Medical Policy

 

Subject: Mesenchymal Stem Cell Therapy For Orthopedic Indications
Document #: TRANS.00035 Publish Date:    12/27/2017
Status: Reviewed Last Review Date:    11/02/2017

Description/Scope

This document addresses the use of mesenchymal stem cell (MSC) therapy for regeneration in orthopedic indications (for example, cartilage, bone or spine).

MSCs are progenitor cells located in the bone marrow and other tissues that may develop into connective tissue and bone (Shen, 2005). MSC therapy refers to the procurement (through autologous or cadaveric allogeneic harvest) of MSCs, processing (such as, concentration and/or expansion of cells) and subsequent infusion or implantation of the MSCs into various anatomic areas to promote healing or regeneration of damaged cartilage or bone.

Note: This document addresses the use of bone graft substitutes involving added or exogenous MSCs. For the use of bone graft products containing endogenous MSCs, see:

Note: For additional information, please see the following related documents:

Position Statement

Investigational and Not Medically Necessary:

Mesenchymal stem cell therapy is considered investigational and not medically necessary for treatment of orthopedic indications.

Rationale

Surgical repair of tendon, ligament, cartilage and bone defects has been the standard therapy, which may be augmented by autologous grafts, cadaveric allografts or synthetic grafts. However, there have been several limitations to the use of grafts in orthopedic therapy. For instance, autologous graft sources may be hampered by comorbid conditions, limited sites are suitable for harvesting, and the potential of graft failure is an ever-present risk of these procedures. Alternative regenerative technologies which could minimize or avoid these issues while regenerating damaged tissue are being actively investigated.

Various agents and techniques to procure and expand MSCs to achieve sufficient numbers for infusion or implantation are being studied and implemented in proprietary processes for diverse orthopedic indications. The processing of cadaveric allogeneic donor MSCs typically involves proprietary techniques and a combination of MSCs with various transport mediums. In addition, it is not clear that mesenchymal stem cells procured from different tissue sources are functionally equivalent. There is a paucity of randomized controlled trials in humans to support the safety and efficacy of using MSC therapy for orthopedic indications, including cartilage and ligament repair and bone regeneration.

At this time, the medical evidence supporting the use of MSCs for orthopedic indications is limited to pre-clinical studies, case series and small, randomized controlled trials. This novel approach has not demonstrated an improved and durable health outcome benefit over standard therapies in robust, large randomized controlled trials with long-term follow-up.

Several preclinical studies have been conducted to evaluate the effectiveness of MSCs in tissue regeneration. Caudwell and colleagues (2014) conducted a systematic review of preclinical studies using MSC and scaffolds in the treatment of knee ligament regeneration. The authors concluded, based on their investigation of 21 articles, that preclinical evidence of ligamentous regeneration with MSC and scaffold use was established, but limited clinical evidence exists to support recently developed scaffolds. Furthermore, no consensus has been reached on the nature of scaffold material that is most suitable.

Lau and colleagues (2014) conducted a systematic review of preclinical and clinical studies. In preclinical studies, evidence from stem cells used as treatment in avascular necrosis of the femoral head demonstrated uniform improvement in osteogenesis and angiogenesis (sources of stem cells varied across studies chosen for inclusion). In clinical trials included for review, significant improvements in participant-reported outcomes were demonstrated across studies but superior hip survivorship was not reported. Authors call for trials to determine “Dose and quality optimization” as well as demonstrable improvement in hip survivorship.

Papakostidis and colleagues (2015) completed a meta-analysis evaluating treatments of osteonecrosis of the femoral head. Simple core decompression (CD) was compared to CD with installation of autologous bone marrow cells containing high concentrations of pluripotent mesenchymal stem cells. In a pooled estimate, the odds of femoral head progression to the collapse stage resulted in a five-fold decrease in the cell therapy group versus the CD group (odds ratio [OR]=0.2; 95% confidence interval [CI]: 0.08–0.6; p=0.02). However, there was statistical heterogeneity. While the odds of conversion to total hip replacement were halved in the cell therapy group compared to the CD group, the results were not statistically significant (OR=0.58; 95% CI: 0.33–1.02; p=0.06). While the findings suggest there is benefit when autologous mesenchymal stem cells are incorporated in CD treatment, better designed, quality RCTs are needed to further define their role in therapy.

In the literature, there is a growing body of reports from the pre-clinical and clinical setting for the potential efficacy of MSC use in tissue regeneration for orthopedic indications. However, well-designed, large randomized comparative clinical trials are needed to demonstrate the efficacy and safety of MSC therapy for orthopedic indications. The variety of MSC sources, proprietary processing and different scaffolds make comparison of products challenging.

A systematic review of preclinical studies was published by Haddad and colleagues (2013) reviewed 19 articles that had used cell-based approaches to tissue-engineered menisci; cell types used included MSCs amongst others. Authors stated that, “The diversity of studies made it impossible to adhere to full guidelines or perform a meta-analysis,” but concluded that overall superior tissue integration and favorable biochemical properties were observed in regenerated tissues when compared to acellular techniques.

In 2011, Wakitani reported long-term follow-up of 45 articular cartilage repairs utilizing autologous bone marrow-derived mesenchymal stem cells (BMSCs) in 41 individuals. With a mean follow-up of 75 months (5 to 137 months), the authors reported no tumors or infections observed in the individuals who were treated between 1998 and November 2008. Although considered a low risk, the authors concluded that, “The possibility that the cells transplanted in joints move and injure other parts of the body remains unresolved” (Wakitani, 2011).

A pilot study was conducted by Wakitani and colleagues (2004) using autologous bone MSC therapy to repair nine full-thickness cartilage defects in the patello-femoral joints of 3 individuals. The assessment of clinical symptoms were rated with the International Knee Documentation Committee Subjective Knee Evaluation Form (IKDC score), with 0 being the worst and 100 being the best rating. IKDC scores improved for all 3 individuals during the follow-up period ranging from 7 to 20 months after receiving mesenchymal therapy. In all 3 cases, the investigators were unable to confirm the material covering the defects was in fact hyaline cartilage resulting from mesenchymal cell therapy.

In 2012, Lee and colleagues conducted a prospective, short-term comparative study to determine if knees with symptomatic cartilage defects treated with outpatient injections of MSCs and hyaluronic acid (HA; n=35) had better outcomes than an open-air implantation of MSCs (n=35). The outcome of interest was the International Cartilage Repair Society (ICRS) Cartilage Injury Evaluation Package and MRI results 1 year post-procedure. No adverse event was reported and significant improvement was seen across several domains of the ICRS evaluation package at final follow-up (mean 24 months). Although MRI results were promising, authors acknowledge that the sensitivity of MRIs in lesion identification was only estimated at 45%. A shortcoming of this study, aside from the small sample size and short-term data, is the inability to distinguish the MSCs effect on outcomes from the HA effect since the control group received neither.

Small, randomized trials have been conducted, evaluating the efficacy of MSC use in orthopedic indications. A randomized, prospective, preliminary study was published in 2013 by Liebergall and colleagues. A total of 24 participants with distal tibial fractures were enrolled to evaluate time to union. Half of participants (n=12) were randomized into the treatment group and received MSCs (harvested from iliac crest bone marrow), platelet-rich plasma and demineralized bone matrix injections under fluoroscopy at the tibial fracture site in conjunction with standard orthopedic surgical intervention (nails or plates implanted for stabilization). The control group (n=12) received no additional intervention during their surgical procedure to stabilize the tibia. Authors found that this minimally invasive procedure reduced time to union from 3 months (control group) to 1.5 months (treatment group) on average. The difference was statistically significant in the unblinded analysis (p<0.03) and significance fell in the blinded analysis (p<0.06). Authors concluded that this minimally invasive technique appears safe and efficient. However, no long-term data are available and superiority was not demonstrated in the unblinded analysis.

A systematic review by Khashan and colleagues (2013), sought to compare the evidence in the literature of cell-based grafts combined with bone extenders to autologous bone grafts. Their review addressed five key questions by examining results from 28 clinical trials. The authors ultimately determined that evidence for each key question was weak or absent and therefore insufficient to support the use of MSC therapy for spinal fusion.

A point of concern raised regarding the status of clinical evidence in tissue engineering, is the need for validated scoring for outcomes to provide a standardized data collection set that will allow comparison of results from different trials. Additional studies are needed to establish validated scoring for histopathologic research. The use of mesenchymal products is unproven for use in spinal fusion and for intervertebral disc regeneration.

In 2013, Wong and colleagues conducted a randomized control trial evaluating 56 participants with unicompartmental, osteoarthritic, varus knees enrolled in either the stem cell recipient group (n=28) or the control group (n=28). The treatment group received intra-articular injections of MSCs and HA 3 weeks post-surgical intervention and the control group received HA only. Participants were re-evaluated at 6-, 12- and 24-month follow-up. The treatment group showed significantly better scores than the control group in Tegner (p=0.021), Lysholm (p=0.016), and IKDC (p=0.01) scores. MRI scans at 1 year follow-up showed significantly better Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scores (p<0.001). Authors conclude that the investigated intervention demonstrated efficacy in short-term clinical and MOCART outcomes. However, data was insufficient to demonstrate clinical improvement and long-term efficacy and safety data.

Vega and colleagues (2015) conducted a small, randomized, controlled trial comparing intra-articular injections of allogeneic bone marrow MSCs and HA in individuals with knee osteoarthritis (n=30). Each participant received either one injection of MSC or HA and were followed for 1 year. Assessed outcomes included evaluations of pain, disability, quality of life and articular cartilage quality as determined by MRI. The MSC group reported a medium to large treatment effect (effect size, 0.58-1.12) while the HA group reported a small treatment effect (effect size, 0.19-0.48). While the MSC group reported improved results over the HA group, it is noted that this is the first study to demonstrate the feasibility, safety and efficacy of the use of allogeneic MSCs in treating osteoarthritis. The authors note that further research is needed on how MSCs “relieve pain, promote regeneration, and become immune evasive.”

In 2014, Vangsness and colleagues performed the first randomized, double-blind controlled clinical trial investigating the efficacy and safety of MSCs in the treatment of an orthopedic indication. A total of 55 participants from seven institutions who were eligible for a partial medial meniscectomy were enrolled and randomized into one of three treatment groups: Group A (n=17) received an injection of 50x106 allogeneic MSCs; Group B (n=18), received 150x106 MSCs; and the control group (n=19) received an HA injection only. Outcomes of interest at intervals over the 2-year follow-up period included safety, meniscus regeneration, overall knee joint condition and clinical outcomes. No adverse events occurred and investigators found a significant increase in meniscal volume (p=0.022; determined by MRI) in both Groups A and B; no participants met the threshold for increased volume (15%) in the control group. Furthermore, both groups A and B reported a significant reduction in pain compared to the control group. Results of this small, Phase I/II clinical trial are promising for use of MSCs in knee-tissue regeneration. Data from larger trials is needed to confirm the early results.

In a systematic review by Longo and colleagues (2011), authors state that the use of MSC therapy for repair of tendon injuries is “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 preclinical studies, case series, and small, randomized trials suggest that MSC therapy may improve regeneration of bone or tissue in orthopedic indications, the lack of validated, comparable scoring, robust sample sizes and long-term follow-up data, preclude definitive conclusions regarding the net health benefit of MSC therapy.  While the results of the early trials have been promising, a number of questions remain (Goldberg, 2017; Viganò, 2016).  The available data has not yet established that MSCs, 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. In addition, the optimal source for MSCs (for example from adipose tissue in bone marrow) has not been clearly identified.

The concentrated autologous MSC products are not regulated by the U.S. Food and Drug Administration (FDA). Currently there are no allogeneic MSC therapies or devices that are approved for marketing by the FDA.

However, there are products containing mesenchymal stem cells that are commercially available for orthopedic indications, which include:

Background/Overview

MSCs are being investigated as a regenerative biologic agent because of their ability to differentiate into multiple tissue types and to self-renew. MSCs can be derived from a variety of sources, including adipose tissue, bone marrow, placenta, and peripheral or umbilical blood. The MSC population in red bone marrow is estimated at 1 per 105 nucleated cells. The incidence of MSCs in adults is 1 per 103 nucleated cells (Piccirilli, 2017). Counts in cord blood or peripheral blood are lower (Bonab, 2006). These tissue sources differ with respect to MSC cell density and differentiation capacity. Bone marrow-derived MSCs are considered the preferred source for bone repair and regeneration as there is better chondrogenic differentiation potential (Shao, 2015). Although other sources for MSCs have been identified, the bone marrow is currently the primary source of procurement.

MSC therapy has been proposed as a treatment option for orthopedic indications that include torn cartilage, osteoarthritis, and bone grafting. The proposed benefits of MSC therapy are improved healing and possible avoidance of surgical procedures with protracted recovery times. MSCs are used as a stand-alone therapy in the form of an injection or in combination with scaffolds (Viganò, 2016),

Optimal materials or grafts that promote bone growth and healing require the following properties (Shen, 2005):

Currently, the risks of MSC therapy for the treatment of orthopedic indications are unknown. Insufficient data have been reported to allow a proper understanding of how this technology may affect individuals either in the short or long-term. Furthermore, there are known risks related to the various methods utilized to harvest MSCs from the bone marrow, including pain and hemorrhage.

Definitions

Stem cells: A type of cell from which other types of cells develop.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

CPT

 

20930

Allograft, morselized, or placement of osteopromotive material, for spine surgery only

20999

Unlisted procedure, musculoskeletal system, general [specified as MSC implant]

38206

Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; autologous

38230

Bone marrow harvesting for transplantation; allogeneic

38232

Bone marrow harvesting for transplantation; autologous

 

 

ICD-10 Diagnosis

 

 

Including, but not limited to, the following:

M15.0-M19.93

Osteoarthritis

M21.00-M21.079

Valgus deformity, not elsewhere classified

M21.10-M21.179

Varus deformity, not elsewhere classified

M21.70-M21.769

Unequal limb length (acquired)

M21.80-M21.869

Other specified acquired deformities of limbs

M21.90-M21.969

Unspecified acquired deformity of limb and hand

M23.000-M23.92

Internal derangement of knee

M24.10-M24.176

Other articular cartilage disorders

M24.20-M24.28

Disorder of ligament

M24.60-M24.676

Ankylosis of joint

M24.7

Protrusio acetabuli

M24.80-M24.876

Other specific joint derangements, not elsewhere classified

M24.9

Joint derangement, unspecified

M25.50-M25.579

Pain in joint

M43.00-M43.9

Other deforming dorsopathies

M47.011-M47.9

Spondylosis

M48.00-M48.9

Other spondylopathies

M50.00-M50.93

Cervical disc disorders

M51.04-M51.9

Thoracic, thoracolumbar, and lumbosacral intervertebral disc disorders

M54.00-M54.9

Dorsalgia

M75.00-M75.92

Shoulder lesions

M84.30XA-M84.9

Disorder of continuity of bone

M87.00-M87.9

Osteonecrosis

M91.0-M94.9

Chondropathies

S43.401A-S43.499S

Sprain of shoulder joint

References

Peer Reviewed Publications:

  1. Bonab MM, Alimoghaddam K, Talebian F, et al. Aging of mesenchymal stem cell in vitro. BMC Cell Biol. 2006; 7:14.
  2. Buda R, Vannini F, Cavallo M, et al. One-step arthroscopic technique for the treatment of osteochondral lesions of the knee with bone-marrow-derived cells: three year results. Musculoskelet Surg. 2013; 97(2):145-151.
  3. Filardo G, Madry H, Jelic M, et al. Mesenchymal stem cells for the treatment of cartilage lesions: from preclinical findings to clinical application in orthopaedics. Knee Surg Sports Traumatol Arthrosc. 2013; 21(8):1717-1729.
  4. Goldberg A, Mitchell K, Soans J, et al. The use of mesenchymal stem cells for cartilage repair and regeneration: a systematic review. J Orthop Surg Res. 2017; 12(1):39.
  5. Haddad B, Pakravan AH, Konan S, et al. A systematic review of tissue engineered meniscus: cell-based preclinical models. Curr Stem Cell Res Ther. 2013; 8(3):222-231.
  6. Hogan MV, Kawakami Y, Murawski CD, Fu FH. Tissue engineering of ligaments for reconstructive surgery. Arthroscopy. 2015; 31(5):971-979.
  7. Khashan M, Inoue S, Berven SH. Cell based therapies as compared to autologous bone grafts for spinal arthrodesis. Spine (Phila Pa 1976). 2013; 38(21):1885-1891.
  8. 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):892-898.
  9. Lau RL, Perruccio AV, Evans HM, et al. Stem cell therapy for the treatment of early stage avascular necrosis of the femoral head: a systematic review. BMC Musculoskelet Disord. 2014; 15:156. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038713/pdf/1471-2474-15-156.pdf. Accessed on September 22, 2017.
  10. Lee K, Wang VT, Chan YH, Hui JH. A novel, minimally-invasive technique of cartilage repair in the human knee using arthroscopic microfracture and injections of mesenchymal stem cells and hyaluronic acid­--a prospective comparative study on safety and short-term efficacy. Ann Acad Med Singapore. 2012; 41(11):511-517.
  11. Liebergall M, Schroeder J, Mosheiff R, et al. Stem-cell based therapy for prevention of delayed fracture union: a randomized and prospective preliminary study. Mol Ther. 2013; 21(8):1631-1638.
  12. Longo UG, Lamberti A, Maffulli N, Denaro V. Tissue engineered biological augmentation for tendon healing: a systematic review. Br Med Bull. 2011; 98:31-59.
  13. Noth U, Steinert AF, Tuan RS. Technology insight: adult mesenchymal stem cells for osteoarthritis therapy. Nat Clin Pract Rheumatol. 2008; 4(7):371-380.
  14. Papakostidis C, Tosounidis TH, Jones E, Giannoudis PV. The role of "cell therapy" in osteonecrosis of the femoral head. A systematic review of the literature and meta-analysis of 7 studies. Acta Orthop. 2016; 87(1):72-78.
  15. Piccirilli M, Delfinis CP, Santoro A, Salvati M. Mesenchymal stem cells in lumbar spine surgery: a single institution experience about red bone marrow and fat tissue derived MSCs. J Neurosurg Sci. 2017; 61(2):124-133.
  16. 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):7960-7970.
  17. Shao J, Zhang W, Yang T. Using mesenchymal stem cells as a therapy for bone regeneration and repairing. Biol Res. 2015, 48:62.
  18. Shen FH, Samartzis D, An HS. Cell technologies for spinal fusion. Spine J. 2005; 5(6 Suppl):231S-239S.
  19. Vangsness CT, Farr J, Boyd J, et al. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medical meniscectomy: a randomized, double-blind, controlled study. J Bone Joint Surg Am. 2014; 96(2): 90-98.
  20. Vega A, Martín-Ferrero MA, Del Canto F, et al. Treatment of Knee Osteoarthritis With Allogeneic Bone Marrow Mesenchymal Stem Cells: A Randomized Controlled Trial. Transplantation. 2015; 99(8):1681-1690.
  21. Viganò M, Sansone V, d'Agostino MC, et al. Mesenchymal stem cells as therapeutic target of biophysical stimulation for the treatment of musculoskeletal disorders. J Orthop Surg Res. 2016; 11(1):163.
  22. Wakitani S, Imoto K, Yamamoto T, et al. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthritis Cartilage. 2002; 10(3):199-206.
  23. 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):595-600.
  24. Wakitani S, Okabe T, Horibe S, et al. Safety of autologous bone marrow-derived mesenchymal stem cell transplantation for cartilage repair in 41 patients with 45 joints followed for up to 11 years and 5 months. J Tissue Eng Regen Med. 2011; 5(2):146-150.
  25. Wong KL, Lee KB, Tai BC, et al. Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: a prospective, randomized controlled clinical trial with 2 years’ follow-up. Arthroscopy. 2013; 39(12):2020-2028.
Websites for Additional Information
  1. U.S National Institute of Health. Stem Cell Information. Available at: http://stemcells.nih.gov/. Accessed on September 21, 2017.
Index

AlloStem®
Cellentra VCBM
Regenexx®
RegenexxAD®
RegenexxSD®

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

Reviewed

11/02/2017

Medical Policy & Technology Assessment Committee (MPTAC) review. The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Rationale, Background, References and Website sections.

 

03/06/2017

Revised note in Scope section to clarify that TRANS.00035 addresses bone graft products with added or exogenous MSCs and that bone graft products with endogenous MSCs are addressed in CG-SURG-45.

Reviewed

11/03/2016

MPTAC review. Removed the products Osteocel, Trinity Evolution and Elite and BIO4 from the rationale. Updated Description, Rationale, References, Website and Index sections.

Reviewed

08/04/2016

MPTAC review. Updated Description, Rationale, Background, References and Websites sections.

 

04/01/2016

Updated Coding section with corrected diagnosis code range for spondylosis; also removed ICD-9 codes.

Reviewed

08/06/2015

MPTAC review. Updated Description/Scope, Rationale, Coding, References, Websites and Index sections.

Reviewed

08/14/2014

MPTAC review. Updated Description/Scope, Rationale, References and Websites sections.

Reviewed

08/08/2013

MPTAC review. Updated Rationale, Background, References and Websites sections.

Reviewed

08/09/2012

MPTAC review. Rationale, Background, References and Websites updated.

 

01/01/2012

Updated Coding section with 01/01/2012 CPT changes.

Reviewed

08/18/2011

MPTAC review. Rationale, Background, References and Websites updated. Updated Coding section with 10/01/2011 ICD-9 changes.

Reviewed

08/19/2010

MPTAC review. Rationale, Background, References and Websites updated.

Reviewed

08/27/2009

MPTAC review. Rationale, websites and references updated.

New

08/28/2008

MPTAC review. Initial document development.