The effect of concentrated bone marrow aspirate in operative treatment of fifth metatarsal stress fractures; a double-blind randomized controlled trial

BMC Musculoskeletal Disorders

Gino M. M. J. Kerkhoffs¹  John G. Kennedy²  J. Carel Goslings⁴  Simon Goedegebuure³  Leendert Blankevoort¹  C. Niek van Dijk¹  Wouter H. Mallee¹  Hanneke Weel¹ 

[1] Department of Orthopaedic Surgery, Orthopaedic Research Center Amsterdam, Academic Medical Center, Meibergdreef 9, Amsterdam, G4-264, 1105, AZ, The Netherlands;Orthopaedic Surgery, Hospital for Special Surgery, 523 East 72nd Street, 5th Floor Rm 514, New York 10021, NY, USA;The Sport Physician Group, Saint Lucas Andreas Hospital department of Sports Medicine, Jan Tooropstraat 164, Amsterdam, 1061, AE, The Netherlands;Department of Surgery, Trauma Unit, Academical Medical Center, Meibergdreef 9, Amsterdam, 1105, AZ, The Netherlands

关键词: Stem cells;    Bone marrow;    Surgery;    Stress fracture;    Metatarsal;   

Others  :  1227672
DOI  :  10.1186/s12891-015-0649-4

 received in 2014-08-06, accepted in 2015-07-27,  发布年份 2015

【 摘 要 】

Background

Fifth metatarsal (MT-V) stress fractures often exhibit delayed union and are high-risk fractures for non-union. Surgical treatment, currently considered as the gold standard, does not give optimal results, with a mean time to fracture union of 12-18 weeks. In recent studies, the use of bone marrow cells has been introduced to accelerate healing of fractures with union problems. The aim of this randomized trial is to determine if operative treatment of MT-V stress fractures with use of concentrated blood and bone marrow aspirate (cB + cBMA) is more effective than surgery alone. We hypothesize that using cB + cBMA in the operative treatment of MT-V stress fractures will lead to an earlier fracture union.

Methods/Design

A prospective, double-blind, randomized controlled trial (RCT) will be conducted in an academic medical center in the Netherlands. Ethics approval is received. 50 patients will be randomized to either operative treatment with cB + cBMA, harvested from the iliac crest, or operative treatment without cB + cBMA but with a sham-treatment of the iliac crest. The fracture fixation is the same in both groups, as is the post-operative care.. Follow up will be one year. The primary outcome measure is time to union in weeks on X-ray. Secondary outcome measures are time to resumption of work and sports, functional outcomes (SF-36, FAOS, FAAM), complication rate, composition of osteoprogenitors in cB + cBMA and cost-effectiveness. Furthermore, a bone biopsy is taken from every stress fracture and analysed histologically to determine the stage of the stress fracture. The difference in primary endpoint between the two groups is analysed using student’s t-test or equivalent.

Discussion

This trial will likely provide level-I evidence on the effectiveness of cB + cBMA in the operative treatment of MT-V stress fractures.

Trial registration

Netherlands Trial Register (reg.nr NTR4377)

【 授权许可】

   
2015 Weel et al.

【 图 表 】

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【 参考文献 】

• [1]Liong SY, Whitehouse RW. Lower extremity and pelvic stress fractures in athletes. Br J Radiol. 2012; 85(1016):1148-56.
• [2]Wentz L, Liu PY, Haymes E, Ilich JZ. Females have a greater incidence of stress fractures than males in both military and athletic populations: a systemic review. Mil Med. 2011; 176(4):420-30.
• [3]Ferry AT, Graves T, Theodore GH, Gill TJ. Stress fractures in athletes. Phys Sportsmed. 2010; 38(2):109-16.
• [4]Lee S, Anderson RB. Stress fractures of the tarsal navicular. Foot Ankle Clin. 2004; 9(1):85-104.
• [5]Warden SJ, Burr DB, Brukner PD. Stress fractures: pathophysiology, epidemiology, and risk factors. Curr Osteoporos Rep. 2006; 4(3):103-9.
• [6]Kaeding CC, Yu JR, Wright R, Amendola A, Spindler KP. Management and return to play of stress fractures. Clin J Sport Med. 2005; 15(6):442-7.
• [7]Fazzalari NL. Bone fracture and bone fracture repair. Osteoporos Int. 2011; 22(6):2003-6.
• [8]Raghavan P, Christofides E. Role of teriparatide in accelerating metatarsal stress fracture healing: a case series and review of literature. Clin Med Insights Endocrinol Diabetes. 2012; 5:39-45.
• [9]Kerkhoffs GM, Versteegh VE, Sierevelt IN, Kloen P, van Dijk CN. Treatment of proximal metatarsal V fractures in athletes and non-athletes. Br J Sports Med. 2012; 46(9):644-8.
• [10]Chuckpaiwong B, Queen RM, Easley ME, Nunley JA. Distinguishing Jones and proximal diaphyseal fractures of the fifth metatarsal. Clin Orthop Relat Res. 2008; 466(8):1966-70.
• [11]Popovic NJ. Proximal fifth metatarsal diaphyseal stress fracture in football players. Foot Ankle Surg. 2005; 11:2005.
• [12]Raikin SM, Slenker N, Ratigan B. The association of a varus hindfoot and fracture of the fifth metatarsal metaphyseal-diaphyseal junction: the Jones fracture. Am J Sports Med. 2008; 36:1367-72.
• [13]Dimitriou R, Tsiridis E, Giannoudis PV. Current concepts of molecular aspects of bone healing. Injury. 2005; 36(12):1392-404.
• [14]Kidd LJ, Stephens AS, Kuliwaba JS, Fazzalari NL, Wu AC, Forwood MR. Temporal pattern of gene expression and histology of stress fracture healing. Bone. 2010; 46(2):369-78.
• [15]Einhorn TA. The cell and molecular biology of fracture healing. Clin Orthop Relat Res. 1998;(355 Suppl):S7-21.
• [16]Marsell R, Einhorn TA. The biology of fracture healing. Injury. 2011; 42(6):551-5.
• [17]Isern J, Mendez-Ferrer S. Stem cell interactions in a bone marrow niche. Curr Osteoporos Rep. 2011; 9(4):210-8.
• [18]Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD et al.. Multilineage potential of adult human mesenchymal stem cells. Science. 1999; 284(5411):143-7.
• [19]Veronesi F, Giavaresi G, Tschon M, Borsari V, Aldini NN, Fini M. Stem Cells Dev. 2013; 22(2):181-92.
• [20]Bhargava R, Sankhla S, Gupta A, Changani R, Gagal K. Percutaneous autologus bone marrow injection in the treatment of delayed or nonunion. Indian J Orthop. 2007; 41(1):67-71.
• [21]Hernigou P, Poignard A, Manicom O, Mathieu G, Rouard H. The use of percutaneous autologous bone marrow transplantation in nonunion and avascular necrosis of bone. J Bone Joint Surg (Br). 2005; 87(7):896-902.
• [22]Block JE. The role and effectiveness of bone marrow in osseous regeneration. Med Hypotheses. 2005; 65(4):740-7.
• [23]Fayaz HC, Giannoudis PV, Vrahas MS, Smith RM, Moran C, Pape HC et al.. The role of stem cells in fracture healing and nonunion. Int Orthop. 2011; 35(11):1587-97.
• [24]Murawski CD, Kennedy JG. Percutaneous internal fixation of proximal fifth metatarsal jones fractures (Zones II and III) with Charlotte Carolina screw and bone marrow aspirate concentrate: an outcome study in athletes. Am J Sports Med. 2011; 39(6):1295-301.
• [25]Liebergall M, Schroeder J, Mosheiff R, Gazit Z, Yoram Z, Rasooly L et al.. Stem cell-based therapy for prevention of delayed fracture union: a randomized and prospective preliminary study. Mol Ther. 2013; 21(8):1631-8.
• [26]Giannotti S, Trombi L, Bottai V, Ghilardi M, D’Alessandro D, Danti S et al.. Use of autologous human mesenchymal stromal cell/fibrin clot constructs in upper limb non-unions: long-term assessment. PLoS One. 2013; 8(8): Article ID e73893
• [27]World Medical Association Declaration of Helsinki. http://www. wma.net/en/30publications/10policies/b3/index.html webcite
• [28]Boutron I, Moher D, Altman DG, Schulz KF, Ravaud P. Extending the CONSORT statement to randomized trials of nonpharmacologic treatment: explanation and elaboration. Ann Intern Med. 2008; 148:295-309.
• [29]Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel group randomized trials. BMC Med Res Methodol. 2001; 1:2. BioMed Central Full Text
• [30]Castor Electronic Data Collection. https://castoredc. com/nl/ webcite
• [31]Huskisson EC. Visual analogue scales. In: Pain measurement and assessment. Melzack R, editor. Raven, New York; 1983: p.33-7.
• [32]Gagliese L, Weizblit N, Ellis W, Chan VW. The measurement of postoperative pain: a comparison of intensity scales in younger and older surgical patients. Pain. 2005; 117:412-420.
• [33]van Bergen CJ, Blankevoort L, de Haan RJ, Sierevelt IN, Meuffels DE, d’Hooghe PR et al.. Pulsed electromagnetic fields after arthroscopic treatment for osteochondral defects of the talus: double-blindrandomized controlled multicenter trial. BMC Musculoskelet Disord. 2009; 10:83. BioMed Central Full Text
• [34]Aaronson NK, Muller M, Cohen PD, Essink-Bot ML, Fekkes M, Sanderman R et al.. Translation, validation, and norming of the Dutch language version of the SF-36 Health Survey in community and chronic disease populations. J Clin Epidemiol. 1998; 51(11):1055-68.
• [35]Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992;30(6):473-83.
• [36]van den Akker-Scheek I, Seldentuis A, Reininga IH, Stevens M. Reliability and validity of the Dutch version of the Foot and Ankle Outcome Score (FAOS). BMC Musculoskelet Disord. 2013; 14:183. BioMed Central Full Text
• [37]Martin RL, Irrgang JJ, Burdett RG, Conti SF, Van Swearingen JM. Evidence of validity for the Foot and Ankle Ability Measure (FAAM). Foot Ankle Int. 2005; 26(11):968-83.
• [38]EuroQol – a new facility for the measurement of healthrelated quality of life. Health Policy. 1990; 16:199-208.
• [39]Lamers LM, Stalmeier PF, McDonnell J, Krabbe PF, van Busschbach JJ. Measuring the quality of life in economic evaluations: the Dutch EQ-5D tariff. Ned Tijdschr Geneeskd. 2005; 149:1574-1578.
• [40]Hakkaart-van Roijen L. Handleiding Short Form- Health and Labour Questionnaire (SF-HLQ). iMTA, Erasmus Universiteit, Rotterdam; 2010. www. imta.nl
• [41]van Roijen L, Essink-Bot ML, Koopmanschap MA, Bonsel G, Rutten FF. Labor and health status in economic evaluation of health care. The Health and Labor Questionnaire. Int J Technol Assess Health Care. 1996; 12(3):405-15.
• [42]Walter SD, Yao X. Effect sizes can be calculated for studies reporting ranges for outcome variables in systematic reviews. J Clin Epidemiol. 2007; 60(8):849-52.
• [43]O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979; 35:549-556.
• [44]International Committee of Medical Journal Editors. http://www. icmje.org webcite
• [45]Den Hartog BD. Fracture of the proximal fifth metatarsal. J Am Acad Orthop Surg. 2009; 17(7):458-464.