The Journal of Bone & Joint Surgery

Symposium Articles | February 01, 2008

Critical Analysis of the Evidence for Current Technologies in Bone-Healing and Repair

Wendy M. Novicoff, PhD; Abhijit Manaswi, MD, MS, DNB, FRCS; MaCalus V. Hogan, MD; Shawn M. Brubaker, DO; William M. Mihalko, MD, PhD; Khaled J. Saleh, MD, FRCSC, MSc(Epid)

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Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from Stryker Inc., and Smith and Nephew, Inc. In addition, one or more of the authors or a member of his or her immediate family received, in any one year, payments or other benefits in excess of $10,000 or a commitment or agreement to provide such benefits from a commercial entity (Stryker Inc. and Ethicon, Inc.). No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

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J Bone Joint Surg Am, 2008 Feb 01;90(Supplement 1):85-91. doi: 10.2106/JBJS.G.01521

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Abstract

Substances that enhance fracture-healing and bone regeneration have valuable clinical application and merit future research. Advances in these technologies will enhance our ability to heal fractures in a more effective and expedient manner. This review provides a brief description of the different techniques and technologies and their respective clinical utility. This paper also reviews the available literature on gene therapy, tissue engineering, growth factors, osteoconductive agents, and physical forces and assesses the evidence regarding the current status of these techniques of healing and regenerating bone.

Only twenty-seven articles met our guidelines for studies containing Level-I evidence. We were able to determine that atrophic nonunions and pseudarthrosis led to poorer outcomes, and the results were uniformly poor irrespective of the technique used.

Although the literature contains a large number of studies on the effects of different agents and modalities on bone repair and healing, it still is not clear how these agents work or in what circumstances they should be used. Many of the treatment modalities of interest are still at an experimental stage, so good evidence to support clinical practice is lacking. Additional multicenter, prospective randomized studies are needed to define the indications, specifications, dosage, limitations, and contraindications in the treatment of nonunions. Studies are also needed to address the full clinical feasibility of the role of each modality in fracture-healing and repair.

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Fractures and the Approach to Bone-Healing

Bone-healing requires a sequence of events to restore the integrity of the bone and its biomechanical properties. Delayed or impaired healing will occur in 5% to 10% of the 5.6 million fractures that occur annually in the United States, and up to 10% of all fractures will require additional surgical procedures for impaired healing¹. Recent studies suggest that the lifetime risk of fracture is 50% for males and 33% for females².

The standard treatment for delayed healing and non-unions has been open surgical fixation with autogenous bone-grafting. This provides essential elements for bone formation: osteoinduction, osteoconduction, and osteoprogenitor cells. However, autogenous bone-grafting provides limited options and is associated with donor-site morbidity³. Many other biological and biophysical approaches have been developed to minimize the occurrence of delayed unions and non-unions. Biological approaches include gene therapy, tissue engineering, osteoconductive biomaterials, growth factors, bone-marrow aspirates, and osteocompetent cells. Physical forces include mechanical stimulation by low-intensity ultrasound, electromagnetic fields, and extracorporeal shock-wave therapy. There have also been recent studies on the impact of drugs and hormonal therapy, especially parathyroid hormone, on bone repair.

Materials and Methods

A literature search of English-language databases (MEDLINE and PubMed) was performed for original studies with clinical information on how various modalities affect bone fracture-healing and nonunion. Additional references were identified by citation tracking, and duplicates were removed. A table in the Appendix shows the search terms used in the literature review, including the different types of bone-healing modalities, and Table I shows the inclusion and exclusion criteria that were employed.

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TABLE I Number of Level-I Studies That Met Inclusion and Exclusion Criteria

Treatment Modality	Number of Studies That Met Inclusion Criteria^*	Number of Remaining Studies After Exclusion Criteria Were Applied†	Number of Manuscripts with Level-I or II Evidence After Review	Number of Manuscripts with Level-I Evidence
Pulsed electrical and electromagnetic fields	50; M = 1, P = 49	14	14	4
Extracorporeal shock-wave therapy	262; M = 126, P = 136	19	19	1
Low-intensity pulsed ultrasound	32; M = 14, P = 18	11	11	4
Calcium sulfate	47; M = 9, P = 38	3	3	0
Calcium phosphate	68; M = 64, P = 4	10	9	0
Tricalcium phosphate	229; M = 203, P = 26	8	8	7
Coralline	184; M = 180, P = 4	4	4	2
Type-I collagen	87; M = 60, P = 27	3	3	2
Growth factors and bone morphogenetic protein	244; M = 108, P = 136	11	11	7
Bone-marrow aspirate	179; M = 165, P = 14	7	7	0
Demineralized bone matrix	122; M = 79, P = 43	8	8	0
Gene therapy	143; M = 127, P = 16	0	0	0
Tissue engineering	16; M = 12, P = 4	0	0	0
Parathyroid hormone	64; M = 0, P = 64	0	0	0
Other nonbiological substances: glass, polymers, metals	295; M = 165, P = 130	0	0	0
Total	2022	98	97	27

To meet inclusion criteria, studies had to be human-subject clinical trials that addressed fracture and bone-healing, nonunion of fracture, and the role of the modality used. M = Number of articles in MEDLINE; P = Number of articles in PubMedExclusion criteria were nonhuman studies, retrospective studies, case reports, and poor experimental design

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TABLE I Number of Level-I Studies That Met Inclusion and Exclusion Criteria

Treatment Modality	Number of Studies That Met Inclusion Criteria^*	Number of Remaining Studies After Exclusion Criteria Were Applied†	Number of Manuscripts with Level-I or II Evidence After Review	Number of Manuscripts with Level-I Evidence
Pulsed electrical and electromagnetic fields	50; M = 1, P = 49	14	14	4
Extracorporeal shock-wave therapy	262; M = 126, P = 136	19	19	1
Low-intensity pulsed ultrasound	32; M = 14, P = 18	11	11	4
Calcium sulfate	47; M = 9, P = 38	3	3	0
Calcium phosphate	68; M = 64, P = 4	10	9	0
Tricalcium phosphate	229; M = 203, P = 26	8	8	7
Coralline	184; M = 180, P = 4	4	4	2
Type-I collagen	87; M = 60, P = 27	3	3	2
Growth factors and bone morphogenetic protein	244; M = 108, P = 136	11	11	7
Bone-marrow aspirate	179; M = 165, P = 14	7	7	0
Demineralized bone matrix	122; M = 79, P = 43	8	8	0
Gene therapy	143; M = 127, P = 16	0	0	0
Tissue engineering	16; M = 12, P = 4	0	0	0
Parathyroid hormone	64; M = 0, P = 64	0	0	0
Other nonbiological substances: glass, polymers, metals	295; M = 165, P = 130	0	0	0
Total	2022	98	97	27

The search was performed on the basis of three criteria: (1) studies focused on osteogenesis and/or fracture-healing and/or bone repair and/or nonunion, (2) controlled clinical trials and/or randomized clinical studies (by publication type), and (3) each individual modality (e.g., ultrasound or growth factors). Citation tracking yielded additional pertinent articles, and all screened articles were abstracted by trained abstractors with use of guidelines developed by Sackett et al.⁴. All articles that were determined to have Level-I evidence were re-reviewed by a second abstractor for agreement. Any differences were resolved by discussion.

Results

Table I shows the number of studies that met inclusion and exclusion criteria, those that had Level-I or II evidence, and those that contained Level-I evidence for each modality. Only twenty-seven articles met the criteria for having Level-I evidence, including articles on growth factors and bone morphogenetic proteins (seven articles), tricalcium phosphate (seven), ultrasound (four), and pulsed electrical and electromagnetic fields (PEMF) treatment modalities (four). Several of the modalities of interest had no articles with Level-I evidence: gene therapy, tissue engineering, calcium sulfate, calcium phosphate, parathyroid hormone, demineralized bone matrix, and nonbiological substances. Tables in the Appendix list the studies with Level-I evidence. Each modality and its available evidence are briefly described below.

Physical Forces on Bone-Healing and Repair

Skeletal tissues respond to environmental physical demands by altering the synthesis and organization of the extracellular matrix. This response may be therapeutically manipulated to stimulate bone-healing and repair.

Many observational studies suggest the efficacy of PEMF in stimulating healing of delayed union and nonunions. Response to treatment of nonunions through this method is related to dose, frequency, amplitude, and duration of treatment^5-12. However, there seems to be little evidence that this method is effective for gap nonunions and pseudarthroses (at least as the sole treatment), and the need for prolonged treatment using this method remains a concern¹³.

Four studies on PEMF met criteria for Level-I evidence. A meta-analysis by Aaron et al.¹⁴ found supporting evidence for the effectiveness of PEMF in the stimulation of bone repair in fractures by comparing regular surgical treatment and PEMF treatment. The overall success rate of PEMF was similar to surgical treatment for tibial nonunions (81% versus 82%). Results favoring PEMF to cast treatment were reported by Simonis et al.¹⁵, Brighton et al.¹⁶, and Sharrard¹⁷.

Extracorporeal shock-wave therapy (ESWT) induces local decortication and fragmentation to stimulate osteogenesis. This modality was introduced by Valchanou and Michailov¹⁸ and Schleberger and Senge^19,20 as a noninvasive treatment for delayed bone-healing^21-23. There are many studies with a wide variety of populations, fracture types, and end points that examine this treatment modality, but there is currently no standard for orthopaedic applications^24-30. Noninvasiveness and low complication rates are cited as advantages^24,25, but definition of indications and dosages awaits prospective randomized studies. While there are no Level-I studies as yet, Birnbaum et al.²⁵ reviewed Level-II ESWT studies on non-unions and concluded that the treatment promotes bone-healing and merits further study.

Low-intensity pulsed ultrasound (LIPUS) is applied percutaneously, but the exact mechanism on bone-healing remains unknown^31-42. Study review suggests that LIPUS promotes healing in new fractures and established nonunions, but the average time to fracture union can be as much as five months^42-48. Outcomes equivalent to surgical intervention were noted in some studies, but these were nonrandomized, non-controlled case series with considerable variation of indications, fracture sites, fracture severities, initial treatments, and extent and number of prior surgical interventions^31-48. Of the four studies with Level-I evidence, three showed that use of LIPUS appreciably reduced healing time by up to 38% compared with other treatments^47,49,50. The fourth did not show a significant difference, but this trial had a relatively small number of enrolled patients⁵¹.

Biological Forces on Bone-Healing and Repair

Osteoconductive materials support new bone formation through ingrowth of host bone into and/or onto a scaffolding material^52-55. There are several types of osteoconductive materials that can be used to potentially heal fractures. Calcium sulfates and phosphates are strong in compression but weak in tension and shear^56,57. Calcium sulfate has predictable resorption in vivo due to minimal trace elements and biodegradability^58-60. Calcium phosphates with osteoconductive and osteointegrative properties are hydroxyapatite and tricalcium phosphate^54,55. Because of its increased porosity and solubility, tricalcium phosphate is more rapidly absorbed than hydroxyapatite, but those same qualities render tricalcium phosphate inadequate when structural support is desired⁵². Another osteoconductive material, type-I collagen, is the most abundant extracellular bone-matrix protein. Alone, type-I collagen is a poor graft substitute, but in combination with bone morphogenetic proteins, osteoprogenitor precursors, or hydroxyapatite, its osteoconductive potential increases considerably⁵⁵. A number of non-biological osteoconductive materials are available, such as bioactive glass, biodegradable polymers, and porous and plasma-coated metals, but all of these materials require more rigorous clinical trials to analyze their effectiveness⁵⁴.

Randomized studies of osteoconductive materials thus far have been encouraging. Shors compared coralline hydroxyapatite to autograft for 174 long-bone defects and found that time to union was not significantly different at 4.5 months⁶¹. Earlier, Bucholz et al. reported similar results with the use of coralline hydroxyapatite in forty tibial plateau fractures⁶². Mattsson and Larsson compared closed reduction and cannulated screw fixation versus cannulated screws plus calcium phosphate cement in the treatment of displaced fractures of the femoral neck and found no difference in pain or muscle strength between groups, but thirty-four patients (fourteen in the control group, twenty in the calcium phosphate group) required conversion to total hip replacement⁶³. Mattsson et al. also reported favorable outcomes with use of calcium phosphate cement in unstable peritrochanteric and displaced femoral neck fractures^64-66. Favorable results with use of calcium phosphate cement have been reported by Cassidy et al.⁶⁷, Zimmermann et al.⁶⁸, and Sanchez-Sotelo et al.⁶⁹. Chapman et al.⁷⁰ compared the use of iliac bone graft to a collagen composite for long-bone fractures and found no difference in outcome except for a higher rate of infection with use of iliac bone graft. Similar results were reported by Cornell et al., who found no significant difference in hospital length of stay or pain scores⁷¹.

Various growth factors are expressed during fracture-healing, and manipulation of their concentration is postulated to influence bone-healing favorably^72,73. Various cell types and growth receptors are present within fracture callus, depending on the stage of healing, leading to a "window of opportunity" for directed use of specific growth factors^73-75. The goal of treatment is to deliver growth factors to the fracture site, so research has focused on the development of appropriate carriers or delivery systems. Several have been developed, including type-I collagen^76,77, synthetic polymers⁷⁷, and hyaluronic acid gels^78,79. Certain growth factors, such as transforming growth factor-beta, insulin-like growth factor, and platelet-derived growth factor, have insufficient data in preclinical trials to determine efficacy^80-87. Bone morphogenetic proteins (BMPs) are the most potent osteoinductive materials, and several clinical trials in humans have proven their efficacy^88-94. Friedlaender et al. concluded that recombinant human bone morphogenetic protein-7 (rhBMP-7) administration was as good as grafting and was not associated with the donor-site morbidity that usually occurs in more than 20% of patients receiving an autograft⁸⁸. The BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group compared the effects of two different exogenous rhBMP-2 concentrations versus no rhBMP-2 on the healing of nailed open tibial fractures⁸⁹. A dose-dependent effect was observed, with faster healing times and fewer secondary interventions for delayed unions and nonunions. Level-I studies by Swiontkowski et al.⁹⁰, Giannoudis and Tzioupis⁹¹, Zimmermann et al.⁹², Bilic et al.⁹³, and Jones et al.⁹⁴ have shown promising results of rhBMPs as well. Appropriate dosages, optimum time, modes of delivery, duration of treatment, and precise clinical indications for use have to be explored further. It will also be important to determine whether or not clinical evidence for this type of fracture repair will justify the cost of treatment.

The use of percutaneous bone-marrow aspirates is an attractive technique for closed treatment of fractures, but, to our knowledge, there are currently no Level-I randomized studies comparing the efficacy of bone-marrow aspirates to that of autologous bone graft. Currently, little information is available regarding the number and concentration of cells that are necessary for bone repair^95,96, and several studies have pointed out the human variability with respect to bone-marrow cellularity and osteoblast progenitor-cell prevalence^97-100. Studies examining growth-factor exposure and combination with collagen¹⁰¹ to increase stem-cell proliferation and differentiation are under way. Randomized clinical studies with strict inclusion and exclusion criteria will better define their role and indications for osseous repair.

Demineralized bone matrix substances are produced by acid extraction of bone and contain noncollagenous proteins, growth factors, bone morphogenetic proteins, and type-I collagen¹⁰². Demineralized bone matrix is available in different formulations: freeze-dried powder, granules, strips, gel, paste, and putty alone or in combination with allograft bone chips or calcium sulfate granules. Although it provides no structural support, demineralized bone matrix is useful for filling bone defects and cavities^103,104. The osteoinductive efficacy of these products ranges widely, depending on bone type, sterilization process, carrier, quantity of BMPs present, and the ratios of each^105,106. There are several animal studies that support the osteoinductive effects of demineralized bone matrix, but to our knowledge there are no randomized controlled trials in humans that compare the efficacy of demineralized bone matrix with that of autologous bone¹⁰². Currently, demineralized bone matrix substances can only be recommended as graft extenders^102,103.

In the past few years, there has been considerable interest in the use of platelet gels, which are created by isolating a concentration of platelets from the patient's own blood. Platelet gels contain many growth factors that can help in bone formation and can play a key role in the formation and maturation of osseous fusions^107,108. Since they lack osteoinductive proteins, they should only be used as graft extenders. Well-controlled randomized clinical studies are required to assess the optimum concentration of the different factors and to determine which factors would provide the greatest effect.

Human gene therapy is another feasible option, and the decreased invasiveness of the technique is attractive, but, to our knowledge, there are currently no Level-I studies to help with clinical decision-making regarding bone repair. This therapy is focused on treating human diseases by transferring genetic material to individual cells¹⁰⁹, thus reestablishing damaged cellular function, introducing a new function, and/or interfering with an existing function¹¹⁰. Success is based on three fundamental steps: identification of the specific genetic material to be transferred, the method of transfer, and the cell type that would incorporate the material^111,112. Promising preclinical data have emerged on tissue repair, cancer, and regeneration of bone, cartilage, ligament, tendon, meniscus, and intervertebral disc^111-114. Other applications include osteoporosis, aseptic loosening, genetic diseases, musculoskeletal infections, and tumors^114-117. Segmental defect repair of long bones and spinal fusion have also been associated with impressive preclinical study results^111,113,114.

Orthopaedic tissue engineering combines the use of three-dimensional scaffold materials, cells, and release of growth factors, but the technique is still in experimental stages¹¹⁸. The goal in tissue engineering is reconstitution of tissues that have failed to regenerate or heal spontaneously. Mesenchymal stem cells are capable of differentiating into bone-forming osteoblasts with appropriate growth factors present both in vitro and in vivo^119,120. These cells are biopsied from the patient and are grown on engineered biomaterials in vitro and implanted at the desired treatment location¹²¹. Many biodegradable polymers and ceramics with absorbed growth factors are in trial as substitutes for skeletal elements such as cartilage and bone^122-125.

Preclinical studies suggest that intermittent exposure to parathyroid hormone may benefit fracture-healing and implant fixation^126-128. Continuous exposure to parathyroid hormone results in bone resorption, but intermittent doses result in bone formation through increased osteoblastic activity^129,130. Clinical studies are required to determine if this hormone will benefit patients with fractures, what the optimal treatment duration might be, and if resorption inhibitor treatment after parathyroid hormone therapy will improve fracture repair^128-130.

Conclusions

Induction of bone-healing by chemical, biophysical, and hormonal means is a rapidly growing area. Many therapies and treatment modalities have the potential to transform future orthopaedic treatment by decreasing invasive procedures and providing shorter healing times. Promising results have been seen in many experimental models and form the basis of increasing clinical application of these therapies in human subjects. However, clinical evidence of the efficacy of these modalities is not clearly defined in the literature. For many modalities, precise clinical indications, timing, dosage, and mode of action are unclear. Most studies lack clear inclusion and exclusion criteria and many were case series involving heterogeneous patient populations with a tendency to combine treatment modalities, which increases the complexity of the analysis. Few randomized clinical trials support many practiced modalities today. No study to date has critically analyzed the difference in time to union with and without these bone-healing therapies. Cost-to-benefit analysis is also lacking. Further preclinical and clinical studies are required to clarify the relative effectiveness of many agents in current use. Better understanding of bone physiology, better surgical management to provide improved environmental condition of surrounding soft tissue, and biomechanical stability of the fracture are some of the fundamental steps that could help to determine outcome.

We conclude that additional focused independent randomized clinical studies with strict inclusion and exclusion criteria are required to accurately define indications and analyze evidence for widespread use of the different modalities for enhancing bone repair and healing in the twenty-first century.

Appendix

Tables showing the literature search terms used and listing the Level-I studies described are available with the electronic versions of this article, on our web site at (go to the article citation and click on "Supplementary Material") and on our quarterly CD-ROM (call our subscription department, at 781-449-9780, to order the CD-ROM). ?

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Topics

fracture ; fracture healing ; growth factor ; osteoplasty

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Wendy M. Novicoff, Abhijit Manaswi, MaCalus V. Hogan, Shawn M. Brubaker, William M. Mihalko, Khaled J. Saleh; Critical Analysis of the Evidence for Current Technologies in Bone-Healing and Repair. The Journal of Bone & Joint Surgery. 2008 Feb;90(Supplement_1):85-91.

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