Evaluating the Risk of a Fifth Metatarsal Stress Fracture by Measuring the Serum 25-Hydroxyvitamin D Levels

Abstract

Background:

The fifth metatarsal bone is a common site of stress fractures in soccer athletes. Although several endocrine risk factors for stress fractures have been proposed, the endocrine risks for fifth metatarsal (5-MT) stress fractures have not been evaluated.

Methods:

To evaluate the endocrine risks of fifth metatarsal stress fractures, we conducted a cumulative case-control study. The present study included 37 athletes, of which 18 had a history of a zone 2 or zone 3 fifth metatarsal stress fracture and 19 controls. We analyzed serum 25-hydroxyvitamin D (25-OHD), serum parathyroid hormone (PTH), as well as biochemical markers of bone turnover by univariate or multivariate analyses.

Results:

Logistic regression analyses adjusted for multiple confounders revealed that insufficient serum 25-OHD levels less than 30 ng/mL (odds ratio [OR], 23.3), higher serum PTH levels (OR, 1.01), or higher serum bone-specific isoform of alkaline phosphatase levels (OR, 1.10) rather than serum tartrate-resistant acid phosphatase 5b were associated with statistically significantly increased odds of 5-MT stress fractures. A postestimation calculation demonstrated that 25-OHD levels of 10 and 20 ng/mL were associated with 5.1 and 2.9 times greater odds for 5-MT stress fractures, respectively.

Conclusion:

25-OHD insufficiency was associated with an increased incidence of 5-MT stress fractures. This insight may be useful for intervening to prevent 5-MT stress fractures.

Level of Evidence:

Level III, case-control study.

Keywords

vitamin D fifth metatarsal stress fracture soccer athletes

Introduction

Stress fractures are a common overuse injury in military recruits and sports athletes. When microdamage accumulates, repetitive loading continues and bone remodeling cannot maintain the integrity of the bone, which may result in a stress fracture.^11,15 The sites of stress fractures are activity-related and often endemic to certain sports.^16,21 Although the overall incidence of stress fractures is relatively low in elite soccer players, the fifth metatarsal was reported to be the most common site of stress structures.⁷ Recently, operative treatment has been advocated^13,18,19 because of a high incidence of nonunion, delayed union, or refracture with nonoperative treatment.^4,6 Because the fifth metatarsal (5-MT) stress fracture resulted in 3 to 5 months’ absence from soccer play even after operative treatment, it is still considered a potentially career-ending injury.⁸

Several risk factors for stress fractures in soccer players such as gender, training program, playing surface, nutrition, and endocrine factors have been proposed.^1,22,26 Regarding the endocrine factors, several studies proposed risk factors in military recruits.^2,3,25 Although the incidence of stress fractures is dependent on the fracture sites, type of sport, and activity level of sport, the contribution of endocrine factors to 5-MT stress fractures in soccer athletes has not been elucidated.

The present study was aimed at evaluating the endocrine risks for a 5-MT stress fracture in university soccer players. Demographic factors and dietary calcium intake were recorded and serum 25-hydroxyvitamin (25-OHD), serum parathyroid hormone (PTH), and biomarkers of general health and bone turnover were evaluated. The results of these investigations were compared with those of soccer athletes, who had and had not experienced a 5-MT stress fracture, using univariate and multivariate analyses.

Methods

We conducted a cumulative case-control study in Japanese male university soccer athletes. We initially recruited 27 soccer athletes with a history of 5-MT stress fractures and 24 soccer athletes as controls. The control athletes were selected to match the frequency of training, race (Japanese), activity level, age (±5 years), gender, playing surface, and playing district. All athletes were members of university soccer club teams, which are classified as division 1 or 2 according to the Kanto University Football Association, and undergoing soccer training 5 or 6 days a week around the Kanto district, which is located at a northern latitude of 35 degrees in Japan. Their Tegner Activity Scales²³ were all 9 and training surfaces were third-generation artificial turf. No medication such as calcium and vitamin D supplementation was used. Blood samples were collected from the athletes at Juntendo University Nerima Hospital, Tokyo, Japan, between 2 and 3 pm in October or November. The history of a 5-MT stress fracture was based on the medical history and x-ray. We enrolled zone 2 or zone 3 5-MT stress fractures in the present study.⁹ Of 51 participants, 8 athletes with ongoing 5-MT stress fracture were excluded because the fracture had not fully healed and they had not returned to full sports activity. Six athletes were excluded because blood samples were not collected in the same season. The remaining 37 subjects were enrolled in this study. This study was approved by the ethics committee of the Juntendo University, and informed consent was obtained from all the participants.

The dietary calcium intake was estimated by using a validated food-frequency questionnaire (FFQ)¹² to determine the dietary intake of calcium and other nutrients relevant to the bone health of the adult Japanese population. This questionnaire has been well correlated with actual calcium intake.²⁴ All the blood samples were analyzed by an auto-analyzer (SRL Inc, Tokyo, Japan). Blood 25-OHD was measured by radioimmunoassay. PTH concentration was also measured by radioimmunoassay, specific for midregion of the PTH molecule.¹⁰ Blood bone-specific isoform of alkaline phosphatase (BAP) was measured by chemoluminescence enzyme immunoassay. Blood tartrate-resistant acid phosphatase 5b (TRACP5b) was measured by enzyme immunoassay. Baseline laboratory data included white blood cell count, hemoglobin, hematocrit, platelet count, C-reactive protein, lactate dehydrogenase, blood urea nitrogen, creatinine, aspartate transaminase, alanine transaminase, creatinine kinase, and inorganic phosphate.

Statistical Analysis

Descriptive statistics were performed to characterize the study groups and to examine case-control differences. In the univariate analysis, unpaired Student t test was used to assess differences in means. To adjust several confounders, we performed multivariate analyses by using a logistic regression analysis adjusted for age (continuous valuables), dietary calcium intake (continuous valuables), and body mass index (BMI) (continuous valuables) as potential confounders to obtain the odds ratio (OR) and the 95% confidence interval (95% CI). Serum 25-OHD status was classified into binary categories (<30 and ≥30 ng/mL) based on the International Osteoporosis Foundation statement.⁵ To predict odds of 5-MT stress fractures for various specific values, estimated ORs in different 25-OHD values at mean BMI (22.4) and age (21.2) were calculated from the postestimation table. As for serum PTH, TRACP5b, and BAP, we performed logistic regression analyses for continuous valuables. All P values were 2-sided and P values less than .05 were considered statistically significant. Statistical analyses were performed with Stata 13.0 (Stata Corp LP, College Station, TX).

Results

Table 1 summarizes the characteristics of all study subjects by 5-MT stress fracture group and control group. Eighteen of the 37 participants had a history of 5-MT stress fractures (5-MT stress fracture group) and 19 did not have the history (Control group). Both groups were similar for age, body height, body weight, BMI, and dietary calcium intake (Table 1). Three athletes, 1 in the 5-MT stress fracture group and 2 in the control group, had a history of lower leg fracture. Laboratory values are shown in Table 2. Both groups were also similar for baseline laboratory data (Table 2). Table 3 shows the results of the univariate analysis. Although the mean blood 25-OHD level in the 5-MT stress fracture group was lower, it was not significantly different, compared with that of the control group (P = .11). The mean serum PTH and BAP levels were significantly higher in the 5-MT stress fracture group, whereas the mean serum TRACP5b levels were similar in both groups (Table 3). The logistic regression analysis adjusted for age and BMI revealed that lower serum 25-OHD levels were associated with a significantly greater risk of 5-MT stress fractures (OR, 23.33, P = .01). A postestimation calculation of ORs for 5-MT stress fracture was completed by using coefficients from the logistic regression model, and specified 25-OHD values of 10, 20, 30, 40, and 50 ng/mL were associated with 5.1, 2.9, 1.7, 1.0, and 0.6 times greater odds, respectively. High serum PTH and BAP levels were also associated with a greater risk of 5-MT stress fractures (ORs, 1.0 and 1.1, respectively) (Table 4). This analysis also showed a linear trend for increased serum PTH levels with increased BMI (P = .049).

Table 1.

Characteristics of the Control and Case Groups.

	Control group (n = 18) (95% CI)	5-MT stress fracture group (n = 19) (95% CI)	P value^a
Age, y	21.1 (20.2-22.0)	21.4 (20.7-22.2)	.49
Body height, cm	174.1 (171.5-176.8)	175.3 (172.9-177.8)	.49
Body weight, kg	69.0 (66.4-71.6)	67.6 (65.0-70.2)	.45
Body mass index, kg/m²	22.8 (22.1-23.5)	22.0 (21.4-22.6)	.09
Dietary calcium intake, mg/d	441.1 (383.6-498.5)	476.3 (337.0-615.5)	.55
Prior lower leg fracture, n	2 (11.1%)	1 (5.3%)

Abbreviations: 5-MT, fifth metatarsal; CI, 95% confidence interval.

All P values are univariate and were derived from unpaired Student t test.

Table 2.

Serum Biochemical Data of the Control and Case Groups.

	Control group (n = 18) (95% CI)	5-MT stress fracture group (n = 19) (95% CI)	P value^a
WBC, μL⁻¹	6760 (5337-8143)	6339 (5676-7001)	.54
Hb, g/dL	15.3 (14.9-15.6)	15.3 (14.9-15.8)	.77
Hct, %	45.5 (44.6-46.5)	46.2 (44.9-47.5)	.39
Plt, ×10⁴/μL	24.2 (22.1-26.4)	24.8 (23.2-26.3)	.66
CRP, mg/dL	0.3 (0.0-0.5)	0.11 (0.1-0.2)	.19
LDH, U/L	222.2 (198.5-189.9)	212.8 (189.9-235.7)	.57
BUN, mg/dL	14.2 (12.5-15.9)	16.0 (14.4-17.5)	.12
Crea, mg/dL	0.83 (0.79-0.87)	0.86 (0.80-0.91)	.35
AST, U/L	26.3 (23.3-29.2)	27.4 (23.2-31.6)	.65
ALT, U/L	21.3 (17.5-25.1)	20.8 (15.2-26.3)	.88
CK, U/L	348.3 (273.1-423.6)	424.2 (236.9-611.5)	.47
Pi, mg/dL	3.8 (3.6-4.0)	3.9 (3.6-4.2)	.62

Abbreviations: 5-MT, fifth metatarsal; ALT, alanine transaminase; AST, aspartate transaminase; BUN, blood urea nitrogen; CI, confidence interval; CK, creatinine kinase; Crea, creatinine; CRP, C-reactive protein; Hb, hemoglobin; Hct, hematocrit; LDH, lactate dehydrogenase; Pi, inorganic phosphate; Plt, platelet count; WBC, blood cell count.

All P values are univariate and were derived from unpaired Student t test.

Table 3.

Univariate Results of the Association Between the Incidence of 5-MT Stress Fractures and Endocrine Factors.

	Control group (n = 18) (95% CI)	5-MT stress fracture group (n = 19) (95% CI)	P value^a
25-OHD, ng/mL	45.4 (38.2-52.7)	36.9 (28.4-45.4)	.11
<30, n	1	8
≥30, n	18	10
PTH, pg/mL	247.4 (193.8-300.9)	319.4 (280.3-358.5)	.04*
BAP, µg/L	28.6 (24.7-32.6)	36.1 (30.6-41.6)	.02*
TRACP5b, mU/dL	487.7 (421.9-553.6)	462.6 (384.5-540.6)	.60

Abbreviations: 25-OHD, 25 hydroxyvitamin D; 5-MT, fifth metatarsal; BAP, bone-specific isoform of alkaline phosphatase; CI, confidence interval; PTH, parathyroid hormone; TRAP5b, tartrate-resistant acid phosphatase 5b.

All P values are univariate and were derived from unpaired Student t test.

Significant difference, P value < .05.

Table 4.

Multivariate Results of the Association Between the Incidence of 5-MT Stress Fractures and Endocrine Factors.

	Adjusted OR^a (95% CI)	P values
25-OHD, ng/mL
<30	23.3 (2.06-264.17)	.01*
10	5.1^b
20	2.9
30	1.7
40	1.0
50	0.6
PTH	1.0 (1.00-1.02)	.04*
BAP	1.1 (1.02-1.21)	.02*
TRACP5b	1.0 (0.99-1.00)	.94

Abbreviations: 25-OHD, 25 hydroxyvitamin D; 5-MT, fifth metatarsal; BAP, bone-specific isoform of alkaline phosphatase; CI, confidence interval; OR, odds ratio; PTH, parathyroid hormone; TRAP5b, tartrate-resistant acid phosphatase 5b.

Logistic regression analysis adjusted for age, body mass index, and dietary calcium intake as continuous variable.

Estimated ORs for 5-MT stress fractures at specified serum 25-OHD values from postestimation calculation.

Significant difference, P value < .05.

Discussion

Vitamin D has a central role in bone health and mineral homeostasis, affecting the intestinal absorption of calcium and phosphate. The most important finding of this study was that vitamin D insufficiency in university elite soccer players was associated with 23.3 times greater odds of having a 5-MT stress fracture. We also calculated estimated ORs for 5-MT stress fractures at specified 25-OHD values. To our knowledge, this is the first report demonstrating the association between an incidence of 5-MT stress fractures and serum vitamin D levels, serum PTH levels, as well as bone turnover levels.

Vitamin D status is known to vary widely among populations and races. However, this information on Asian soccer athletes is highly limited. According to the International Osteoporosis Foundation statement, vitamin D insufficiency is defined as serum 25-OHD levels <30 or <20 ng/mL.⁵ Mithal et al reviewed population-based reports regarding vitamin D status in 6 different regions in the world, and most studies used the serum 25-OHD level of 30 ng/mL as the cut-off in Asian regions.¹⁷ Consequently, we defined <30 ng/mL as vitamin D insufficiency. In this study, 8 athletes had insufficient serum 25-OHD levels in the 5-MT stress fracture group, whereas only 1 athlete had an insufficient level in the control group (Table 3). Because serum 25-OHD levels are reported to vary more than 30% between winter and summer in nonobese young men,¹⁴ the incidence of vitamin D insufficiency is expected to increase in winter.

We also showed that higher serum PTH levels were associated with a history of 5-MT stress fracture by multivariate analysis. High serum PTH levels are shown to be a risk factor for stress fractures in military recruits in a prospective cohort study.²⁵ PTH stimulates the renal expression of 1-alpha hydroxylase, which converts an inactive form of 25-OHD to its active form of 1,25-(OH)₂D. A number of reports have shown an inverse correlation between serum PTH and 25-OHD levels in young adolescents.²⁷ In the present study, although this correlation was not significant, the tendency was observed by multivariate analysis (r = −0.05, P = .07, data not shown) adjusted for age, BMI, and dietary calcium intake. High serum PTH levels in the 5-MT stress fracture group could be explained by secondary feedback in response to vitamin D insufficiency.

TRACP5b, mainly expressed by osteoclasts and used as a marker of bone resorption, was not associated with the incidence of 5-MT stress fractures in the present study. The mean TRACP5b levels of both groups (462.6 for the 5-MT stress fracture group and 487.7 mU/dL for the control group) were relatively high, compared with the reports on the Japanese young men population, in which mean serum 25-OHD levels were reported from 340 to 360 mU/dL.²⁰ High serum levels of BAP, which is known as a marker of bone formation, were observed in the 5-MT stress fracture group by multivariate analysis. Because bone remodeling coupled with bone formation and bone absorption is an essential process to fracture healing, persistent bone remodeling expends vitamin D in the body, which may result in a 5-MT stress fracture.

Our study has several strengths. First, the cumulative case-control design has advantages over other designs, especially a cohort study. Case-control studies offer greater statistical power to the study of a relatively rare injury such as a 5-MT stress fracture and allow rapid and cost-effective study performance. Second, we selected the control from a matched population in terms of age, geography (the Kanto district in Japan, located at a northern latitude of 35 degrees), race (Japanese), gender (male), demography (elite university soccer athletes), and training on the same third-generation artificial turf. Third, we included potential confounders that could influence vitamin D status in the regression models. Several factors including age, BMI, season, gender, dietary calcium intake, sun exposure time, and race has been reported to influence vitamin D.¹⁴ Among these potential confounders, the exact sun exposure time of each athlete was not available in this study. However, we assume that the effects on relative risk were limited because all the athletes were trained in the field 5 to 6 days a week in the same district and all the samples were collected in the same season and year.

On the other hand, the present study has some limitations. First, we were only able to enroll a relatively small number of subjects due to the low incidence of 5-MT stress fractures, which inevitably limited the precision of our estimates of relative risk. Second, inherent selection bias was attributed to the method used in recruiting the control in this study, though controls with similar background were provided. Third, we could not prove the causality of an association between vitamin D insufficiency and incidence of 5-MT stress fractures in elite soccer athletes because this study was not designed prospectively. Because several studies have demonstrated that vitamin D insufficiency ended up with a higher overall incidence of stress fractures, vitamin D insufficiency seems to lead to 5-MT stress fractures.

Conclusion

Our study demonstrated that insufficiency levels of 25-OHD vitamin D were associated with an increased incidence of 5-MT stress fractures in elite university soccer players. One future challenge will be to evaluate whether there is an improvement in the incidence of 5-MT stress fractures by vitamin D supplementation in our athletic population. This could provide a safe, easy, and inexpensive intervention that could improve general bone health in young athletes.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Bennell

Malcolm

Wark

Brukner

. Models for the pathogenesis of stress fractures in athletes. Br J Sports Med. 1996;30:200-204.

Burgi

Gorham

Garland

. High serum 25-hydroxyvitamin D is associated with a low incidence of stress fractures. J Bone Miner Res. 2011;26:2371-2377.

Chatzipapas

Drosos

Kazakos

Tripsianis

Iatrou

Verettas

. Stress fractures in military men and bone quality related factors. Int J Sports Med. 2008;29:922-926.

Clapper

O’Brien

Lyons

. Fractures of the fifth metatarsal: analysis of a fracture registry. Clin Orthop Relat Res. 1995;315:238-241.

Dawson-Hughes

Mithal

Bonjour

. IOF position statement: vitamin D recommendations for older adults. Osteoporos Int. 2010;21:1151-1154.

DeLee

Evans

Julian

. Stress fracture of the fifth metatarsal. Am J Sports Med. 1983;11:349-353.

Ekstrand

Torstveit

. Stress fractures in elite male football players. Scand J Med Sci Sports. 2012;22:341-346.

Ekstrand

van Dijk

. Fifth metatarsal fractures among male professional footballers: a potential career-ending disease. Br J Sports Med. 2013;47:754-758.

Fetzer

Wright

. Metatarsal shaft fractures and fractures of the proximal fifth metatarsal. Clin Sports Med. 2006;25:139-150.

10.

Fukase

Fujita

Matsumoto

. Clinical studies using a highly sensitive radioimmunoassay for mid-region and carboxy terminus of parathyroid hormone in normal, hypo- and hypercalcemic states. Nihon Naibunpi Gakkai Zasshi. 1989;65:807-827.

11.

Hanyu

Wehbi

Hayata

. Anabolic action of parathyroid hormone regulated by the beta2-adrenergic receptor. Proc Natl Acad Sci U S A. 2012;109:7433-7438.

12.

Ishii

Ito

Mizutani

. Actual practice of nutritional education for patients with osteoporosis. Clin Calcium. 2005;15:1523-1528.

13.

Kelly

Glisson

Fink

Easley

Nunley

. Intramedullary screw fixation of jones fractures. Foot Ankle Int. 2001;22(7):585-589.

14.

Lagunova

Porojnicu

Lindberg

Hexeberg

Moan

. The dependency of vitamin D status on body mass index, gender, age and season. Anticancer Res. 2009;29:3713-3720.

15.

Zhang

Chen

Wang

. Radiographic and histologic analyses of stress fracture in rabbit tibias. Am J Sports Med. 1985;13:285-294.

16.

Maquirriain

Ghisi

. The incidence and distribution of stress fractures in elite tennis players. Br J Sports Med. 2006;40:454-459; discussion 459.

17.

Mithal

Wahl

Bonjour

. Global vitamin D status and determinants of hypovitaminosis D. Osteoporos Int. 2009;20:1807-1820.

18.

Mologne

Lundeen

Clapper

O’Brien

. Early screw fixation versus casting in the treatment of acute jones fractures. Am J Sports Med. 2005;33:970-975.

19.

Nagao

Saita

Kameda

. Headless compression screw fixation of jones fractures: an outcomes study in Japanese athletes. Am J Sports Med. 2012;40:2578-2582.

20.

Nishizawa

Inaba

Ishii

. Reference intervals of serum tartrate-resistant acid phosphatase type 5b activity measured with a novel assay in japanese subjects. J Bone Miner Metab. 2008;26:265-270.

21.

Ranawat

Dowell

Heywood-Waddington

. Stress fractures of the lumbar pars interarticularis in athletes: a review based on long-term results of 18 professional cricketers. Injury. 2003;34:915-919.

22.

Sundgot-Borgen

Torstveit

. The female football player, disordered eating, menstrual function and bone health. Br J Sports Med. 2007;41(suppl 1):i68-i72.

23.

Tegner

Lysholm

. Rating systems in the evaluation of knee ligament injuries. Clin Orthop Relat Res. 1985;198:43-49.

24.

Uenishi

Ishida

Nakamura

. Development of a simple food frequency questionnaire to estimate intakes of calcium and other nutrients for the prevention and management of osteoporosis. J Nutr Sci Vitaminol (Tokyo). 2008;54:25-29.

25.

Valimaki

Alfthan

Lehmuskallio

. Risk factors for clinical stress fractures in male military recruits: a prospective cohort study. Bone. 2005;37:267-273.

26.

Warden

Creaby

Bryant

Crossley

. Stress fracture risk factors in female football players and their clinical implications. Br J Sports Med. 2007;41(suppl 1):i38-i43.

27.

Yoshimura

Muraki

Oka

. Profiles of vitamin D insufficiency and deficiency in Japanese men and women: association with biological, environmental, and nutritional factors and coexisting disorders: The ROAD study. Osteoporos Int. 2013;24:2775-2787.