Advertisement

International Orthopaedics

, Volume 42, Issue 7, pp 1545–1549 | Cite as

Imbalanced bone turnover markers and low bone mineral density in patients with osteonecrosis of the femoral head

  • Lulu Tian
  • Seung-Hoon Baek
  • JinAn Jang
  • Shin-Yoon Kim
Original Paper

Abstract

Purpose

There have been few studies investigating the cumulative effect of individual factors related to bone metabolism on the systemic balance between bone formation and resorption in patients with osteonecrosis of the femoral head (ONFH). We investigated bone mineral density (BMD) of lumbar spine and bone turnover markers that reflect systemic bone metabolism.

Methods

Two-hundred twenty patients with ONFH were matched to 220 healthy subjects according to age, gender, and body mass index. ONFH patients were divided into steroid-induced (18%), alcoholic (21%), and idiopathic ONFH (61%) and subgroup analysis was performed to exclude the effect of steroid and malnutrition on bone metabolism. We compared lumbar spine bone mineral density (BMD) between groups and measured serum bone-specific alkaline phosphatase (BALP) and urinary deoxypyridinoline/creatinine (Dpd/Cr) ratio.

Results

Logistic regression analysis revealed low spine BMD was significantly associated with each subgroup of ONFH when compared with that of the control group (odds ratio of 2.27, 4.24, and 1.86 in alcoholic, steroid, and idiopathic ONFH, respectively). The mean value of serum BALP (27.02 U/L) was within the normal reference range while average urine Dpd/Cr ratio (6.24 nM/mM) increased in ONFH group when compared with respective reference range.

Conclusion

Spine BMD decreased and urinary Dpd/Cr ratio increased in patients with non-traumatic ONFH. Further studies will be necessary to identify whether non-traumatic ONFH is merely a regional disease confined to the femoral head or may affect systemic bone metabolism.

Keywords

Osteonecrosis of femoral head Bone mineral density Bone turnover makers Bone-specific alkaline phosphatase Deoxypyridinoline/creatinine ratio 

Introduction

Osteonecrosis of the femoral head (ONFH) is defined as the death of osteocytes and bone marrow cells due to ischemia. Although a variety of conditions including trauma, use of corticosteroid, consumption of alcohol, hyperlipidemia, fat emboli, some autoimmune diseases, and increased intravascular coagulation have been proposed to explain the pathogenesis of ONFH, the precise mechanism is still unclear [1, 2, 3]. Regardless of the aetiology, the final pathway of ONFH is collapse of the femoral head [4].

Repair capacity and bone remodeling are important in the progression and severity of ONFH [5]. Bone remodeling is a physiological process comprised of two balanced phases: bone resorption by osteoclasts followed by de novo bone formation by osteoblasts [6]. There have been conflicting reports regarding the osteogenic differentiation capacity and the gene expression of individual factors regulating bone formation and remodeling of bone marrow stromal cells (BMSCs) in patients with ONFH. Some studies reported decreased osteogenic differentiation capacity of BMSCs [7, 8] and depressed individual osteogenic gene expression such as Runx2, vascular endothelial growth factor (VEGF), bone morphogenetic protein 2 (BMP-2), and osteocalcin [9, 10] whereas others have shown no alteration in osteogenic capacity or increased gene expression of BMP-2, BMP-7, and Runx2 in patients with ONFH [11, 12]. However, there have been few studies investigating the cumulative effect of these individual variations on the systemic balance between bone formation and resorption in patients with ONFH. Moreover, BMSCs or histopathologic samples in the previous studies were isolated or obtained from proximal femur [7, 11] or iliac crest [8, 9, 10, 12] which was close to ONFH lesion and, thus, might not be appropriate for reflecting systemic bone metabolism.

Therefore, we hypothesized that the balance of systemic bone metabolism is disrupted in patients with ONFH when compared with that of healthy control, and investigated bone mineral density (BMD) of lumbar spine and the bone turnover markers (BTMs) that reflect systemic bone metabolism.

Materials and methods

Demographics

This was a retrospective, comparative study. The Institutional Review Board of our institution approved this study and all subjects provided written informed consent.

From January 2006 to October 2012, 220 patients were diagnosed with non-traumatic ONFH by plain radiographs and magnetic resonance images (MRI) and included in ONFH group. Patients with previous history of hip trauma, spine instrumentation, and medication affecting bone metabolism such as bisphosphonate and hormone replacement therapy, concurrent vascular disease, renal disease, and thyroid disorder were excluded from this study. Questionnaires were surveyed to collect data regarding smoking and drinking habits, and background medical history including previous fracture around the hip joint, present illness, and concurrent medication. There were 165 males and 55 females with an average age of 53.5 ± 14.3 years (range, 20–80 years) and mean body mass index (BMI) of 23.2 ± 3.0 kg/m2 (Table 1). Based on past history and chart review, patients were divided into steroid-induced ONFH (40 patients, 18%), alcoholic ONFH (45 patients, 21%), and idiopathic ONFH (135 patients, 61%) subgroups and subgroup analysis was performed to exclude the effect of steroid and malnutrition on bone metabolism. Steroid-induced ONFH (SONFH) was defined for those who took prednisolone more than 1800 mg or an equivalent over four weeks [13], and alcoholic ONFH (AONFH) was diagnosed in those who consumed more than 400 ml of pure ethanol per week [14]. Two hundred twenty control subjects were matched by age, gender, and BMI among those who had visited to Health Promotion Center in our institution for regular checkups during same period and same exclusion criteria were applied to the control group. Subjects who had hip joint pain according to questionnaires were excluded as well. The average age of subjects in the control group was 53.1 ± 14.3 years (range, 20–80 years) and the mean BMI was 23.6 ± 2.9 kg/m2.
Table 1

Demographic data of study subjects

 

ONFH group

Control group

p value

Numbers

220

220

NA

Age (years)*

53.5 ± 14.3

53.1 ± 14.3

0.755

Gender (F:M)

55:165

55:165

NA

BMI (kg/m2)*

23.2 ± 3.0

23.6 ± 2.9

0.168

ONFH osteonecrosis of the femoral head, NA not applicable, F female, M male, BMI body mass index

*Expressed as mean ± standard deviation

BMD

The BMD of lumbar spine at L1 to L4 was measured by dual energy X-ray absorptiometry (DEXA) using Lunar Prodigy Advance® (GE Healthcare, Madison, WI, USA) in both ONFH and control groups. Hip BMD was not evaluated because it was not included in the screening test for regular medical checkup at the Health Promotion Center in our institution. Following World Health Organization criteria, subjects were divided into normal, osteopenia, and osteoporosis using T score [15, 16]. Low BMD was defined when T score was lower than − 1.0.

BTMs

BTMs were measured only in the ONFH group because the same biochemical markers were not included in the screening test for regular medical checkup at the Health Promotion Center in our institution. We measured serum bone-specific alkaline phosphatase (BALP), a reliable indicator for biosynthetic activity of bone-forming cells, and urinary deoxypyridinoline/creatinine (Dpd/Cr) ratio, a proven sensitive marker for early assessment of bone resorption [17, 18]. Blood samples were collected in the morning after overnight fasting and spot urine was collected during daytime. The mean values of serum BALP and urine Dpd/Cr ratio in the ONFH group were compared with the reference range of normal population and the proportion of outliers matched with age was calculated.

Statistical analysis

Independent t test and chi-square test were performed to compare variables, and logistic analysis was conducted using the SAS version 9.2 software (SAS Institute Inc., Cary, NC, USA). Null hypotheses of no difference were rejected if p values were less than 0.05, or, equivalently, if the 95% confidence intervals (CIs) of risk point estimates excluded.

Results

There were no significant differences in age, gender, and BMI between two groups (Table 1). The T and Z scores in BMD of lumbar spine at L1 to L4 (− 1.09 and − 0.57, respectively) were significantly lower in ONFH group (p < 0.0001) and the prevalence of low BMD (48.6%) including osteoporosis and osteopenia was significantly higher in ONFH group compared to that of control group (30.5%, p < 0.01) (Table 2). After adjustment for confounding factors such as age, gender, and BMI, logistic regression analysis revealed low BMD was significantly associated with each subgroup of ONFH (Table 3): alcoholic ONFH group with odds ratio (OR) of 2.27 (95% CI 1.11–4.66, p < 0.05), steroid-induced ONFH group with OR of 4.24 (95% CI 1.94–9.25, p < 0.01), and idiopathic ONFH group with OR of 1.86 (95% CI 1.17–2.95, p < 0.01) when compared with that of the control group.
Table 2

BMD and prevalence of osteoporosis, osteopenia, and low BMD

 

ONFH group

Control group

p value

BMD, L1–L4 spine*

 BMD (g/cm2)

1.04 ± 0.17

1.13 ± 0.17

< 0.0001

 Spine T score

− 1.09 ± 1.33

− 0.32 ± 1.39

< 0.0001

 Spine Z score

− 0.57 ± 1.35

0.09 ± 1.23

< 0.0001

Prevalence

 Osteoporosis (N, %)

36 (16.4)

10 (4.5)

< 0.01

 Osteopenia (N, %)

71 (32.3)

57 (25.9)

NS

 Low BMD (N, %)

107 (48.6)

67 (30.5)

< 0.01

ONFH osteonecrosis of the femoral head, BMD bone mineral density, N number of patients, NS not significant

*Expressed as mean ± standard deviation

Table 3

Prevalence and adjusted odds ratio of osteoporosis, osteopenia, and low BMD

 

ONFH group

Control group

Crude

Adjusted*

OR [95% CI]

p value

OR [95% CI]

p value

AONFH group

 Osteoporosis (N, %)

5 (11.1)

10 (4.6)

3.19 [1.00–10.13]

< 0.05

5.94 [1.46–24.13]

< 0.05

 Osteopenia (N, %)

16 (35.6)

57 (25.9)

1.79 [0.89–3.61]

NS

1.97 [0.93–4.21]

< 0.05

 Low BMD (N, %)

21 (46.7)

67 (30.5)

2.00 [1.04–3.84]

< 0.05

2.27 [1.11–4.66]

< 0.05

SONFH group

 Osteoporosis (N, %)

6 (15)

10 (4.5)

5.10 [1.66–15.69]

< 0.0001

17.34[4.30–9.95]

< 0.0001

 Osteopenia (N, %)

16 (40)

57 (25.9)

2.39 [1.14–5.00]

< 0.01

3.52 [1.54–8.05]

< 0.01

 Low BMD (N, %)

22 (55)

67 (30.5)

2.79 [1.41–5.54]

< 0.01

4.24 [1.94–9.25]

< 0.01

IONFH group

 Osteoporosis (N, %)

25 (18.5)

10 (4.5)

5.39 [2.46–11.82]

< 0.0001

4.81 [2.10–11.00]

< 0.01

 Osteopenia (N, %)

39 (28.9)

57 (25.9)

1.47 [0.90–2.42]

NS

1.41 [0.86–2.34]

NS

 Low BMD (N, %)

64 (47.4)

67 (30.5)

2.06 [1.32–3.21]

< 0.01

1.86 [1.17–2.95]

< 0.01

ONFH osteonecrosis of the femoral head, OR odds ratio, CI confidence interval, AONFH alcoholic ONFH, SONFH steroid-induced ONFH, IONFH idiopathic ONFH, N number of patients, NS not significant, BMD bone mineral density

*Adjusted for age, gender, and BMI

Serum BALP level (27.02 ± 13.48 U/L) was within the normal reference range whereas urine Dpd/Cr ratio (6.24 ± 2.87 nM/mM) increased in ONFH group (Table 4). The proportion of outliers in BALP was 26.8% (range, 3.06~103.06 U/L) while that in Dpd/Cr ratio was 47.3% (range, 1.57~19.13 nM/mM) in ONFH group.
Table 4

Comparison of level of bone turnover markers in ONFH group with reference range (expressed as mean ± standard deviation)

ONFH group

BALP (U/L)

Dpd/Cr ratio (nM/mM)

Male

28.1 ± 13.2 (reference, 15~41.3)

5.9 ± 2.8 (reference, 2.5~5.5)

Female

Premenopausal: 21.9 ± 12.0 (reference, 11.6~29.6)

7.22 ± 3.00 (reference, 2.5~6.5)

Postmenopausal: 24.8 ± 14.9 (reference, 14.2~42.7)

ONFH osteonecrosis of femoral head, BALP serum bone-specific alkaline phosphatase, Dpd/Cr urinary deoxypyridinoline-creatinine

Discussion

Regardless of various conditions related to ONFH, the final step of it is collapse of the femoral head [4], and bone remodeling which consists of bone resorption by osteoclasts followed by bone formation by osteoblasts plays an important role in the progression of it [6]. There have been conflicting reports regarding the osteogenic differentiation capacity and the gene expression of individual factors regulating bone formation and remodeling of BMSCs in patients with ONFH [7, 8, 9, 10, 11, 12]. However, there have been few studies investigating the cumulative effect of these individual variations on the systemic balance between bone formation and resorption in patients with ONFH. Moreover, histopathologic samples in the previous studies were obtained from proximal femur [7, 11] or iliac crest [8, 9, 10, 12] which was close to ONFH lesion site and, thus, might not be appropriate for reflecting systemic bone metabolism. These made us to explore the cumulative effect of these individual variations on the balance of systemic bone metabolism using lumbar BMD and BTMs in patients with ONFH.

Our study showed that the lumbar spine BMD was lower (p < 0.0001) and the prevalence of low BMD, osteoporosis in particular, was higher in patients with ONFH (p < 0.01) when compared with those in the control group. Because the use of steroid and consumption of alcohol had been known to inhibit bone formation and reduce bone mass [19, 20], we performed subgroup analysis according to aetiology of ONFH and found that low BMD was significantly associated not only with steroid-induced or alcoholic ONFH, but also with idiopathic ONFH, suggesting that low BMD might be a natural process in the onset or progress in non-traumatic ONFH.

Serum BALP, a bone formation marker in patients with ONFH, was within the normal range whereas urine Dpd/Cr ratio, a bone resorption marker, increased in comparison with the reference range of normal population. These suggest that the balance of systemic bone metabolism might be disrupted mainly due to the increased bone resorption and we believe that our findings could provide clinical background for the potential benefits from the use of bisphosphonates, an antiresorptive agent, to treat patients with ONFH. Alendronate was reported to increase bone mass in the trabecular region of the femoral head, inhibit the subchondral bone resorption, and reduce cartilage degeneration in the acetabulum in adult rabbit model with ONFH [21]. In spite of many controversies regarding clinical implication of these findings, alendronate demonstrated to improve clinical function and reduce the rate of collapse in patients with early-stage ONFH [22], and even in patients with collapsed femoral head (ARCO stage III), some benefits have been obtained from alendronate treatment [23, 24]. In addition to the potential effect on the progress of ONFH itself, bisphosphonates might improve imbalance of systemic bone metabolism in patients with ONFH by suppressing the increased bone resorption and, thus, could treat the possible concurrent osteopenia or osteoporosis. Moreover, it might improve the surgical outcome in patients with ONFH when it failed to prevent collapse of the femoral head because it has been reported to have short- and mid-term efficacy on reducing the periprosthetic bone loss after hip arthroplasty, the most common procedure worldwide for ONFH [25].

Although control subjects were matched by age, gender, and BMI to minimize confounding, our study had some limitations. First, we compared the biochemical markers of patients group with the reference normal range instead of those of control group because they were not included in the screening test for regular medical checkup at the Health Promotion Center in our institution. Second, only spine BMD which could be affected by degenerative change was compared. However, hip BMD of contralateral side could be also affected by silent ONFH in which bilateral involvement has been reported to be common. Third, the average age of cohort (53.5 ± 14.3 years) in this study was slightly higher than that of ordinary patients with ONFH, and thus, we may not generalize our findings to typical patients of young age with ONFH. Fourth, we could not exclude the effect of inactivity due to hip pathology in patients with ONFH on spine BMD. However, our routine protocol once the diagnosis of ONFH was made included spine BMD, and therefore, the effect of inactivity might be considered less in clinical setting. Lastly, this study included Asian people only, and thus, we could not extend our conclusion to other ethnicities. However, we believe that our findings are valuable because this is the first study to compare BMD and BTMs between healthy subjects and patients with non-traumatic ONFH providing further research potential for possible systemic effect of ONFH.

In conclusion, spine BMD decreased and urinary Dpd/Cr ratio increased in patients with non-traumatic ONFH. Our findings may provide a useful clinical background for the potential benefits from the use of bisphosphonates in patients with ONFH and further studies will be necessary to identify whether non-traumatic ONFH is merely a regional disease confined to the femoral head or may affect systemic bone metabolism.

Notes

Acknowledgements

We thank professor Won Kee Lee for statistical analysis.

Funding

We thank professor Won Kee Lee for statistical analysis. This work was supported by Institute for Information & communications, Technology Promotion (IITP) grant funded by the Korea government (MSIP) (B0101-18-1081).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Sohn WY, Lee SH, Min KK, Nam HW, Kim HJ (1999) Lipid profile in patients with osteonecrosis of the femoral head. J Korean Orthop Assoc 34:1059–1065Google Scholar
  2. 2.
    Ha YC, Koo KH, Hwang SC, Kim JR, Park HB, Kim SR, Kim KM (2002) Thrombotic and fibrinolytic abnormality in nontraumatic osteonecrosis of the femoral head. J Korean Orthop Assoc 37:31–35CrossRefGoogle Scholar
  3. 3.
    Jones JP Jr (1985) Fat embolism and osteonecrosis. Orthop Clin North Am 16:595–633PubMedGoogle Scholar
  4. 4.
    Mont MA, Jones LC, Einhorn TA, Hungerford DS, Reddi AH (1998) Osteonecrosis of the femoral head. Potential treatment with growth and differentiation factors. Clin Orthop Relat Res:S314–335Google Scholar
  5. 5.
    Radke S, Battmann A, Jatzke S, Eulert J, Jakob F, Schutze N (2006) Expression of the angiomatrix and angiogenic proteins CYR61, CTGF, and VEGF in osteonecrosis of the femoral head. J Orthop Res 24:945–952.  https://doi.org/10.1002/jor.20097 CrossRefPubMedGoogle Scholar
  6. 6.
    Karsenty G (2000) How many factors are required to remodel bone? Nat Med 6:970–971.  https://doi.org/10.1038/79655 CrossRefPubMedGoogle Scholar
  7. 7.
    Hernigou P, Beaujean F, Lambotte JC (1999) Decrease in the mesenchymal stem-cell pool in the proximal femur in corticosteroid-induced osteonecrosis. J Bone Joint Surg Br 81:349–355CrossRefPubMedGoogle Scholar
  8. 8.
    Hernigou P, Beaujean F (1997) Abnormalities in the bone marrow of the iliac crest in patients who have osteonecrosis secondary to corticosteroid therapy or alcohol abuse. J Bone Joint Surg Am 79:1047–1053CrossRefPubMedGoogle Scholar
  9. 9.
    Yeh CH, Chang JK, Ho ML, Chen CH, Wang GJ (2009) Different differentiation of stroma cells from patients with osteonecrosis: a pilot study. Clin Orthop Relat Res 467:2159–2167.  https://doi.org/10.1007/s11999-009-0803-0 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Chang JK, Ho ML, Yeh CH, Chen CH, Wang GJ (2006) Osteogenic gene expression decreases in stromal cells of patients with osteonecrosis. Clin Orthop Relat Res 453:286–292.  https://doi.org/10.1097/01.blo.0000238869.99980.b2 CrossRefPubMedGoogle Scholar
  11. 11.
    Tingart M, Beckmann J, Opolka A, Matsuura M, Wiech O, Grifka J, Grassel S (2008) Influence of factors regulating bone formation and remodeling on bone quality in osteonecrosis of the femoral head. Calcif Tissue Int 82:300–308.  https://doi.org/10.1007/s00223-008-9111-z CrossRefPubMedGoogle Scholar
  12. 12.
    Yoo JJ, Song WS, Koo KH, Yoon KS, Kim HJ (2009) Osteogenic abilities of bone marrow stromal cells are not defective in patients with osteonecrosis. Int Orthop 33:867–872.  https://doi.org/10.1007/s00264-008-0524-0 CrossRefPubMedGoogle Scholar
  13. 13.
    Koo KH, Kim R, Kim YS, Ahn IO, Cho SH, Song HR, Park YS, Kim H, Wang GJ (2002) Risk period for developing osteonecrosis of the femoral head in patients on steroid treatment. Clin Rheumatol 21:299–303.  https://doi.org/10.1007/s100670200078 CrossRefPubMedGoogle Scholar
  14. 14.
    Matsuo K, Hirohata T, Sugioka Y, Ikeda M, Fukuda A (1988) Influence of alcohol intake, cigarette smoking, and occupational status on idiopathic osteonecrosis of the femoral head. Clin Orthop Relat Res:115–123Google Scholar
  15. 15.
    World Health Organization (1994) Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO study group. World Health Organ Tech Rep Ser 843:1–129Google Scholar
  16. 16.
    Kanis JA, Gluer CC (2000) An update on the diagnosis and assessment of osteoporosis with densitometry. Committee of Scientific Advisors, International Osteoporosis Foundation. Osteoporos Int 11:192–202CrossRefPubMedGoogle Scholar
  17. 17.
    Civitelli R, Armamento-Villareal R, Napoli N (2009) Bone turnover markers: understanding their value in clinical trials and clinical practice. Osteoporos Int 20:843–851.  https://doi.org/10.1007/s00198-009-0838-9 CrossRefPubMedGoogle Scholar
  18. 18.
    Terreni A, Pezzati P (2012) Biochemical markers in the follow-up of the osteoporotic patients. Clin Cases Miner Bone Metab 9:80–84PubMedPubMedCentralGoogle Scholar
  19. 19.
    Lukert BP, Raisz LG (1990) Glucocorticoid-induced osteoporosis: pathogenesis and management. Ann Intern Med 112:352–364CrossRefPubMedGoogle Scholar
  20. 20.
    Maurel DB, Boisseau N, Benhamou CL, Jaffre C (2012) Alcohol and bone: review of dose effects and mechanisms. Osteoporos Int 23:1–16.  https://doi.org/10.1007/s00198-011-1787-7 CrossRefPubMedGoogle Scholar
  21. 21.
    Hofstaetter JG, Wang J, Yan J, Glimcher MJ (2009) The effects of alendronate in the treatment of experimental osteonecrosis of the hip in adult rabbits. Osteoarthr Cartil 17:362–370.  https://doi.org/10.1016/j.joca.2008.07.013 CrossRefPubMedGoogle Scholar
  22. 22.
    Chen CH, Chang JK, Lai KA, Hou SM, Chang CH, Wang GJ (2012) Alendronate in the prevention of collapse of the femoral head in nontraumatic osteonecrosis: a two-year multicenter, prospective, randomized, double-blind, placebo-controlled study. Arthritis Rheum 64:1572–1578.  https://doi.org/10.1002/art.33498 CrossRefPubMedGoogle Scholar
  23. 23.
    Agarwala S, Shah S, Joshi VR (2009) The use of alendronate in the treatment of avascular necrosis of the femoral head: follow-up to eight years. J Bone Joint Surg Br 91:1013–1018.  https://doi.org/10.1302/0301-620X.91B8.21518 CrossRefPubMedGoogle Scholar
  24. 24.
    Lai KA, Shen WJ, Yang CY, Shao CJ, Hsu JT, Lin RM (2005) The use of alendronate to prevent early collapse of the femoral head in patients with nontraumatic osteonecrosis. A randomized clinical study. J Bone Joint Surg Am 87:2155–2159.  https://doi.org/10.2106/jbjs.d.02959 CrossRefPubMedGoogle Scholar
  25. 25.
    Lin T, Yan SG, Cai XZ, Ying ZM (2012) Bisphosphonates for periprosthetic bone loss after joint arthroplasty: a meta-analysis of 14 randomized controlled trials. Osteoporos Int 23:1823–1834.  https://doi.org/10.1007/s00198-011-1797-5 CrossRefPubMedGoogle Scholar

Copyright information

© SICOT aisbl 2018

Authors and Affiliations

  • Lulu Tian
    • 1
  • Seung-Hoon Baek
    • 2
    • 3
  • JinAn Jang
    • 3
  • Shin-Yoon Kim
    • 1
    • 2
    • 3
  1. 1.Musculoskeletal Genome Research CenterKyungpook National University HospitalDaeguSouth Korea
  2. 2.Department of Orthopedic Surgery, School of MedicineKyungpook National UniversityDaeguSouth Korea
  3. 3.Department of Orthopedic SurgeryKyungpook National University HospitalDaeguSouth Korea

Personalised recommendations