SUBJECT TO DEBATE: ORTHOBIOLOGICS IN ORTHOPAEDICS
From the 8th Annual Chicago Trauma Symposium
| REVIEW OF ORTHOBIOLOGICS: THE BURDEN OF PROOF —Thomas A. Einhorn, MD, Professor and Chairman,
Department of Orthopaedic Surgery, Boston University, Boston, MA
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| Evidence-based approach: effectiveness determined by randomized controlled trials (RCTs) and results of follow-
up; Journal of Bone and Joint Surgery now requires authors to state quality of evidence that led to their conclusions
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 | Levels of evidence: level I—randomized controlled trial; level II—prospective cohort study or RCT with limitations;
level III—case controlled or retrospective cohort study; level IV—case series (most common in orthopaedic
literature); level V—expert opinion
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| Underlying hypothesis: in context of ≈8 million fractures annually in United States (10%-20% experience difficulty
healing); healing would be enhanced by amplification of efficacy of specific molecules that participate in
healing process provided to patients with fresh fractures, nonunions, or delayed healing
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| Strategies to enhance skeletal repair:
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| Osteogenic materials: autologous bone (gold standard but never underwent RCT); allogeneic bone; autologous
bone marrow; autologous blood concentrates
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| Osteoconductive materials: calcium phosphate/hydroxyapatite; calcium sulfate; calcium sulfate/collagen composites;
demineralized bone matrix (DBM)
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| Tissue repair factors: status uncertain—thrombin peptides (failed RCT); vascular endothelial growth factor;
growth hormone; insulin-like growth factor; fibroblast growth factor; RCT pending—platelet-derived growth
factor; prostaglandin agonists
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| Osteoinductive factors: bone morphogenic protein (BMP)
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| Autologous blood concentrates: no evidence available; existing studies not applicable clinically; RCT required;
(level-IV study found autologous growth factors inferior to autologous bone graft in arthrodesis of spine)
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| Autologous bone marrow: speaker has “intuitive faith” bone marrow useful as adjunctive therapy; level III
evidence—cohort study demonstrated healing benefit in noninfected nonunions; involved carefully planned technique
that increased concentration of osteoprogenitor cells from bone marrow aspiration
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| Bone morphogenic protein: discovery (35 yr ago) that mammalian bone contains regenerative component led to
development of DBM and BMPs (15 known in humans); recombinant BMP products—BMP-2 marketed by
Medtronics as Infuse; BMP-7 (osteogenic protein [OP]-1) marketed by Stryker Biotech as OP-1 Putty
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| Level II evidence: showed DBM effective in arthrodeses of spine; DBM combined with small quantity of autologous
bone graft found equally effective as equivalent volume of autologous bone graft
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| Level I evidence: RCT of OP-1 in tibial nonunions; intramedullary (IM) nailing plus OP-1 on type 1 collagen carrier
found as effective as IM nailing plus autologous bone graft (standard of care); OP-1 granted new humanitarian
device approval for use on long-bone nonunions
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| Level I evidence: RCT of BMP-2 in open tibial shaft fractures; at time of definitive wound closure and fixation, patients
randomized to standard of care (no further treatment) or low-dose or high-dose BMP-2; results at 12
mo—high-dose BMP-2 group had 44% reduction in number of secondary interventions (follow-up operations),
fewer hardware failures and infections, and faster wound healing
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| Subgroup analysis: included Gustilo-Anderson open fractures grade I, II, IIIA, and IIIB; benefit limited to grade
IIIA and IIIB fractures; similar results—found in study of OP-1
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| DEBATE: STEM CELLS—FUTURE OF FRACTURE SURGERY —Matthew L. Jimenez, MD, Clinical Associate
Professor, Chicago Medical School at Rosalind Franklin University of Medicine and Science, and Chief of Orthopaedic
Trauma Services, Illinois Bone and Joint Institute, Lutheran General Hospital, Park Ridge, IL; Jeffrey O. Anglen,
MD, Professor and Chairman, Department of Orthopaedics, Indiana University School of Medicine,
Indianapolis, IN
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Pro: Dr. Jimenez
| Adult stem cells: uncommitted progenitor and precursor cells harvested from iliac crest and sent to Aastrom for
augmentation; returned in 2 wk as committed progenitor and precursor cells, termed tissue repair cells (TRCs)
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| Pilot trial: for determining safety and efficacy; limited to 36 patients; early results—for 7 patients with recalcitrant
atrophic nonunions (open tibia fractures); all healed within 24 wk
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| Surgical technique: goal to create stable mechanical construct and enhance biologic environment for bone and
vascular regeneration; remove previous fixation if necessary; hematologist obtains cell aspirate (20-50 mL) for
augmentation; resulting TRCs extracted with syringe and dripped on allograft; TRCs bind to allograft (placed under
vascularized muscular bed)
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| Conclusion: use of stem cells safe and efficacious in early results; adult stem cells represent future of fracture healing
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Con: Dr. Anglen
| Proposition: speaker’s formulation of debate topic; “stem cells will in the future dramatically reduce the need for
fracture surgery”; response—osteogenic stem cells may find limited role in extremely difficult fracture healing
problems; no more than adjunct to well-performed surgery
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| Impact on fracture surgery: time course of healing—stem cells recruited from blood and surrounding tissue at
initial stage and differentiated into factors involved in healing; stem cell recruitment probably lasts ≤2 wk (injection
of dedicated stem cells unlikely to affect need for surgery); nonunion—biology and biomechanics underlie
healing, ie, provide vascularity and stability; no evidence lack of stem cells contribute to nonunion; without blood
supply, stem cells unable to affect healing
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Rejoinders
| Dr. Jimenez: orthopaedics needs alternative to iliac crest for dependable graft; donor site morbidity presents problem
(major source of pain); osteobiologic industry developed in response; stem cells offer means for producing
grafts approaching quality of autograft
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| Dr. Anglen: Hope or Hype title of book about obsession with medical advances and high cost of false promises; existing
treatments already available for many innovations; new technologies may prove harmful or ineffective only
after many patients exposed to risk without benefit, eg, pedicle screws; summary—be skeptical; wait for evidence;
treat patients as you would want to be treated; take time to educate patients unable to evaluate new treatment
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| DEBATE: DEMINERALIZED BONE MATRIX: A USEFUL ADJUNCT? —Bruce H. Ziran, MD, Associate Professor
of Orthopaedic Surgery, Northeastern Ohio Universities College of Medicine, and Director of Orthopaedic Trauma,
St. Elizabeth Health Center, Youngstown, OH; Bradley R. Merk, MD, Assistant Professor of Orthopaedic Surgery,
Feinberg School of Medicine, Northwestern University, Chicago, IL
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Pro: Dr. Ziran
| Alternatives to DBM: autograft—gold standard; but problems include surgical complications (at best 5%-10% of
cases), long-term pain, limited quantity, and expense; reamer irrigator aspirator (RIA)—looks promising; but requires
second-site surgical preparation, lacks documented efficacy, and adds to expense; BMP—has level I evidence;
expensive; potential safety issues (antibody response; muscle calcification; neoplasms); expense leaves
those most in need less able to pay (eg, cuts in Medicare; federal denial shifts cost to states, then to hospitals [focused
on short-term budget cuts])
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| Advantages of DBM: use long established; relatively inexpensive; low morbidity; safety outstanding; especially
useful as graft extender; many level 3 to level 4 studies show DBM almost as effective as autograft
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| Conclusion: consider DBM current standard until alternative proven better; safe and affordable
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Con: Dr. Merk
| Market forces drive use of DBM: since considered “minimally manipulated human tissue allograft,” DBM has
not undergone rigorous studies required of other technologies; explains why “every company has one”
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| Limitation of studies: while available for spine, prospective studies unavailable for fractures, segmental defects,
or nonunions
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| Disadvantages: although easily available, DBM has limited structural support and osteoconductivity; effectiveness
not well established
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| Recent article in Spine: found wide variability among BMP products (BMP-4 undetectable; BMP-2 and BMP-7
found in nanogram concentrations); study questioned DBM’s reliability and possible efficacy in providing osteoinduction
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| Conclusion: DBM useful when acceptable iliac crest graft unavailable (eg, rheumatic nonunion); iliac crest remains
choice for challenging bone loss and segmental defects
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Rejoinders
| Dr. Ziran: level 1 studies may not be feasible; “this stuff works most of the time”; inexpensive and safe; when
rising costs may lead to choosing between “good OR (operating room) help and BMP,” DBM provides reasonable
option
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| Dr. Merk: companies not going to fund level I trial; speaker challenges surgeons to publish accumulated experience
providing level III and level IV evidence to increase understanding of DBM
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| DEBATE: BONE MORPHOGENIC PROTEIN IN FRACTURE HEALING —Kevin J. Pugh, MD, Ohio Limb Reconstruction
Center, Grant Medical Center, Division of Orthopaedic Trauma, The Ohio State University Medical
Center, Columbus, OH; Brent L. Norris, MD, Clinical Associate Professor, University of Illinois Chicago, Rockford
Campus, and Rockford Orthopaedic Associates, Rockford, IL
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Pro: Dr. Pugh
| Role of BMP: Dr. Einhorn presented main points; BMP-2 (Infuse) and BMP-7 (OP-1) commercially available;
BMP causes recruitment of stem cells to site of injury; BMP binds to stem cells before differentiation and amplification
of fracture healing
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| Study of BMP-2: RCT compared IM nailing with BMP with IM nailing alone; found 41% decrease in risk of secondary
interventions, 29% decrease in rate of nonunion; no increase in wound infections (decreased in high-grade
fractures); analysis of grade IIIA and IIIB fractures showed 90% decrease in unplanned bone grafts for nonunion
and 68% decrease in secondary interventions; surgical indications—open tibia fractures; currently off-label—
nonunions; smokers; poor hosts (eg, diabetes or organ transplantation); complex fractures with slow healing time
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Con: Dr. Norris
| Fracture healing process: 3 steps—gene expression at time of injury; biochemical stimulants (proinflammatory
cytokines); biomechanics (surgical intervention); BMP recruits cells and causes differentiation; process
requires delicate balance of many proteins (beyond BMP-2 and BMP-7); supratherapeutic doses of specific
protein not sufficient
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| Limitation of BMP: fracture healing requires more than BMP; BMP provides osteoinductive component; healing
also needs presence of cell lines (requires vascularity) and osteoconductive substrate; “too many unanswered
questions”—eg, pertaining to adequacy of substrate and method of application; safety issues—BMP’s role not limited
to bone healing; long-term safety unknown; may increase vascular calcification
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| Conclusion: BMP offers promise; but overused and misused; better research needed
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Rejoinders
| Dr. Pugh: while effective surgery essential for biomechanical support of biologic process, modulation of process
needed; BMP offers means of modulating fracture healing; available data demonstrate BMP effective; BMP provides
current option in selected patients
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| Dr. Norris: discusses RIA for harvesting bone; provides less invasive way to retrieve adult stem cells; reamer inserted
into bone canal; investigators confirmed presence of stem cells in canal (source of more protein stimulants
than iliac crest); final comment on BMP—offers viable alternative until supplanted by more effective option
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Educational Objectives
| The goal of this program is to educate the listener about the role of osteobiologics in orthopaedics. After hearing and
assimilating this program, the clinician will be better able to:
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| 1. Explain the purpose of adopting 5 levels of evidence as a standard component of the orthopaedic literature.
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| 2. Evaluate the underlying evidence for use of osteobiologic materials in orthopaedic surgery.
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| 3. Consider the future of stems cells in fracture surgery.
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| 4. Employ demineralized bone matrix as an adjunct in fracture surgery.
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| 5. Identify indications for the use of bone morphogenic protein to enhance fracture healing.
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Suggested Reading
Cammisa FP Jr et al: Two-year fusion rate equivalency between Grafton DBM gel and autograft in posterolateral
spine fusion: a prospective controlled trial employing a side-by-side comparison in the same patient. Spine 29:660,
2004; Cassidy C et al: Norian SRS cement compared with conventional fixation in distal radial fractures. A randomized
study. J Bone Joint Surg Am 85-A:2127, 2003; Devo RA, Donald L: Hope or Hype: The Obsession with
Medical Advances and the High Cost of False Promises. New York, NY: AMACOM, 2005;, Friedlaender GE et al:
Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am83-A
Suppl 1:S151, 2001; Friedlaender GE: Osteogenic protein-1 in treatment of tibial nonunions: current status. Surg
Technol Int13:249, 2004; Govender S et al: Recombinant human bone morphogenetic protein-2 for treatment of
open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg
Am 84-A:2123, 2002; Hernigou P et al: Percutaneous autologous bone-marrow grafting for nonunions. Surgical
technique. J Bone Joint Surg Am 88 Suppl 1 Pt 2:322, 2006; Lobenhoffer P et al: Use of an injectable calcium
phosphate bone cement in the treatment of tibial plateau fractures: a prospective study of twenty-six cases with
twenty-month mean follow-up. J Orthop Trauma 16:143, 2002; Nordsletten L: Recent developments in the use of
bone morphogenetic protein in orthopaedic trauma surgery. Curr Med Res Opin22 Suppl 1:S13, 2006; Patel TC et
al: Osteogenic protein-1 overcomes the inhibitory effect of nicotine on posterolateral lumbar fusion. Spine 26:1656,
2001; Starr AJ: Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures. J Bone
Joint Surg Am 85-A:2049; author replies 2049, 2003; Swiontkowski MF et al: Recombinant human bone morphogenetic
protein-2 in open tibial fractures. A subgroup analysis of data combined from two prospective randomized
studies. J Bone Joint Surg Am 88:1258, 2006; Urist MR: Bone: formation by autoinduction. 1965. Clin Orthop Relat
Res:4, 2002; Weiner BK et al: Efficacy of autologous growth factors in lumbar intertransverse fusions. Spine
28:1968, 2003; White AP et al: The 2002 Marshall Urist Young Investigator Award Paper. Lumbar arthrodesis
gene expression: a comparison of autograft with osteogenic protein-1. Clin Orthop Relat Res:330, 2004.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following
has been disclosed: Dr. Anglen—EBI, Inc. (consultant); Dr. Einhorn—Eli Lilly, Stryker Biotech, Biometrics (consultant;
grant recipient); Pfizer, Osteotech (consultant); Dr. Jimenez—Synthes (consultant); Zimmer, Exatech (research
support); Dr. Pugh—Smith&Nephew Orthopaedic (consultant).
The speakers were recorded at the 8th Annual Chicago Trauma Symposium, Matthew L. Jimenez, Course Chairman,
held July 27-30, 2006, in Chicago, IL. The Audio-Digest Foundation thanks Dr. Jimenez and all the speakers for their
cooperation in the production of this program.
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