Mesenchymal Stem Cell Therapy for Orthopedic Indications. Original Policy Date

Transcription

1 MP Mesenchymal Stem Cell Therapy for Orthopedic Indications Medical Policy Section Medicine Issue 12:2013 Original Policy Date 12:2013 Last Review Status/Date Local policy created/12:2013 Return to Medical Policy Index Disclaimer Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically. Description Mesenchymal stem cells or MSCs are multipotent stem cells that can differentiate into a variety of cell types. Mesenchymal stem cells have been classically obtained from the bone marrow, and have been shown to differentiate into various cell types, including osteoblasts, chondrocytes, myocytes, adipocytes, and neuronal cells. MSCs are being investigated as a regenerative biologic agent because of the ability to differentiate into multiple tissue types and to self-renew (Bonab, 2006). The MSC population in bone marrow is estimated at 1 in 3.1 x10 4 mononuclear cells, and is even lower in cord blood or peripheral blood (Bonab, 2006). Although other sources for MSCs have been identified, the bone marrow is currently the primary source of procurement. Mesenchymal stem cell therapy has been proposed as a treatment option for orthopedic indications that include torn cartilage, osteoarthritis, and bone grafting. The proposed benefits of mesenchymal stem cell therapy are improved healing and possible avoidance of surgical procedures with protracted recovery times. Optimal materials or grafts that promote bone growth and healing require the following properties (Shen, 2005): Osteogenic: contains osteoprogenitor cells that can lay down a new bone matrix Osteoinductive: provides signals required to induce differentiation of MSCs into mature osteoblasts Osteoconductive: passive scaffolding to promote vascular invasion and bone apposition on the surface for new bone formulation The available data has not yet established that mesenchymal stem cells, when infused or transplanted into an area, can 1) truly regenerate by incorporating themselves into the native tissue, surviving, and differentiating or 2) promote the preservation of injured tissue and tissue remodeling.

2 Currently, the risks of mesenchymal stem cell therapy for the treatment of orthopedic indications are unknown. Insufficient data has been reported to allow a proper understanding of how this technology may affect individuals either in the short or long term. However, there are known risks related to the various methods utilized to harvest mesenchymal stem cells from the bone marrow, including pain and hemorrhage. Policy Mesenchymal stem cell therapy is considered investigational and not medically necessary for treatment of orthopedic indications. Rationale Tendon, ligament, cartilage and bone defects have typically been surgically repaired and may be augmented by utilizing autologous grafts, cadaveric allografts or synthetic grafts. However, there have been limitations to the graft sources such as comorbid conditions, and limited autologous grafts as well as graft failures. Therefore, alternative regenerative technologies continue to be investigated. Various agents and techniques to procure and expand mesenchymal stem cells to achieve sufficient numbers for infusion or implantation are being studied and utilized in proprietary processes for diverse orthopedic indications. The processing of cadaveric allogeneic donor MSCs typically involves proprietary techniques and combination of MSCs with various transport medium. However, there is a paucity of randomized controlled trials in humans to support the safety and efficacy of using mesenchymal stem cell therapy for orthopedic indications, including cartilage and ligament repair and bone regeneration. At this time, the medical evidence supporting the use of mesenchymal stem cells for orthopedic indications is limited to a series of animal studies and small case series without long-term follow-up results. This novel approach has not demonstrated in randomized controlled trials an improved and durable health outcome benefit over standard therapies. In a pilot study of seven individuals with skeletal defects of the femur and tibia, Kitoh (2004) used mesenchymal stem cells in a gel suspension during ten distraction osteogenesis procedures to lengthen limbs. The goal was to reduce the treatment period and complications, which included pin loosening, pin track infections, delayed consolidation, joint contractures and fractures. Only three individuals were assessable after pin removal. The authors compared results from two of the three mesenchymal transplant individuals, to eight historic cases treated at the same institution, with an average healing index of 22.0 days/centimeter (cm) and 37.8 days/cm, respectively. The investigators noted the healing index is "based on various parameters such as the patient's age, amount of length gained, and the location of the osteotomy." Additional study is required to determine the optimal amount and type of mesenchymal stem cells for transplantation, and to evaluate long-term outcomes. Wakitani and colleagues (2004) conducted a pilot study using autologous bone marrow mesenchymal cell therapy to repair nine full-thickness cartilage defects in the patello-femoral joints of three individuals. The assessment of clinical symptoms were rated with the International Knee Documentation Committee Subjective Knee Evaluation Form (IKDC score), with zero being the worst and one hundred being the best rating. IKDC scores improved for all

3 three individuals during the follow-up period ranging from 7 to 20 months after receiving mesenchymal therapy. In all three cases, the investigators were unable to confirm the material covering the defects was in fact hyaline cartilage resulting from mesenchymal cell therapy. Currently, there are ongoing clinical trials to investigate the effects of mesenchymal stem cell therapy in open tibial fractures, lumbar fusion, osteoarthritis, cartilage defects and meniscectomy (U.S. National Institutes of Health). The American Academy of Orthopaedic Surgeons (2007) provides information on stem cells: Bone marrow stromal cells are mesenchymal stem cells that, in the proper environment, can differentiate into cells that are part of the musculoskeletal system. They can help to form trabecular bone, tendon, articular cartilage, ligaments and part of the bone marrow. At this point, stem cell procedures in orthopaedics are still at an experimental stage. Most procedures are performed at research centers as part of controlled clinical trials. In a systematic review by Longo and colleagues (2011), the use of MSC therapy for repair of tendon injuries "are at an early stage of development. Although these emerging technologies may develop into substantial clinical treatment options, their full impact needs to be critically evaluated in a scientific fashion." Although results of small case series suggest that MSC therapy may improve regeneration of bone or tissue in orthopedic indications, the lack of adequate controls, randomization and blinding and the small sample sizes preclude definitive conclusions regarding the net health benefit of MSC therapy. Helm and colleagues (2001) stated that although autologous bone remains the gold standard for stimulating bone repair and regeneration, the advent in molecular biology as well as bioengineering techniques has produced materials that exhibit potent osteogenic activities. Recombinant human osteogenic growth factors (e.g., BMP) are now produced in highly concentrated and pure forms and have been shown to be extremely potent bone-inducing agents when delivered in vivo in rats, dogs, primates, and humans. They noted that the delivery of MSCs, derived from adult bone marrow, to regions requiring bone formation is also compelling, and it has been shown to be successful in inducing osteogenesis in many preclinical animal studies. Finally, the identification of biological and non-biological scaffolding materials is a crucial component of future bone graft substitutes, not only as a delivery vehicle for bone growth factors and MSCs, but also as an osteo-conductive matrix to stimulate bone deposition directly. Recently, MSCs has been studied for its use in orthopedic application (e.g., healing long bone defects, intervertebral disc repair and regeneration as well as spinal arthrodesis procedures). Acosta et al (2005) noted that although important obstacles to the survival and proliferation of MSCs within the degenerating intervertebral disc need to be overcome, the potential for this therapy to slow or reverse the degenerative process remains substantial. Leung et al (2006) stated that in the past several years, significant progress has been made in the field of stem cell regeneration of the intervertebral disc. Autogenic MSCs in animal models can arrest intervertebral disc degeneration or even partially regenerate it, and the effect is suggested to be dependent on the severity of degeneration. Mesenchymal stem cells are able to escape alloantigen recognition which is an advantage for allogenic transplantation. A number of injectable scaffolds have been described and various methods to pre-modulate MSCs' activity

4 have been tested. They noted that more work is needed to address the use of MSCs in large animal models as well as the fate of the implanted MSCs, especially the long-term outcomes. Mclain et al (2005) noted that successful arthrodesis in challenging clinical scenarios is facilitated when the site is augmented with autograft bone. The iliac crest has long been the preferred source of autograft material, but graft harvest is associated with frequent complications and pain. Connective tissue progenitor cells aspirated from the iliac crest and concentrated with allograft matrix and demineralized bone matrix provide a promising alternative to traditional autograft harvest. The vertebral body, an even larger reservoir of myeloproliferative cells, should provide progenitor cell concentrations similar to those of the iliac crest. In this study, a total of 21 adults (11 men and 10 women with a mean age of 59 +/- 14 years) undergoing posterior lumbar arthrodesis and pedicle screw instrumentation underwent transpedicular aspiration of connective tissue progenitor cells. Aspirates were obtained from two depths within the vertebral body and were quantified relative to matched, bilateral aspirates from the iliac crest that were obtained from the same patient at the same time. Histochemical analysis was used to determine the prevalence of vertebral progenitor cells relative to the depth of aspiration, the vertebral level, age, and gender, as compared with the iliac crest standard. The cell count, progenitor cell concentration (cells/cc marrow), and progenitor cell prevalence (cells/million cells) were calculated. Aspirates of vertebral marrow demonstrated comparable or greater concentrations of progenitor cells compared with matched controls from the iliac crest. Progenitor cell concentrations were consistently higher than matched controls from the iliac crest (p = 0.05). The concentration of osteogenic progenitor cells was, on the average, 71 % higher in the vertebral aspirates than in the paired iliac crest samples (p = 0.05). With the numbers available, there were no significant differences relative to vertebral body level, the side aspirated, the depth of aspiration, or gender. An age-related decline in cellularity was suggested for the iliac crest aspirates. The authors concluded that the vertebral body is a suitable site for aspiration of bone marrow for graft augmentation during spinal arthrodesis. They also stated that future clinical studies will attempt to confirm the ability to obtain fusion using only this source of connective tissue progenitor cells. Anderson and colleagues (2005) reviewed the rationale and discussed the results of cellular strategies that have been proposed or investigated for disc degeneration. These investigators noted that although substantial work remains, the future of cellular therapies for symptomatic disc degeneration appears promising. They concluded that continued research is warranted to further define the optimal cell type, scaffolds, and adjuvants that will allow successful disc repair in human patients. Risbud and colleagues (2006) evaluated the osteogenic potential of MSCs isolated from the bone marrow of the human vertebral body (VB). Marrow samples from VB of patients undergoing lumbar spinal surgery were collected; marrow was also harvested from the iliac crest (IC). Progenitor cells were isolated and the number of colony forming unit-fibroblastic (CFU-F) determined. The osteogenic potential of the cells was characterized using biochemical and molecular biology techniques. Both the VB and IC marrow generated small, medium, and large sized CFU-F. Higher numbers of CFU-F were obtained from the VB marrow than the IC (p < 0.05). Progenitor cells from both anatomic sites expressed comparable levels of CD166, CD105, CD49a, and CD63. Moreover, progenitor cells from the VB exhibited an increased level of alkaline phosphatase activity. MSCs of the VB and the IC displayed similar levels of expression of Runx-2, collagen Type I, CD44, ALCAM, and ostecalcin. The level of expression of bone sialoprotein was higher in MSC from the IC than the VB. VB and IC cells mineralized their extracellular matrix to a similar extent. The authors concluded that their findings show that

5 CFU-F frequency is higher in the marrow of the VB than the IC. Progenitor cells isolated from both sites respond in a similar manner to an osteogenic stimulus and express common immunophenotypes. Based on these findings, these researchers proposed that progenitor cells from the lumbar vertebral marrow would be suitable candidate for osseous graft supplementation in spinal fusion procedures. They stated that studies must now be conducted using animal models to ascertain if cells of the VB are as effective as those of the IC for the fusion applications. Minamide et al (2007) examined the ability of BMP and basic fibroblast growth factor (FGF) to enhance the effectiveness of bone marrow-derived MSCs in lumbar arthrodesis. They found that MSCs cultured with BMP-2 and basic FGF act as a substitute for autograft in lumbar arthrodesis. This technique may yield a more consistent quality of fusion bone as compared to that with autograft. They stated that these results are encouraging and warrant further studies with the suitable dose of BMP-2 and basic FGF, and may provide a rational basis for their clinical application. Further investigation is needed to study the value of MSC therapy in orthopedic applications before it can be used in the clinical setting. References: 1. Bonab MM, Alimoghaddam K, Talebian F, et al. Aging of mesenchymal stem cell in vitro. BMC Cell Biol. 2006; 7: Kitoh H, Kitakoji T, Tsuchiya H, et al. Transplantation of marrow-derived mesenchymal stem cells and platelet-rich plasma during distraction osteogenesis-a preliminary result of three cases. Bone. 2004; 35(4): Longo UG, Lamberti A, Maffulli N, Denaro V. Tissue engineered biological augmentation for tendon healing: a systematic review. Br Med Bull. 2011; Noth U, Steinert AF, Tuan RS. Technology Insight: Adult mesenchymal stem cells for osteoarthritis therapy. Nat Clin Pract Rheumatol. 2008; 4(7): Rai B, Lin JL, Lim ZX, et al. Differences between in vitro viability and differentiation and in vivo bone-forming efficacy of human mesenchymal stem cells cultured on PCL-TCP scaffolds. Biomaterials. 2010; 31(31): Shen FH, Samartzis D, An HS. Cell technologies for spinal fusion. Spine J. 2005; 5(6 Suppl):231S-239S. 7. Wakitani S, Mitsuoka T, Nakamura N, et al. Autologous bone marrow and stromal cell transplantation for repair of full-thickness articular cartilage defects in human patellae: two case reports. Cell Transplant. 2004; 13(5): Helm GA, Dayoub H, Jane JA Jr. Bone graft substitutes for the promotion of spinal arthrodesis. Neurosurg Focus. 2001;10(4):E4. 9. Acosta FL Jr, Lotz J, Ames CP. The potential role of mesenchymal stem cell therapy for intervertebral disc degeneration: A critical overview. Neurosurg Focus. 2005;19(3):E4 10. Helm GA, Gazit Z. Future uses of mesenchymal stem cells in spine surgery. Neurosurg Focus. 2005;19(6):E13.

6 11. Leung VY, Chan D, Cheung KM. Regeneration of intervertebral disc by mesenchymal stem cells: Potentials, limitations, and future direction. Eur Spine J. 2006;15 Suppl 3:S406-S Minamide A, Yosida M, Kawakami M, et al. The effects of bone morphogenic protein and basic fibroblast growth factor on cultured mesenchymal stem cells for spinal fusion. Spine. 2007;32(10): McLain RF, Fleming JE, Boehm CA, Muschler GF. Aspiration of osteoprogenitor cells for augmenting spinal fusion: Comparison of progenitor cell concentrations from the vertebral body and iliac crest. Bone Joint Surg Am. 2005;87(12): Anderson DG, Albert TJ, Fraser JK, et al. Cellular therapy for disc degeneration. Spine. 2005;30(17 Suppl):S14-S Risbud MV, Shapiro IM, Guttapalli A, et al. Osteogenic potential of adult human stem cells of the lumbar vertebral body and the iliac crest. Spine. 2006;31(1): Codes Number Description CPT ICD-10 Diagnosis (effective 10/1/13) M15.0-M19.93 M21.00-M M21.10-M M21.70-M M21.80-M M21.90-M M M23.92 M24.10-M M24.20-M24.28 M24.60-M Unlisted procedure, musculoskeletal system, general [specified as MSC implant] Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; autologous Bone marrow harvesting for transplantation; allogeneic Bone marrow harvesting for transplantation; autologous Osteoarthritis Valgus deformity, not elsewhere classified Varus deformity, not elsewhere classified Unequal limb length (acquired) Other specified acquired deformities of limbs Unspecified acquired deformity of limb and hand Internal derangement of knee Other articular cartilage disorders Disorder of ligament Ankylosis of joint

7 M24.7 Protrusio acetabuli M24.80-M Other specific joint derangements, not elsewhere classified M24.9 Joint derangement, unspecified M25.50-M M75.00-M75.92 M87.00-M87.9 S43.401A-S43.499S Pain in joint Shoulder lesions Osteonecrosis Sprain of shoulder joint ICD-9 Diagnosis Osteoarthritis and allied disorders Pain in joint, stiffness of joint Disorders of bursae and tendons in shoulder region (rotator cuff syndrome) Partial tear of rotator cuff Aseptic necrosis of bone Nonunion of fracture Sprains and strains of shoulder, rotator cuff HCPCS No Code Type of Service Medical/Diagnostic Place of Service Outpatient/ Office