Efficacy and safety of autologous mononuclear cells transplantation in osteonecrosis of the femoral head: a meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

CHEN Lei ¹ , AI Jinwei ² , YU Hui ¹ , QU Gaojing ¹ , ZHU Haoming ¹ , HUANG Guoxin ¹ , WANG Qian ² ,  PEI Bin ¹

1. Center of Evidence-Based Medicine, Xiangyang No.1 People’s Hospital, Hubei University of Medicine, Xiangyang 442000, P.R.China;
2. Department the Third Ward of Orthopedic, Xiangyang No.1 People’s Hospital, Hubei University of Medicine, Xiangyang 442000, P.R.China;

Corresponding author：

PEI Bin, Email: binpei@hbmu.edu.cn

Keywords：

Femur head necrosis; Mononuclear cell; Bone marrow aspirate concentrate; Safety; Efficacy; Meta-analysis

DOI：

10.7507/1672-2531.202010143

Video：

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Objective To systematically review the efficacy and safety of autologous mononuclear cells transplantation in osteonecrosis of the femoral head.Methods PubMed, EMbase and The Cochrane Library were electronically searched to collect randomized and non-randomized controlled trials on autologous mononuclear cells transplantation for osteonecrosis of the femoral head from inception to July 31^th, 2020. Two reviewers independently screened literatures, extracted data and assessed risk of bias of included studies. Meta-analysis was then performed using RevMan 5.4 software.Results A total of 17 studies involving 645 hips in mononuclear cells group and 557 hips in cell-free group were included. The results of meta-analysis showed that compared with cell-free therapy, mononuclear cells therapy could improve hip function in term of Hairrs score (MD=8.11, 95%CI 4.36 to 11.87, P<0.000 1), Merle D`Aubigné Postel score (MD=2.23, 95%CI 0.97 to 3.49, P=0.000 5), WOMAC score (MD=−10.81, 95%CI −15.80 to −5.81, P<0.000 1), Lequesne index (MD=−2.97, 95%CI −5.42 to −0.52, P=0.02) and alleviate the pain (MD=−9.13, 95%CI −12.40 to −5.86, P<0.000 01), delay the progression of radiological staging (RR=0.55, 95%CI 0.34 to 0.89, P=0.01) and reduce the rate of total hip arthroplasty (RR=0.61, 95%CI 0.43 to 0.86, P=0.005). In terms of safety, mononuclear cell therapy did not increase the rate of complications (RR=0.77, 95%CI 0.33 to 1.83, P=0.56).Conclusions The current evidence shows that autologous mononuclear cells therapy is a safe and effective way for osteonecrosis of the femoral head. Due to limited quality and quantity of the included studies, more high quality studies are required to verify above conclusions.

Citation： CHEN Lei, AI Jinwei, YU Hui, QU Gaojing, ZHU Haoming, HUANG Guoxin, WANG Qian, PEI Bin. Efficacy and safety of autologous mononuclear cells transplantation in osteonecrosis of the femoral head: a meta-analysis. Chinese Journal of Evidence-Based Medicine, 2021, 21(4): 446-456. doi: 10.7507/1672-2531.202010143 Copy

1.	中华医学会骨科学分会关节外科学组. 股骨头坏死临床诊疗规范(2015年版). 中华关节外科杂志(电子版), 2015, 9(1): 97-100.
2.	Moya-Angeler J, Gianakos AL, Villa JC, et al. Current concepts on osteonecrosis of the femoral head. World J Orthop, 2015, 6(8): 590-601.
3.	Lamb JN, Holton C, O'Connor P, et al. Avascular necrosis of the hip. BMJ, 2019, 365: l2178.
4.	Zhao DW, Yu M, Hu K, et al. Prevalence of nontraumatic osteonecrosis of the femoral head and its associated risk factors in the Chinese population: results from a nationally representative survey. Chin Med J (Engl), 2015, 128(21): 2843-2850.
5.	Zalavras CG, Lieberman JR. Osteonecrosis of the femoral head: evaluation and treatment. J Am Acad Orthop Surg, 2014, 22(7): 455-464.
6.	Arbab D, König DP. Atraumatic femoral head necrosis in adults. Dtsch Arztebl Int, 2016, 113(3): 31-38.
7.	Chughtai M, Piuzzi NS, Khlopas A, et al. An evidence-based guide to the treatment of osteonecrosis of the femoral head. Bone Joint J, 2017, 99-B(10): 1267-1279.
8.	Mont MA, Cherian JJ, Sierra RJ, et al. Nontraumatic osteonecrosis of the femoral head: where do we stand today? A ten-year update. J Bone Joint Surg Am, 2015, 97(19): 1604-1627.
9.	Ohzono K, Saito M, Takaoka K, et al. Natural history of nontraumatic avascular necrosis of the femoral head. J Bone Joint Surg Br, 1991, 73(1): 68-72.
10.	Dion NT, Bragdon C, Muratoglu O, et al. Durability of highly cross-linked polyethylene in total hip and total knee arthroplasty. Orthop Clin North Am, 2015, 46(3): 321-327.
11.	Li R, Lin QX, Liang XZ, et al. Stem cell therapy for treating osteonecrosis of the femoral head: from clinical applications to related basic research. Stem Cell Res Ther, 2018, 9(1): 291.
12.	Bulgin D. Therapeutic angiogenesis in ischemic tissues by growth factors and bone marrow mononuclear cells administration: biological foundation and clinical prospects. Curr Stem Cell Res Ther, 2015, 10(6): 509-522.
13.	Hernigou P, Beaujean F. Treatment of osteonecrosis with autologous bone marrow grafting. Clin Orthop Relat Res, 2002, (405): 14-23.
14.	Kang JS, Moon KH, Kim B, et al. Clinical results of auto-iliac cancellous bone grafts combined with implantation of autologous bone marrow cells for osteonecrosis of the femoral head: a minimum 5-year follow-up. Yonsei Med J, 2013, 54(2): 510-515.
15.	Hernigou P, Trousselier M, Roubineau F, et al. Stem cell therapy for the treatment of hip osteonecrosis: a 30-year review of progress. Clin Orthop Surg, 2016, 8(1): 1-8.
16.	Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev, 2015, 4(1): 1.
17.	Hernigou P, Dubory A, Homma Y, et al. Cell therapy versus simultaneous contralateral decompression in symptomatic corticosteroid osteonecrosis: a thirty year follow-up prospective randomized study of one hundred and twenty five adult patients. Int Orthop, 2018, 42(7): 1639-1649.
18.	Mao Q, Wang W, Xu T, et al. Combination treatment of biomechanical support and targeted intra-arterial infusion of peripheral blood stem cells mobilized by granulocyte-colony stimulating factor for the osteonecrosis of the femoral head: a randomized controlled clinical trial. J Bone Miner Res, 2015, 30(4): 647-656.
19.	Pepke W, Kasten P, Beckmann NA, et al. Core decompression and autologous bone marrow concentrate for treatment of femoral head osteonecrosis: a randomized prospective study. Orthop Rev (Pavia), 2016, 8(1): 6162.
20.	Sen RK, Tripathy SK, Aggarwal S, et al. Early results of core decompression and autologous bone marrow mononuclear cells instillation in femoral head osteonecrosis: a randomized control study. J Arthroplasty, 2012, 27(5): 679-686.
21.	Ma Y, Wang T, Liao J, et al. Efficacy of autologous bone marrow buffy coat grafting combined with core decompression in patients with avascular necrosis of femoral head: a prospective, double-blinded, randomized, controlled study. Stem Cell Res Ther, 2014, 5(5): 115.
22.	Hauzeur JP, De Maertelaer V, Baudoux E, et al. Inefficacy of autologous bone marrow concentrate in stage three osteonecrosis: a randomized controlled double-blind trial. Int Orthop, 2018, 42(7): 1429-1435.
23.	Pilge H, Bittersohl B, Schneppendahl J, et al. Bone marrow aspirate concentrate in combination with intravenous iloprost increases bone healing in patients with avascular necrosis of the femoral head: a matched pair analysis. Orthop Rev (Pavia), 2017, 8(4): 6902.
24.	Tabatabaee RM, Saberi S, Parvizi J, et al. Combining concentrated autologous bone marrow stem cells injection with core decompression improves outcome for patients with early-stage osteonecrosis of the femoral head: a comparative study. J Arthroplasty, 2015, 30(9 Suppl): 11-15.
25.	Gangji V, Hauzeur JP, Matos C, et al. Treatment of osteonecrosis of the femoral head with implantation of autologous bone-marrow cells: a pilot study. J Bone Joint Surg Am, 2004, 86(6): 1153-1160.
26.	Gangji V, De Maertelaer V, Hauzeur JP. Autologous bone marrow cell implantation in the treatment of non-traumatic osteonecrosis of the femoral head: five year follow-up of a prospective controlled study. Bone, 2011, 49(5): 1005-1009.
27.	Yan D, Chen L, Li Z, et al. Autologous mesenchymal stem cell implantation in the management of osteonecrosis of the femoral head. Curr Orthop Pract, 2015, 26(3): 265-268.
28.	Yamasaki T, Yasunaga Y, Ishikawa M, et al. Bone-marrow-derived mononuclear cells with a porous hydroxyapatite scaffold for the treatment of osteonecrosis of the femoral head: a preliminary study. J Bone Joint Surg Br, 2010, 92(3): 337-341.
29.	Kang JS, Suh YJ, Moon KH, et al. Clinical efficiency of bone marrow mesenchymal stem cell implantation for osteonecrosis of the femoral head: a matched pair control study with simple core decompression. Stem Cell Res Ther, 2018, 9(1): 274.
30.	Liu Y, Liu S, Su X. Core decompression and implantation of bone marrow mononuclear cells with porous hydroxylapatite composite filler for the treatment of osteonecrosis of the femoral head. Arch Orthop Trauma Surg, 2013, 133(1): 125-133.
31.	Cruz-Pardos A, Garcia-Rey E, Ortega-Chamarro JA, et al. Mid-term comparative outcomes of autologous bone-marrow concentration to treat osteonecrosis of the femoral head in standard practice. Hip Int, 2016, 26(5): 432-437.
32.	Lim YW, Kim YS, Lee JW, et al. Stem cell implantation for osteonecrosis of the femoral head. Exp Mol Med, 2013, 45(11): e61.
33.	Nally FJ, Zanotti G, Buttaro MA, et al. THA conversion rate comparing decompression alone, with autologous bone graft or stem cells in osteonecrosis. Hip Int, 2018, 28(2): 189-193.
34.	Parsons SJ, Steele N. Osteonecrosis of the femoral head: part 1-aetiology, pathogenesis, investigation, classification. Orthop Trauma, 2007, 21(6): 457-463.
35.	Lau RL, Perruccio AV, Evans HMK, et al. Stem cell therapy for the treatment of early stage avascular necrosis of the femoral head: a systematic review. BMC Musculoskelet Disord, 2014, 15(1): 156-165.
36.	Gao YS, Zhang CQ. Cytotherapy of osteonecrosis of the femoral head: a mini review. Int Orthop, 2010, 34(6): 779-782.
37.	Kim H, Park JS, Choi YJ, et al. Bone marrow mononuclear cells have neurovascular tropism and improve diabetic neuropathy. Stem Cells, 2009, 27(7): 1686-1696.
38.	Yamasaki T, Yasunaga Y, Terayama H, et al. Transplantation of bone marrow mononuclear cells enables simultaneous treatment with osteotomy for osteonecrosis of the bilateral femoral head. Med Sci Monit, 2008, 14(4): CS23-30.
39.	Kamihata H, Matsubara H, Nishiue T, et al. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation, 2001, 104(9): 1046-1052.
40.	Xu S, Zhang L, Jin H, et al. Autologous stem cells combined core decompression for treatment of avascular necrosis of the femoral head: a systematic meta-analysis. Biomed Res Int, 2017, 2017: 6136205.
41.	Yuan HF, Zhang J, Guo CA, et al. Clinical outcomes of osteonecrosis of the femoral head after autologous bone marrow stem cell implantation: a meta-analysis of seven case-control studies. Clinics (Sao Paulo), 2016, 71(2): 110-113.
42.	Papakostidis C, Tosounidis TH, Jones E, et al. The role of "cell therapy" in osteonecrosis of the femoral head. A systematic review of the literature and meta-analysis of 7 studies. Acta Orthop, 2016, 87(1): 72-78.
43.	Zhang C, Fang X, Huang Z, et al. Addition of bone marrow stem cells therapy achieves better clinical outcomes and lower rates of disease progression compared with core decompression alone for early stage osteonecrosis of the femoral head: a systematic review and meta-analysis. J Am Acad Orthop Surg, 2020, 28(23): 973-979.

1. 中华医学会骨科学分会关节外科学组. 股骨头坏死临床诊疗规范(2015年版). 中华关节外科杂志(电子版), 2015, 9(1): 97-100.
2. Moya-Angeler J, Gianakos AL, Villa JC, et al. Current concepts on osteonecrosis of the femoral head. World J Orthop, 2015, 6(8): 590-601.
3. Lamb JN, Holton C, O'Connor P, et al. Avascular necrosis of the hip. BMJ, 2019, 365: l2178.
4. Zhao DW, Yu M, Hu K, et al. Prevalence of nontraumatic osteonecrosis of the femoral head and its associated risk factors in the Chinese population: results from a nationally representative survey. Chin Med J (Engl), 2015, 128(21): 2843-2850.
5. Zalavras CG, Lieberman JR. Osteonecrosis of the femoral head: evaluation and treatment. J Am Acad Orthop Surg, 2014, 22(7): 455-464.
6. Arbab D, König DP. Atraumatic femoral head necrosis in adults. Dtsch Arztebl Int, 2016, 113(3): 31-38.
7. Chughtai M, Piuzzi NS, Khlopas A, et al. An evidence-based guide to the treatment of osteonecrosis of the femoral head. Bone Joint J, 2017, 99-B(10): 1267-1279.
8. Mont MA, Cherian JJ, Sierra RJ, et al. Nontraumatic osteonecrosis of the femoral head: where do we stand today? A ten-year update. J Bone Joint Surg Am, 2015, 97(19): 1604-1627.
9. Ohzono K, Saito M, Takaoka K, et al. Natural history of nontraumatic avascular necrosis of the femoral head. J Bone Joint Surg Br, 1991, 73(1): 68-72.
10. Dion NT, Bragdon C, Muratoglu O, et al. Durability of highly cross-linked polyethylene in total hip and total knee arthroplasty. Orthop Clin North Am, 2015, 46(3): 321-327.
11. Li R, Lin QX, Liang XZ, et al. Stem cell therapy for treating osteonecrosis of the femoral head: from clinical applications to related basic research. Stem Cell Res Ther, 2018, 9(1): 291.
12. Bulgin D. Therapeutic angiogenesis in ischemic tissues by growth factors and bone marrow mononuclear cells administration: biological foundation and clinical prospects. Curr Stem Cell Res Ther, 2015, 10(6): 509-522.
13. Hernigou P, Beaujean F. Treatment of osteonecrosis with autologous bone marrow grafting. Clin Orthop Relat Res, 2002, (405): 14-23.
14. Kang JS, Moon KH, Kim B, et al. Clinical results of auto-iliac cancellous bone grafts combined with implantation of autologous bone marrow cells for osteonecrosis of the femoral head: a minimum 5-year follow-up. Yonsei Med J, 2013, 54(2): 510-515.
15. Hernigou P, Trousselier M, Roubineau F, et al. Stem cell therapy for the treatment of hip osteonecrosis: a 30-year review of progress. Clin Orthop Surg, 2016, 8(1): 1-8.
16. Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev, 2015, 4(1): 1.
17. Hernigou P, Dubory A, Homma Y, et al. Cell therapy versus simultaneous contralateral decompression in symptomatic corticosteroid osteonecrosis: a thirty year follow-up prospective randomized study of one hundred and twenty five adult patients. Int Orthop, 2018, 42(7): 1639-1649.
18. Mao Q, Wang W, Xu T, et al. Combination treatment of biomechanical support and targeted intra-arterial infusion of peripheral blood stem cells mobilized by granulocyte-colony stimulating factor for the osteonecrosis of the femoral head: a randomized controlled clinical trial. J Bone Miner Res, 2015, 30(4): 647-656.
19. Pepke W, Kasten P, Beckmann NA, et al. Core decompression and autologous bone marrow concentrate for treatment of femoral head osteonecrosis: a randomized prospective study. Orthop Rev (Pavia), 2016, 8(1): 6162.
20. Sen RK, Tripathy SK, Aggarwal S, et al. Early results of core decompression and autologous bone marrow mononuclear cells instillation in femoral head osteonecrosis: a randomized control study. J Arthroplasty, 2012, 27(5): 679-686.
21. Ma Y, Wang T, Liao J, et al. Efficacy of autologous bone marrow buffy coat grafting combined with core decompression in patients with avascular necrosis of femoral head: a prospective, double-blinded, randomized, controlled study. Stem Cell Res Ther, 2014, 5(5): 115.
22. Hauzeur JP, De Maertelaer V, Baudoux E, et al. Inefficacy of autologous bone marrow concentrate in stage three osteonecrosis: a randomized controlled double-blind trial. Int Orthop, 2018, 42(7): 1429-1435.
23. Pilge H, Bittersohl B, Schneppendahl J, et al. Bone marrow aspirate concentrate in combination with intravenous iloprost increases bone healing in patients with avascular necrosis of the femoral head: a matched pair analysis. Orthop Rev (Pavia), 2017, 8(4): 6902.
24. Tabatabaee RM, Saberi S, Parvizi J, et al. Combining concentrated autologous bone marrow stem cells injection with core decompression improves outcome for patients with early-stage osteonecrosis of the femoral head: a comparative study. J Arthroplasty, 2015, 30(9 Suppl): 11-15.
25. Gangji V, Hauzeur JP, Matos C, et al. Treatment of osteonecrosis of the femoral head with implantation of autologous bone-marrow cells: a pilot study. J Bone Joint Surg Am, 2004, 86(6): 1153-1160.
26. Gangji V, De Maertelaer V, Hauzeur JP. Autologous bone marrow cell implantation in the treatment of non-traumatic osteonecrosis of the femoral head: five year follow-up of a prospective controlled study. Bone, 2011, 49(5): 1005-1009.
27. Yan D, Chen L, Li Z, et al. Autologous mesenchymal stem cell implantation in the management of osteonecrosis of the femoral head. Curr Orthop Pract, 2015, 26(3): 265-268.
28. Yamasaki T, Yasunaga Y, Ishikawa M, et al. Bone-marrow-derived mononuclear cells with a porous hydroxyapatite scaffold for the treatment of osteonecrosis of the femoral head: a preliminary study. J Bone Joint Surg Br, 2010, 92(3): 337-341.
29. Kang JS, Suh YJ, Moon KH, et al. Clinical efficiency of bone marrow mesenchymal stem cell implantation for osteonecrosis of the femoral head: a matched pair control study with simple core decompression. Stem Cell Res Ther, 2018, 9(1): 274.
30. Liu Y, Liu S, Su X. Core decompression and implantation of bone marrow mononuclear cells with porous hydroxylapatite composite filler for the treatment of osteonecrosis of the femoral head. Arch Orthop Trauma Surg, 2013, 133(1): 125-133.
31. Cruz-Pardos A, Garcia-Rey E, Ortega-Chamarro JA, et al. Mid-term comparative outcomes of autologous bone-marrow concentration to treat osteonecrosis of the femoral head in standard practice. Hip Int, 2016, 26(5): 432-437.
32. Lim YW, Kim YS, Lee JW, et al. Stem cell implantation for osteonecrosis of the femoral head. Exp Mol Med, 2013, 45(11): e61.
33. Nally FJ, Zanotti G, Buttaro MA, et al. THA conversion rate comparing decompression alone, with autologous bone graft or stem cells in osteonecrosis. Hip Int, 2018, 28(2): 189-193.
34. Parsons SJ, Steele N. Osteonecrosis of the femoral head: part 1-aetiology, pathogenesis, investigation, classification. Orthop Trauma, 2007, 21(6): 457-463.
35. Lau RL, Perruccio AV, Evans HMK, et al. Stem cell therapy for the treatment of early stage avascular necrosis of the femoral head: a systematic review. BMC Musculoskelet Disord, 2014, 15(1): 156-165.
36. Gao YS, Zhang CQ. Cytotherapy of osteonecrosis of the femoral head: a mini review. Int Orthop, 2010, 34(6): 779-782.
37. Kim H, Park JS, Choi YJ, et al. Bone marrow mononuclear cells have neurovascular tropism and improve diabetic neuropathy. Stem Cells, 2009, 27(7): 1686-1696.
38. Yamasaki T, Yasunaga Y, Terayama H, et al. Transplantation of bone marrow mononuclear cells enables simultaneous treatment with osteotomy for osteonecrosis of the bilateral femoral head. Med Sci Monit, 2008, 14(4): CS23-30.
39. Kamihata H, Matsubara H, Nishiue T, et al. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation, 2001, 104(9): 1046-1052.
40. Xu S, Zhang L, Jin H, et al. Autologous stem cells combined core decompression for treatment of avascular necrosis of the femoral head: a systematic meta-analysis. Biomed Res Int, 2017, 2017: 6136205.
41. Yuan HF, Zhang J, Guo CA, et al. Clinical outcomes of osteonecrosis of the femoral head after autologous bone marrow stem cell implantation: a meta-analysis of seven case-control studies. Clinics (Sao Paulo), 2016, 71(2): 110-113.
42. Papakostidis C, Tosounidis TH, Jones E, et al. The role of "cell therapy" in osteonecrosis of the femoral head. A systematic review of the literature and meta-analysis of 7 studies. Acta Orthop, 2016, 87(1): 72-78.
43. Zhang C, Fang X, Huang Z, et al. Addition of bone marrow stem cells therapy achieves better clinical outcomes and lower rates of disease progression compared with core decompression alone for early stage osteonecrosis of the femoral head: a systematic review and meta-analysis. J Am Acad Orthop Surg, 2020, 28(23): 973-979.

Chinese Journal of Evidence-Based Medicine

Efficacy and safety of autologous mononuclear cells transplantation in osteonecrosis of the femoral head: a meta-analysis

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