J Am Acad Orthop Surg, Vol 16, No suppl_1, July 2008, S72-S75.
© 2008 the American Academy of Orthopaedic Surgeons
What potential biologic treatments are available for osteolysis?
Edward M. Schwarz, PhD
Dr. Schwarz is Professor, Department of Orthopaedics, University of Rochester Medical Center, Rochester, NY.
*The Implant Wear Symposium 2007 Biologic Work Group included Thomas W. Bauer, MD, PhD, Joan Bechtold, PhD, Mathias Bostrom, MD, Patricia A. Campbell, PhD, Victor Goldberg, MD, Stuart B. Goodman, MD, PhD, Ed M. Greenfield, PhD, Joshua J. Jacobs, MD, Yrjö Konttinen, MD, PhD, Regis O’Keefe, MD, PhD, Francis Young-In Lee, MD, Edward M. Schwarz, PhD, Arun S. Shanbhag, PhD, MBA, Robert Lane Smith, PhD, Rocky S. Tuan, PhD, and J. Mark Wilkinson, PhD, FRCS(Tr&Orth).
Dr. Schwarz or a member of his immediate family has received research or institutional support from the National Institutes of Health, DePuy, and Amgen; has received miscellaneous nonincome support, commercially derived honoraria, or other nonresearch-related funding from Amgen; has stock or stock options in Amgen; and is a consultant to or an employee of Amgen.
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Abstract
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The host response to wear debris particles constitutes a major component of periprosthetic osteolysis and aseptic loosening. Thus, biologic interventions represent a logical approach to prevent this complication of total joint replacement. Several major obstacles must be overcome before a therapeutic intervention can emerge, most notably the development of a safe and effective drug, as well as the development of a quantitative outcome measure that can prove efficacy in a relatively small multicenter trial of patients with established osteolysis. Research is needed in several areas, including whether a threshold phenomenon exists for osteolytic progression, whether anabolic agents administered postoperatively can significantly increase osteointegration of the implant and reduce the potential for aseptic loosening, and whether RANKL antagonists can inhibit the progression of periprosthetic osteolysis. Imaging advancements and an osteolysis registry would significantly enhance the potential for a successful clinical trial.
The emergence of highly effective biologic therapies to prevent bone loss in patients with specific diseases (eg, osteoporosis, rheumatoid arthritis, bone cancer) indicates that a therapeutic intervention for periprosthetic osteolysis should already be available. However, several practical issues with drug development and testing have prevented attainment of this goal. The most important of these issues are (1) whether the treatment should be prophylactic, since most joint arthroplasty patients do not develop significant periprosthetic osteolysis; (2) the absence of a quantitative outcome measure of the progression of osteolysis in patients; (3) our inability to predict the risk of osteolysis progression and catastrophic failure in a given patient; (4) issues related to commercialization, such as the risk-benefit potential of a drug specifically developed for aseptic loosening; and (5) the absence of an osteolysis registry that would facilitate investigator-initiated clinical trials in patients with established periprosthetic osteolysis. On the positive side, several candidate drugs could prove to be beneficial based on their clinical success in other indications (Table 1; Figure 1). These major issues must be addressed in the development of a biologic treatment for osteolysis.
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Figure 1 Potential biologic treatments for aseptic loosening and their mechanism of action. Macrophages (M ) are the primary responder cells to wear debris, which results in the production of proinflammatory factors, including transforming necrosis factor (TNF) and interleukin (IL)-1. These factors have pleiotropic effects because they both stimulate osteoclastic bone resorption and inhibit osteoblastic bone formation. Thus, biologic antagonists (ie, etanercept, anakinra) would inhibit bone resorption and promote bone formation. Prostaglandin E2 (PGE2) is also produced by macrophages and other cells in response to wear debris. Blocking this process with nonsteroidal anti-inflammatory drugs (NSAIDs) inhibits both bone resorption and bone formation. While bisphosphonates (eg, alendronate) inhibit mature osteoclasts from resorbing bone in settings of noninflammatory bone loss, RANKL inhibition by a selective antagonist (ie, denosumab) has the unique ability of directly inhibiting osteoclast formation, activation, and survival in settings of metabolic and inflammatory bone loss. The primary mechanism of action of anabolic agents (eg, teriparatide) is to promote osteoblast activity and survival to increase bone formation.
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That aseptic loosening occurs in only a small fraction of patients who undergo total joint arthroplasty suggests that prophylaxis is not justified based on safety and economic considerations. However, given that superior implant fixation would be beneficial to all, particularly the individual who will go on to develop osteolysis, an effective intraoperative and/or short-term postoperative treatment is worthy of consideration. Potential biologic treatments include antiresorptive agents such as the bisphosphonates (eg, alendronate, risedronate, zoledronic acid) and receptor activator of nuclear factor-
B ligand (RANKL) antagonists (ie, denosumab), which would allow for greater bone stock development during osseointegration. Another potential prophylactic approach is the use of anabolic agents, such as recombinant human parathyroid hormone (teriparatide) following surgery that could enhance osseointegration by increasing bone formation around the implant.
Because of the enormous expense of developing a novel drug for a new indication such as aseptic loosening, the pharmaceutical industry demands great commercial potential before undertaking drug development. The number of patients with aseptic loosening does not support a highly favorable commercial model, so successful drug therapy will likely emerge from an existing drug with US Food and Drug Administration approval that was developed originally for another indication. Several such candidate drugs are worthy of consideration based on their success in preventing inflammatory bone loss, most notably in rheumatoid arthritis, and their preclinical efficacy in models of wear debris–induced osteolysis. Unfortunately, these do not include the bisphosphonates, which have failed to meet the prospective end point of treatment of focal periarticular erosions in clinical trials in patients with rheumatoid arthritis.1-4 Furthermore, despite broad off-label use of bisphosphonates in patients with periprosthetic osteolysis, successful treatment has yet to be reported. This lack of efficacy in conditions of inflammatory bone loss has been ascribed to the anti-apoptotic inflammatory signals that render osteoclasts insensitive to bisphosphonate-induced apoptosis.5
These observations led to the suggestion that anti-inflammatory drugs, such as traditional nonsteroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase (COX) inhibitors (eg, celecoxib), tumor necrosis factor (TNF) antagonists (eg, etanercept, infliximab, adalimumab), and interleukin-1 antagonists (eg, anakinra) would be useful in preventing osteolysis progression. Although this may be the case, the side effects of these drugs are of concern, most notably the antianabolic effects of NSAIDs and COX-2 inhibitors, and the immunosuppressive effects of all of these anti-inflammatory drugs. This latter point is of particular importance given that periprosthetic osteolysis may not be aseptic but rather may be associated with ongoing infection.
Since the discovery of RANKL and osteoprotegerin (OPG) as the final effectors of osteoclastogenesis and bone resorption,6 an aggressive effort has been underway to develop a biologic antagonist of this pathway as a therapeutic modality for metabolic bone disease. In addition to their dominant mechanism of action in preventing wear-induced osteolysis in animal models,7-10 RANKL antagonists have consistently demonstrated no immunosuppressive effects. Moreover, the recent discovery that a human recessive null mutation in RANKL results in clinical osteopetrosis without immunosuppression formally demonstrates the specificity of this drug target for the skeletal versus the immune system.11 Thus, RANKL antagonists are now considered to be the most promising candidates for nonsurgical management of osteolysis.12 Although early candidate OPG molecules failed to meet clinical expectations, a human monoclonal antibody that recognizes RANKL (ie, denosumab) is showing promise in phase II and phase III clinical trials.13 Data from the definitive phase III osteoporosis trial are expected within 2 years.
Another important consideration for a biologic therapy is whether the drug should be given systemically or locally. Although this is less of a concern for a drug with a well-established safety profile, drug delivery restricted to the affected joint remains the goal. Delivery could be accomplished by intra-articular injection, through a drug-eluting device, or, potentially, via gene therapy. For example, local gene delivery of a soluble inhibitor of TNF (sTNFR:Fc) has been shown to prevent wear-induced osteolysis in a mouse model.14 The sTNFR:Fc fusion protein contains the extracellular domain of the human type I TNF receptor fused to the Fc region of mouse immunoglobulin. It acts by binding to TNF and prevents signaling through the membrane-bound TNF receptors. Likewise, systemic etanercept (human sTNFR:Fc protein therapy) also can reduce osteoclastic bone resorption in vitro and in the mouse calvarial osteolysis model,15 but it failed to demonstrate an obvious effect in a small feasibility pilot of patients with osteolysis.16 Given its known immunosuppressive effects, which can lead to opportunistic infections and malignancies,17 the risk versus benefit of anti-TNF therapy needs to be considered.
Since a reasonable phase III trial to assess the efficacy of a drug therapy to prevent the progression of osteolysis is likely to be investigator-initiated, such a study would have limited size and scope, perhaps including 300 patients over 3 years. Thus, the primary outcome measure must have sufficient sensitivity to detect significant progression of osteolysis. Moreover, biomarkers that can eliminate from the study the majority of patients in whom osteolysis will not progress, and the identification of those rare patients who are unknowingly in need of revision surgery due to loosening, are both needed to optimize rigid entry criteria that maximize the chance that the trial will be successful. Sophisticated three-dimensional longitudinal imaging will clearly be required to quantify the amount of osteolysis serially. One candidate approach is computed tomography, which has been independently used to correlate two-dimensional polyethylene wear and osteolytic volume and to demonstrate significant osteolytic progression over 1 year in patients with osteolytic lesions >10 mL.18,19 Although progress has been encouraging, future studies are needed to refine these imaging outcomes for analysis of cancellous bone and for more reliable predictions of the potential for progression of osteolysis. This new information could provide critical insight into the biologic factors that determine the risk of aseptic loosening.
If there is to be an investigator-initiated drug trial for osteolysis, how will sufficient numbers of patients be recruited? Preliminary power calculations indicate that at least 200 total hip arthroplasty patients with periacetabular osteolytic lesions >10 mL might be suitable for an efficacy trial.16 Spatial location and distribution of the osteolytic lesions might also be a crucial variable. Given that patients with extensive periprosthetic osteolytic lesions matching this size criterion are rare, efforts to generate a novel clinical database of patients who are treated in large clinical centers are warranted.
It is also important to recognize that once an implant is mechanically loose, continuous micromotion will prevent reintegration even if osteolysis is arrested. Thus, pharmacologic attempts to rescue a failing implant probably are not indicated for an implant that is already mechanically loose as these patients are at high risk for catastrophic fracture.
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Future Directions for Research
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Based on the remarkable progress that has been made toward developing a complete understanding of wear debris–induced osteolysis and aseptic loosening from research in preclinical models, several hypotheses have emerged that warrant investigation in patients with total joint arthroplasty. The first is whether a threshold phenomenon exists for osteolytic progression. Based on the results from two small clinical pilot studies that indicated a marked increase in osteolysis progression in patients with lesions >10 mL versus patients with smaller lesions, attempts to explain this observation through finite element modeling of biomechanical forces on the bone could further substantiate this critical biomarker. There is also a need to investigate the effects of anabolic agents postoperatively to see whether they can significantly increase osteointegration of the implant and thus decrease the potential for aseptic loosening. Finally, although a large body of preclinical data has demonstrated that RANKL antagonists are effective in all models of inflammatory bone loss, including wear debris–induced osteolysis, it remains to be seen whether such a drug (ie, denosumab) can inhibit the progression of periprosthetic osteolysis. Further advances in imaging the cancellous bone adjacent to the implant and the genesis of an osteolysis patient registry will markedly enhance the potential for a successful clinical trial.
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Tables
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References
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- Ralston SH, Hacking L, Willocks L, Bruce F, Pitkeathly DA: Clinical, biochemical, and radiographic effects of aminohydroxypropylidene bisphosphonate treatment in rheumatoid arthritis. Ann Rheum Dis 1989; 48:396-399. [Abstract/Free Full Text]
- Eggelmeijer F, Papapoulos SE, van Paassen HC, et al: Increased bone mass with pamidronate treatment in rheumatoid arthritis: Results of a three-year randomized, double-blind trial. Arthritis Rheum 1996; 39:396-402. [ISI][Medline]
- Jarrett SJ, Conaghan PG, Sloan VS, et al: Preliminary evidence for a structural benefit of the new bisphosphonate zoledronic acid in early rheumatoid arthritis. Arthritis Rheum 2006; 54:1410-1414. [ISI][Medline]
- Valleala H, Laasonen L, Koivula MK, et al: Two year randomized controlled trial of etidronate in rheumatoid arthritis: Changes in serum aminoterminal telopeptides correlate with radiographic progression of disease. J Rheumatol 2003; 30:468-473. [ISI][Medline]
- Zhang Q, Badell IR, Schwarz EM, et al: Tumor necrosis factor prevents alendronate-induced osteoclast apoptosis in vivo by stimulating Bcl-xL expression through Ets-2. Arthritis Rheum 2005; 52:2708-2718. [ISI][Medline]
- Boyle WJ, Simonet WS, Lacey DL: Osteoclast differentiation and activation. Nature 2003; 423:337-342. [Medline]
- Childs LM, Paschalis EP, Xing L, et al: In vivo RANK signaling blockade using the receptor activator of NF-kappaB:Fc effectively prevents and ameliorates wear debris-induced osteolysis via osteoclast depletion without inhibiting osteogenesis. J Bone Miner Res 2002; 17:192-199. [ISI][Medline]
- Clohisy JC, Frazier E, Hirayama T, Abu-Amer Y: RANKL is an essential cytokine mediator of polymethylmethacrylate particle-induced osteoclastogenesis. J Orthop Res 2003; 21:202-212. [ISI][Medline]
- Ulrich-Vinther M, Carmody EE, Goater JJ, Sb K, O’Keefe RJ, Schwarz EM: Recombinant adeno-associated virus-mediated osteoprotegerin gene therapy inhibits wear debris-induced osteolysis. J Bone Joint Surg Am 2002; 84:1405-1412. [Abstract/Free Full Text]
- Schwarz EM, O’Keefe RJ, Xing L, Looney RJ, Ritchlin CT: Receptor activator of nuclear [kappa]B ligand and osteoprotegerin: Where are we now and what about future treatment uses? Curr Opin Orthop 2005; 16:370-375.
- Sobacchi C, Frattini A, Guerrini MM, et al: Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat Genet 2007; 39:960-962. [ISI][Medline]
- Abu-Amer Y, Darwech I, Clohisy JC: Aseptic loosening of total joint replacements: Mechanisms underlying osteolysis and potential therapies. Arthritis Res Ther 2007; 9 (suppl 1):S6. [Medline]
- Schwarz EM, Ritchlin CT: Clinical development of anti-RANKL therapy. Arthritis Res Ther 2007; 9 (suppl 1):S7. [Medline]
- Childs LM, Goater JJ, O’Keefe RJ, Schwarz EM: Effect of anti-tumor necrosis factor-alpha gene therapy on wear debris-induced osteolysis. J Bone Joint Surg Am 2001; 83:1789-1797. [Abstract/Free Full Text]
- Childs LM, Goater JJ, O’Keefe RJ, Schwarz EM: Efficacy of etanercept for wear debris-induced osteolysis. J Bone Miner Res 2001; 16:338-347. [ISI][Medline]
- Schwarz EM, Campbell D, Totterman S, Boyd A, O’Keefe RJ, Looney RJ: Use of volumetric computerized tomography as a primary outcome measure to evaluate drug efficacy in the prevention of peri-prosthetic osteolysis: A 1-year clinical pilot of etanercept vs. placebo. J Orthop Res 2003; 21:1049-1055. [ISI][Medline]
- Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V: Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: Systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006; 295:2275-2285. [Abstract/Free Full Text]
- Looney RJ, Boyd A, Totterman S, et al: Volumetric computerized tomography as a measurement of periprosthetic acetabular osteolysis and its correlation with wear. Arthritis Res 2002; 4:59-63. [ISI][Medline]
- Howie DW, Neale SD, Stamenkov R, McGee MA, Taylor DJ, Findlay DM: Progression of acetabular periprosthetic osteolytic lesions measured with computed tomography. J Bone Joint Surg Am 2007; 89:1818-1825. [Abstract/Free Full Text]
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Abstract
Future Directions for Research
