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AAOS Now

Published 10/1/2015
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Philipp Leucht, MD; J. Tracy Watson, MD

Orthobiologics for Fracture Healing: Opportunities and Risks

Understanding of the biology of bone healing has increased dramatically, with a corresponding surge in the number of orthobiologics available for use in augmenting fracture healing and bone defect management. This often makes it problematic for surgeons to determine the correct biologic (osteogenic, osteoconductive, or osteoinductive) for a given clinical problem. Little formal guidance is available to help surgeons make educated decisions regarding the indicated use for a biologic or for the adjuvant that will have the most predictable and successful outcome for the specified indication.

Bone healing is a complex process involving many different cell types, tissues, and signaling pathways. As with a complex computer algorithm, the failure of one small component may crash the entire program. During fracture healing, the crucial interplay of biomechanics and biology may be affected by compromised blood supply, stripped periosteum, age-related decline in osteoprogenitor cells, systemic factors (immune suppression, malnutrition), mechanical instability, a critical sized bone defect, or a host of other conditions.

The orthopaedic surgeon must be able to correctly identify these obstacles and then address them, either by altering the conventional treatment strategy or by changing the healing environment by using exogenous stimuli. This is where orthobiologics can have their biggest effect. If a deficit is correctly identified, then, theoretically, the surgeon can restore the complete algorithm by simply adding the missing piece.

However, these impediments to fracture healing are not always easily identified. Providing an inappropriate adjuvant may have no effect at all or may be detrimental by preventing the fracture healing cascade from progressing normally.

Orthobiologics can be grouped into the following three categories:

  • matrix substitutes (osteoconductive)
  • growth factors (osteoinductive)
  • stem/progenitor cells (osteogenic)

This article describes the most commonly used members of each group (Table 1) and identifies their appropriate indications, risks, and potential outcomes.

Matrix substitutes
Matrix substitutes, including bone grafts (autograft and allograft) and bone graft substitutes (calcium ceramics such as tricalcium phosphate and tricalcium sulfate), comprise the most commonly utilized group of orthobiologics. Matrix substitutes have a very low risk profile and are indicated as bone void filler for metaphyseal defects.

These materials provide a substrate for native bone-forming cells to attach to and subsequently remodel into normal bone. They must be placed in a biologically active environment with a competent blood supply. The appropriate local environment should provide the proper biomechanics and cellular components for these materials to osteointegrate.

Autograft serves as the gold standard for almost all situations in which the use of orthobiologics is indicated. Autograft offers nearly every essential component involved in fracture healing, including stem cells, growth factors, bone matrix, and vascular progenitor cells. Therefore, if possible, autograft should be considered as the first line of treatment, because it is almost free of risks and side effects, except for donor site morbidity.

Alloplastic matrix substitutes are considered osteoconductive and provide strong compressive structural support, which makes them good candidates for bone voids if biomechanical strength is sought. Usually, alloplastic matrix substitutes are used in conjunction with stable internal fixation. The time to resorption of these materials is highly variable, ranging from weeks to years (sulfate < phosphate < ceramic) and should be taken into consideration when choosing them.

Growth factors
The U.S. Food and Drug Administration (FDA) has approved certain growth factors and allied substances for specific indications. These include the bone morphogenetic proteins (BMP)-2 and -7 and platelet-rich plasma (PRP). Platelet-derived growth factor (PDGF) is approved for use in Canada. Several additional agents, including sclerostin antibody and parathyroid hormone (PTH), are currently undergoing clinical trials and may enter the market in the near future.

Basic science investigators continue to identify critical signaling components of fracture healing. Every time a new therapeutic target is identified, a preclinical trial is undertaken to investigate the success and utility of the newly engineered protein.

DBM—Demineralized bone matrix (DBM) is used as a bridge material for a host of indications. It provides a tremendous surface area and can serve as a cellular attachment site. It functions much like the alloplastic bone void fillers, although without their compressive strength.

In theory, DBM contains a rich source of inductive growth factors, including BMP-2 and BMP-7, and other inductive factors found in the transforming growth factor (TGF)-β group of proteins. Numerous DBM formulations are available, based on refinements of the manufacturing process. They are available as freeze-dried powder, granules, gel, putty, or strips. They have also been developed as combination products with other materials such as allogeneic bone chips and calcium sulfate granules.

Its “off-the-shelf” availability makes DBM an attractive option in many clinical indications. Although both animal and human studies demonstrate comparable efficacy of DBM when combined with autograft or compared to autograft alone, additional high level-of-evidence studies are required to clearly define the indications and appropriate patient populations that will benefit from its use.

PRP—Autogenous PRP contains many endogenous growth factors found in platelets; basic science research suggests that this material offers a ready source of potent growth factors. By providing a variety of concentrated growth factors, PRP may play a role in enhancing bone healing.

Currently, it is common to combine the platelet-rich material with autograft, allograft, DBM, or other graft material (See “MMTGs in a Nutshell,” AAOS Now, March 2008). The initial enthusiasm of this material has been tempered by clinical results indicating that using PRP to augment bone formation may be most effective in diabetic fracture models; it may also be used to augment wound or tendinopathy healing.

BMP—Only BMP-2 and BMP-7 have made a significant impact in the treatment of posttraumatic bone defects. After an initial enthusiastic use of these materials clinically, very limited data have been published on the use of these devices within their strict on-label indications. Recent studies have uncovered potentially troublesome side effects, such as heterotopic bone formation, graft osteolysis, increased infection, radiculitis, and perhaps an increased risk for neoplasm.

Most growth factors have to be used in superphysiologic doses to elicit an effect similar to that engendered by their endogenous equivalents. Until safe and effective alternatives are identified, orthopaedic surgeons should be aware of the risks and examine other options before using this treatment approach.

Stem cells
Cellular therapies may eventually represent the most promising adjunct for the treatment of large bone defects. Stem cells have been used in a variety of medical specialties to restore organs and improve quality of life. Orthopaedic surgery has been slower in the advancement of cell therapy approaches for musculoskeletal conditions; however, recent advances are promising. Available cell-based strategies include targeting local cells with the use of scaffolds or bioactive factors and transplanting autogenous connective tissue progenitor cells derived from bone marrow or other tissues.

Stem cells may be the ideal biologic treatment because they recreate the original microenvironment and supply paracrine factors to the fracture. Bone marrow aspirate contains a variety of different cell types, such as endothelial progenitor cells (EPCs), osteoprogenitor cells (OPCs), stem cell niche-supporting cells, and cytokines. It may be the most meaningful and low-risk cell-based therapy.

The future of orthobiologics is bright. It is on us, orthopaedic surgeons, to be mindful and careful about the use of these products during the early, investigational phase. Once clinical indications are better defined, our patients will greatly benefit from their use.

Philipp Leucht, MD, is an assistant professor in the department of orthopaedic surgery at the New York University School of Medicine–Hospital for Joint Diseases; J. Tracy Watson, MD, is a member of the AAOS Biological Implants Committee and professor of orthopedic surgery, chief of the orthopedic trauma service in the department of orthopedic surgery at Saint Louis University School of Medicine.

References:

  1. Devine JG, Dettori JR, France JC, Brodt E, McGuire RA: The use of rhBMP in spine surgery: Is there a cancer risk? Evid Based Spine Care J 2012;3(2):35-41.
  2. Cooper GS, Kou TD: Risk of cancer after lumbar fusion surgery with recombinant human bone morphogenic protein-2 (rh-BMP-2). Spine (Phila Pa 1976) 2013;38(21):1862-1868.
  3. Lad SP, Bagley JH, Karikari IO, et al: Cancer after spinal fusion: The role of bone morphogenetic protein. Neurosurgery 2013;73(3):440-449.