surgery in orthopaedic trauma patients receiving vitamin D and calcium supplementation. We hypothesized that initial and repeat 25(OH)D levels have an inverse relationship with fracture healing complications.

PATIENTS AND METHODS After Institutional Review Board approval, a retrospective review was performed of all orthopaedic trauma patients J Orthop Trauma  Volume 30, Number 9, September 2016

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J Orthop Trauma  Volume 30, Number 9, September 2016

with a fracture at our American College of Surgeons verified level I university trauma center from January 1, 2009 to September 30, 2010. Patient inclusion criteria were age 18 years or older, a fracture managed by 1 of 4 attending orthopaedic trauma surgeons, an available serum 25(OH)D level within 2 weeks of injury (before supplementation) and an available repeat 25(OH)D level a minimum of 8 weeks after the initial serum level. Two hundred and one orthopaedic trauma patients with fractures (mean age of 58 years at surgery, range = 18–98 years) met the inclusion criteria and underwent our vitamin D and calcium supplementation protocol as previously described (Fig. 1).38 Supplementation was started as soon as possible given patients’ NPO status in the perioperative period. All patients were prescribed 1000 IU of vitamin D3 and 1500 mg of calcium daily based on previously published supplementation data.39 Patients with serum 25(OH)D deficiency or insufficiency40 also received an 8-week regimen of 50,000 IU of ergocalciferol (D2) weekly until 25(OH)D levels were normalized (serum 25(OH)D . 32 ng/mL) or fracture healing was demonstrated, which Hathcock et al41 demonstrated as a safe and effective supplementation protocol. Patients with either a history of hypercalcemia or at risk for hypercalcemia were excluded from the study. Standard clinic follow-up was performed at 2-, 6-, and 12-week visits and then every 2–3 months until fracture healing. Follow-up serum 25(OH)D levels were encouraged after the 8-week course of ergocalciferol per our protocol. Serum 25(OH)D levels were measured because this inactive form is the most accurate measurement of systemic

Do 25-Hydroxyvitamin D Levels Correlate With Fracture Complications?

vitamin D levels.40 No compliance monitoring for taking the supplements was performed except for questioning at each follow-up appointment and reenforcement of the importance of the supplements. Patients were also given a handout regarding rationale for supplementation.

Statistical Methods Descriptive statistics including the mean, median, and mode were calculated. Data were pooled and means 6 standard deviations determined for initial and repeat 25(OH)D levels and for deficient (less than 20 ng/mL), insufficient (between 20 and 32 ng/mL), and normal (32 ng/mL or greater) 25(OH)D level cohorts. Data were compared for significant differences using t test (initial vs. repeat levels) or one-way ANOVA (levels among cohorts). The number of patients within each 25(OH)D level cohort was determined for initial levels, repeat levels, patients experiencing healing complications, patients undergoing repeat orthopaedic surgeries, and patients undergoing nonorthopaedic surgeries. Proportions in each cohort were compared for significant differences using Fisher exact test or x2 analyses. Significance was set at P , 0.05.

Definitions A healing complication was defined as nonunion, malunion, delayed union, wound problem, or infection that required operative management. Vitamin D deficiency was defined as serum 25(OH)D level less than 20 ng/mL. Vitamin D insufficiency was defined as serum 25(OH)D level between

FIGURE 1. Flowchart breakdown of inclusion/exclusion criteria for study subjects. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

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20 and 32 ng/mL.41 By comparison, the Institute of Medicine and the Endocrine Society define deficiency as less than 20 ng/ mL and insufficiency as between 21 and 29 ng/mL.42

RESULTS Two hundred and one orthopaedic trauma patients met the inclusion criteria and underwent our vitamin D and calcium supplementation protocol.38 The mean time between initial and repeat 25(OH)D levels was 211 days. The mean initial 25(OH)D level for all 201 orthopaedic trauma surgery patients was 22.9 6 0.7 ng/mL. Initially, 81 (40.3%) patients were deficient, 88 patients (43.8%) were insufficient, and 32 patients (15.9%) had normal levels. After implementing our supplementation protocol, 22 patients (10.9%) were deficient, 78 patients (38.8%) were insufficient, and 101 patients (50.2%) had normal levels (Table 1). The mean repeat level after supplementation was 33.0 6 0.9 ng/mL, which was a statistically significant increase (P , 0.0001) (Table 2). Of the patients who had normal initial levels, 84% maintained their normal level, whereas 16% became insufficient or deficient. Of the insufficient group, 54.5% improved to normal and 8% became deficient. Of the deficient group, 26% remained deficient and 74% improved to insufficient. No complications were noted related to the supplementation therapy. Of the 201 fracture patients, 15 patients had fracture healing complications. These complications included infection (12/201, 6%), nonunion (6/201, 3%), osteomyelitis (3/201, 1.5%), wound dehiscence (3/201, 1.5%), malunion (1/201, 0.5%), and joint contracture (1/201, 0.5%). The 6 nonunions were as follows: 4 distal femurs, 1 tibial diaphysis, and 1 tibial plafond. The malunion occurred in the tibial diaphysis. There was no significant difference between initial (P = 0.9) or repeat (P = 0.9) 25(OH)D levels between patients with and without fracture healing complications. There were no significant differences in likelihood of fracture healing complications based on initial (P . 0.4) or repeat 25(OH)D levels (P . 0.1). We found that 28 of these 201 patients required repeat orthopaedic surgery. There was no significant difference between initial (P = 0.6) or repeat (P = 0.2) 25(OH)D levels between patients that did or did not require repeat orthopaedic surgery. There were no significant differences in likelihood for repeat orthopaedic surgery based on initial (P . 0.2) or repeat 25(OH)D levels (P . 0.4). Of the 28 patients that required repeat orthopaedic surgery, 15 had fracture healing complications and 13 did not. There was no significant difference between initial (P = 0.5) or repeat (P = 0.2) vitamin D levels between patients with and without fracture healing complications in this

TABLE 1. Response to Vitamin D Supplementation in Orthopaedic Trauma Patients

Deficient (,20 ng/mL) Insufficient ($20 to ,32 ng/mL) Normal ($32 ng/mL)

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Initial Vitamin D

Repeat Vitamin D

Level (%)

Level (%)

81 (40.3) 88 (43.8) 32 (15.9)

22 (10.9) 78 (38.8) 101 (50.2)

TABLE 2. Outcomes for Orthopaedic Trauma Patients Supplemented With Vitamin D

All patients (201) Required repeat orthopaedic surgery (28) Did not require repeat orthopaedic surgery (173) P value Had fracture healing complications (15) Did not have fracture healing complications (186) P value Had fracture healing complications and repeat orthopaedic surgery (15) Did not have fracture healing complications and had repeat orthopaedic surgery (13) P value Required repeat orthopaedic surgery and nonorthopaedic surgery (6) Required repeat orthopaedic surgery but did not require nonorthopaedic surgery (22) P value Required nonorthopaedic surgery (26) Did not require nonorthopaedic surgery (175) P value

Initial Vitamin D (ng/mL) 6 SD

Repeat Vitamin D (ng/mL) 6 SD

P

22.8 6 9.9 22.7 6 9.1

33.0 6 12.7 35.1 6 15.8

,0.0001 0.0009

22.8 6 10.1

32.6 6 12.1

0.0001

0.62 22.5 6 8.7

0.18 33.3 6 14.7

0.0253

22.8 6 10.0

32.9 6 12.6

0.0001

0.92 22.5 6 8.7

0.91 33.3 6 14.7

0.0253

22.9 6 9.7

37.1 6 16.8

0.0176

0.50 20.2 6 8.6

0.20 35.0 6 8.4

0.0201

23.4 6 9.1

35.1 6 17.3

0.0090

0.46 21.9 6 9.4

0.99 32.7 6 10.1

0.0002

22.8 6 10.1

33.1 6 13.0

0.0001

0.66

0.89

subgroup analysis. There were no significant differences in likelihood of fracture healing complications based on initial (P . 0.5) or repeat 25(OH)D levels (P . 0.6) in this subgroup. Of the 28 patients that required repeat orthopaedic surgery, 6 also required nonorthopaedic surgery. There was no significant difference between initial (P = 0.5) or repeat (P = 1) 25(OH)D levels between patients that did or did not require nonorthopaedic surgery. There were no significant differences in likelihood of requiring nonorthopaedic surgery based on initial (P . 0.1) or repeat 25(OH)D levels (P . 0.4). Of the 201 fracture patients, a total of 26 required nonorthopaedic surgeries. There was no significant difference between initial (P = 0.4) or repeat (P = 0.3) 25(OH)D levels between patients that did or did not require nonorthopaedic Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

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J Orthop Trauma  Volume 30, Number 9, September 2016

surgery. There were no significant differences in likelihood of requiring nonorthopaedic surgery based on initial (P . 0.1) or repeat 25(OH)D levels (P . 0.1). To address age and 25(OH)D levels, patients younger than 65 years of age (134 of 201 patients) had mean initial 25 (OH)D levels of 23.2 ng/mL and repeat levels of 33.3 ng/mL. Patients 65 years of age and older (67 of 201 patients) had mean initial 25(OH)D levels of 22.0 ng/mL and repeat levels of 32.3 ng/mL. There were no significant differences between initial 25(OH)D levels (P = 0.4218) or repeat 25(OH)D levels (P = 0.6292) when comparing these age groups. To address differences between patients that did and did not require repeat orthopaedic surgery, 12 of the 28 (42.9%) patients requiring repeat orthopaedic surgery were initially vitamin D deficient and another 12 patients (42.9%) were vitamin D insufficient. Comparatively, 69 of the 173 patients (39.9%) not requiring repeat orthopaedic surgery were initially vitamin D deficient and another 76 patients (43.9%) were vitamin D insufficient. The differences between these are not statistically significant.

DISCUSSION Although using a safe and effective vitamin D supplementation protocol,38,41 our group was able to monitor for fracture healing and healing complications in a relatively large orthopaedic trauma population compared with previously published literature.8,38,43–45 This supplementation protocol was initiated in response to a high prevalence of vitamin D deficiency and insufficiency in our patients.37 In our study, initial and repeat 25(OH)D levels did not predict or correlate with fracture healing complications (power of 0.81 for initial levels, 0.80 for repeat levels), reoperation (power of 0.14 for initial levels, 0.20 for repeat levels), or the need for nonorthopaedic injury-related surgery (power less than 0.10 for initial and repeat levels). Previous work has associated low vitamin D levels with increased bone loss, increased bone turnover, fragility fractures, and tibial nonunions.2–5,45 Many orthopaedic surgeons prescribe vitamin D and calcium supplementation to fracture patients, particularly in elderly patients after fragility fractures46–51; no human studies however have demonstrated increased fracture healing with vitamin D supplementation. Animal studies have shown a potential role for vitamin D in fracture healing.28,29 One study demonstrated an increase in the risk of conversion to hip arthroplasty after internal fixation of femoral neck fracture during the winter,30 thought to be due to seasonal variation of serum vitamin D levels.31–33 Another study demonstrated lower serum levels of 25(OH)D in patients during the curative period of tibial and femoral shaft fractures,34 but this was disputed by another cohort study.35 There is evidence of patients with nonunion having a lower serum vitamin D levels and correcting that has been proposed as part of the treatment protocol.6–9 Because of this and the literature regarding the interaction between the metabolic and endocrine systems with bone biology, many traumatologists have supplemented fracture patients with vitamin D and calcium. Although these data and the efforts to prevent fracture healing complications have so recently been initiated, there is little long-term data on outcomes for fracture patients Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Do 25-Hydroxyvitamin D Levels Correlate With Fracture Complications?

receiving vitamin D and calcium supplementation. However, Brinker et al8 demonstrated a possible link between correcting metabolic and endocrine abnormalities and achieving bony union in patients that coincidently presented with recalcitrant fracture nonunions. On the other hand, 2 small (sample sizes of 15 and 35) retrospective case–control studies showed no difference in the prevalence of vitamin D deficiency in patients with nonunion.52,53 To our knowledge, this study is the largest of its kind to analyze fracture healing complications in patients supplemented with vitamin D and calcium, showing that 25(OH)D levels have no correlation with an adequately powered sample size. The limitations of this study include its retrospective design, a relatively small sample size (but the largest of its kind to date and the first with adequate power), reliance on supplementation compliance, and seasonal variation in vitamin D levels. Although the protocol instituted during that time was to get a repeat serum level, out of the 889 patients that were part of the initial patient pool, only 201 met inclusion criteria. This was mainly due to patients being lost to follow-up or from a great distance that caused them to follow up at an outside facility. All patients were prescribed daily vitamin D and calcium supplementation in addition to weekly ergocalciferol if they were vitamin D deficient or insufficient. Although we saw a significant rise in 25(OH)D levels, medication adherence was not monitored by pill counts. At each follow-up appointment, patients were asked if they were taking their medications documented in the medical record and the patients were given a handout on the importance of supplementation. If they were not taking the supplements as prescribed, they were encouraged to comply. Stricter protocols could have been implemented to increase the accuracy of the supplementation protocol. Reviewing the literature, compliance to medication regimens are estimated to be 79% 6 14% with once-daily dosing as this study used.54 It has been established that vitamin D levels fluctuate with the time of year.31–33 However, over the 20month initial capture period, there did not appear to be any significant differences that were found in our initial evaluation of the 889 patients. Seasonal variation in 25(OH)D levels has been noted to only be 3 ng/mL (26.8 ng/mL in the winter and 29.8 in the summer). This may be statistically significant but does not appear to be practically significant.55 There is no evidence in this paper that this does not fall within the standard deviation of testing variance. Lastly, our 25(OH)D levels were drawn an average of 211 days after the initial injury. It should be emphasized that serum 25(OH)D reaches a plateau concentration at approximately 1 month within the range of our supplementation protocol.56 Therefore, 25(OH)D levels from the fracture healing period (approximately 6–8 weeks) would unlikely vary significantly from the reported levels at 30 weeks. This study demonstrates that calcium and vitamin D supplementation may not have a large impact on fracture healing in orthopaedic trauma patients. Additional research should be performed to determine the physiological role of vitamin D in fracture healing. Future studies should prospectively evaluate treatment regimens, including varying vitamin D3 and D2 supplementation, with stricter compliance www.jorthotrauma.com |

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J Orthop Trauma  Volume 30, Number 9, September 2016 47. Bogoch ER, Elliot-Gibson V, Beaton DE, et al. Effective initiation of osteoporosis diagnosis and treatment for patients with a fragility fracture in an orthopaedic environment. J Bone Joint Surg Am. 2006;88: 25–34. 48. Rozental TD, Makhni EC, Day CS, et al. Improving evaluation and treatment for osteoporosis following distal radial fractures. A prospective randomized intervention. J Bone Joint Surg Am. 2008;90:953–961. 49. Bunta AD. It is time for everyone to own the bone. Osteoporos Int. 2011; 22:477–482. 50. Ekman EF. The role of the orthopaedic surgeon in minimizing mortality and morbidity associated with fragility fractures. J Am Acad Orthop Surg. 2010;18:278–285. 51. Gass M, Dawson-Hughes B. Preventing osteoporosis-related fractures: an overview. Am J Med. 2006;119:S3–S11.

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Do 25-Hydroxyvitamin D Levels Correlate With Fracture Complications? 52. Haining SA, Atkins RM, Guilland-Cumming DF, et al. Vitamin D metabolites in patients with established non-union of fracture. Bone Miner. 1986;1:205–209. 53. Boszczyk AM, Zakrzewski P, Pomianowski S. Vitamin D concentration in patients with normal and impaired bone union. Pol Orthop Traumatol. 2013;78:1–3. 54. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther. 2001;23: 1296–1310. 55. Bee CR, Sheerin DV, Wuest TK, et al. Serum vitamin D levels in orthopaedic trauma patients living in the northwestern United States. J Orthop Trauma. 2013;27:e103–106. 56. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999;69:842–856.

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