Stem Cell Therapy for Orthopedic Indications (Including Allograft Bone Products used with Stem Cells)
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This policy governs the medical coverage stance for mesenchymal stem cell (MSC) therapies and related allograft bone products used for orthopedic/musculoskeletal indications for Blue Cross Blue Shield - Iowa members.
Clarified that concentrated autologous MSCs do not require FDA approval, whereas expanded/engineered MSC products for orthopedic applications are not FDA-approved.
Policy affirms MSC therapy and allograft bone products containing viable stem cells are considered investigational for all orthopedic applications.
Coverage Criteria and Evidence Summary
Not covered (Investigational)
Covered when ALL of the following are met
The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
Not covered (Investigational) - Allograft products
The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
Evidence selection and intended use population
Evidence review PICO and study selection
This PICO was used to select literature for the review.
See Study Selection Criteria.
Evidence by MSC source
Synthesis by MSC source and study quality
See systematic reviews and Table summaries.
Adverse events reported were generally transient injection-site pain and swelling; no tumorigenesis reported.
Findings question incremental benefit of BMAC.
Coverage rationale and evidence summary
Summary stance derived from evidence across indications in the provided excerpts
See section summaries for cartilage and meniscal defects.
References include phase 3 trials and systematic reviews.
Study selection and evidence limitations
Evidence review and study selection principles
These principles guided inclusion and exclusion of studies in the review.
Section summaries note limited certainty and heterogeneity.
Evidence synthesis — fusion procedures
Reported outcomes from observational and early-phase studies
Wind et al.; posthoc analyses included.
Goldman et al., Vanichkachorn et al., Peppers et al.
Donaghue et al., multicenter trials.
Section summary: Joint Fusion Procedures.
Osteonecrosis — scope and outcomes
Osteonecrosis PICO
PICO guided study selection for osteonecrosis.
Osteonecrosis — evidence summary
Findings from randomized trials and systematic review
Further high-quality, multicenter, long-term RCTs are needed to establish safety and efficacy.
This evidence review does not address stem cell therapy for disorders of the hematopoietic system or hematopoietic stem cell transplantation. Refer to medical policy 07.03.11 (Hematopoietic Stem Cell Transplantation Autologous and Allogeneic) for coverage and prior authorization requirements for those indications.
The U.S. Food and Drug Administration does not consider the use of stem cells for orthopedic procedures to be homologous use. Products that do not meet HCT/P criteria (minimal manipulation, homologous use, limited combination with other articles, and specified systemic effect/autologous/allogeneic conditions) may be regulated as drugs, biologics, or devices and therefore require appropriate premarket review.
Expanded or engineered mesenchymal stem cell products for orthopedic applications are not FDA-approved. Therapies without FDA approval and those lacking consistent, high-quality evidence of clinical benefit (including many MSC preparations and delivery methods) may be excluded from coverage or require case‑by‑case review.
No discrete population exclusions are specified in this evidence review, but the available literature is limited in scope and generalizability. Most data derive from early‑phase, nonrandomized, small or retrospective studies and industry‑sponsored series; applicability to broader patient populations is therefore uncertain.
Major professional societies have expressed caution about stem cell injections for musculoskeletal indications. The AAOS states injectable stem cell biologics cannot be recommended for glenohumeral osteoarthritis and calls for better standardization and high‑quality trials. The ACR/Arthritis Foundation gave a strong recommendation against stem cell injections for knee and hip osteoarthritis. The VA/DoD guideline issued a weak against recommendation for stem cell injections for knee OA.
The reference list includes systematic reviews, randomized trials, health technology assessments, and professional guidelines. Refer to the cited literature (References section) for primary sources, systematic reviews, and guideline documents supporting the evidence summaries in this policy.
Use appropriate CPT, HCPCS, revenue, and ICD diagnosis codes to report provider services. A list of representative CPT and Category II/III or unlisted codes related to stem cell and allograft procedures is provided elsewhere in this policy and should be used for claims reporting.
Expanded/engineered mesenchymal stem cell products for orthopedic uses are not approved by the U.S. Food and Drug Administration. Concentrated autologous MSC preparations (eg, point‑of‑care concentrates) may not require FDA premarket approval in the same manner, but expanded MSCs intended for implantation or injection in orthopedic indications lack FDA approval and remain investigational.
Two randomized trials of bone marrow aspirate concentrate (BMAC) for knee osteoarthritis reported no clear superiority to control comparators: one trial found similar pain relief between BMAC and saline, and a larger trial found no advantage over corticosteroid injection. These findings indicate BMAC has not consistently demonstrated benefit over placebo or corticosteroid for OA‑related knee pain.
The available trial data on BMAC question its incremental clinical benefit. Because randomized evidence has not shown consistent superiority of BMAC versus placebo or corticosteroid in knee OA, routine coverage of BMAC for OA-related knee pain is not supported by the evidence presented in this policy.
Overall, the evidence base for MSC therapies across orthopedic indications is limited. Much of the literature consists of early‑phase or nonrandomized studies, with variable protocols, heterogeneous products, and short follow‑up, which together preclude definitive conclusions about efficacy and long‑term safety.
Guideline positions summarized: AAOS does not recommend injectable stem cell biologics for glenohumeral OA and highlights lack of reliable evidence; ACR/Arthritis Foundation issued a strong recommendation against stem cell injections for knee/hip OA; VA/DoD provided a weak against recommendation for knee OA, reflecting the consistent theme of insufficient, heterogeneous evidence across guidelines.
Evidence for other indications such as tendon and ligament injuries, spinal applications, and cartilage repair is reported in the references but is heterogenous. This policy does not provide specific coverage determinations for those indications beyond the general investigational stance for orthopedic uses; see cited primary studies and systematic reviews for indication‑specific data.
The references section lists numerous citations (systematic reviews, randomized trials, guideline documents) that inform the evidence synthesis. The excerpts do not include explicit ‘not medically necessary’ declarations within the reference list itself; determinations are presented in the policy text and rationale sections.
Coding and Device Clearance
| No codes listed |
| 20999 | Unlisted procedure, musculoskeletal system, general |
| 27599 | Unlisted procedure, femur or knee (may be utilized for Lipogems) |
| 38205 | Blood derived hematopoietic progenitor cell harvesting for transplantation, per collection allogeneic |
| 38206 | Blood derived hematopoietic progenitor cell harvesting for transplantation autologous |
| 38212 | Transplant preparation of hematopoietic progenitor cells; red blood cell removal |
| 38215 | Transplant preparation of hematopoietic progenitor cells; cell concentration in plasma, mononuclear or buffy coat layer |
| 38230 | Bone marrow harvesting for transplantation allogeneic |
| 38232 | Bone marrow harvesting for transplantation autologous |
| 38240 | Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor |
| 38241 | Hematopoietic progenitor cell (HPC); autologous transplantation |
Provider Requirements, Authorization, and Documentation
Authorization may be needed for non‑361 regulated HCT/Ps
Prior authorization may be required when HCT/Ps or MSC-based products do not meet FDA section 361 criteria (minimal manipulation, homologous use, limited combination with other articles, and specified systemic effect/autologous/allogeneic conditions), because such products are regulated as drugs/devices/biologics and may need premarket review.
- FDA does not consider stem cell use for orthopedic procedures to be homologous use
- HCT/Ps not meeting section 361 criteria may be regulated as drugs/devices/biologics
Prior authorization likely for orthopedic MSC therapies
Given the lack of FDA approval for the MSC methods described and heterogeneous, limited evidence across indications, prior authorization is likely to be required to evaluate indication, prior treatments, and supporting evidence before coverage is considered.
- FDA approval for these MSC methods has not been obtained
- Heterogeneous evidence and limited quality may prompt case‑by‑case prior authorization review
Prior authorization not specified in study summaries
Some study reporting sections describe trial outcomes and imaging assessments but do not specify a prior authorization process; prior authorization requirements are not detailed in those study summaries.
- Clinical studies report radiographic fusion assessed by dynamic radiographs and CT and patient‑reported outcomes
- Prior authorization processes are not described in these study report fragments
Society guideline recommendations may affect authorization
Major specialty society guidance (AAOS; ACR/Arthritis Foundation) recommends against or does not support stem cell injections for certain osteoarthritis indications, which may inform prior authorization decisions.
- AAOS states injectable biologics such as stem cells cannot be recommended for glenohumeral OA
- ACR/Arthritis Foundation gave a strong recommendation against stem cell injections for knee and/or hip OA
No prior authorization specified in reference fragments
In other reference fragments of the policy, no explicit prior authorization requirements are specified for the orthopedic MSC sections.
- Reference sections list trials, reviews, and guidelines but do not state prior authorization rules
Policy history noted; no explicit authorization tasks here
No additional provider action requirements are specified in these particular excerpted fragments.
- Policy history indicates periodic reviews and revisions but does not add explicit provider actions in these excerpts
Provider action: Acknowledge investigational coverage stance
Placeholder — follow the policy: MSC therapies and cellular allografts for orthopedic indications are considered investigational; ensure requests include justification and supporting evidence if a review is sought.
- Policy stance: MSC therapy investigational for all orthopedic applications
- Allograft bone products containing viable stem cells are investigational
Document conservative therapies and surgical comparators
Comparators considered in the evidence base include conservative management (medication, hyaluronic acid injections), microfracture, and autologous chondrocyte implantation; these are standard alternatives referenced in study selection.
- Conservative options noted: medication, hyaluronic acid (HA) injection
- Surgical comparators: microfracture and autologous chondrocyte implantation
Conservative therapy often used as comparator in trials
Comparative trials frequently used conservative comparators (placebo, hyaluronic acid, corticosteroid); evidence does not consistently demonstrate superiority of MSCs over these conservative treatments.
- BMAC trials reported similar outcomes to placebo or corticosteroid injections
- Systematic reviews report little to no pain relief for knee OA with intra‑articular MSCs compared with controls
Record use of iliac crest graft and core decompression as comparators
Evidence comparators specifically noted for fusion and osteonecrosis include iliac crest bone graft and core decompression; document attempts at these standard comparators in the medical record if relevant.
- Iliac crest bone graft is a comparator for fusion procedures
- Core decompression is a comparator for osteonecrosis
Document core decompression when applicable
Core decompression is explicitly listed as a comparator in osteonecrosis studies and should be documented when relevant to claims or prior authorization requests.
- Core decompression cited as standard comparator in osteonecrosis trials
No step therapy rules specified in excerpts
No step therapy rules are stated in these excerpts; the document references AAOS statements and guidelines but does not establish required prior steps before MSC therapy.
- AAOS position statements are referenced but do not define step therapy in this policy excerpt
- No explicit step therapy requirements are included in the provided text
No further provider action specified
No additional provider actions are specified in the referenced fragments.
- Policy history and references provided, but no new provider instructions in these chunks
Submit clinical outcomes and imaging to support review
Provide clinical outcome measures and imaging used in studies (WOMAC, VAS, ODI, EQ‑5D, Neck Disability Index, MOCART, ICRS macroscopic assessment) when submitting cases for review to support assessment of benefit.
- Patient‑reported outcomes: WOMAC, VAS, ODI, EQ‑5D, Neck Disability Index
- Imaging/repair assessment: MOCART, ICRS macroscopic assessment, dynamic radiographs, CT
Attach arthroscopic/MRI assessments when available
Clinical trial reports referenced include arthroscopic and MRI‑based assessments (ICRS macroscopic assessment, MRI cartilage repair scores) and meniscal volume by MRI; include these imaging reports when available.
- ICRS macroscopic cartilage repair assessment (arthroscopic)
- MRI measures of cartilage repair and meniscal volume
Provide radiographic fusion and PRO documentation
Studies used radiographic fusion confirmation (dynamic radiographs and CT) and patient‑reported outcomes (ODI, VAS, EQ‑5D, Neck Disability Index) to measure clinical effect; provide these data to demonstrate fusion or functional improvement.
- Radiographic fusion assessed by dynamic radiographs and CT
- Functional outcomes: ODI, VAS, EQ‑5D, Neck Disability Index
Prefer RCT evidence when submitting supporting studies
Comparative controlled prospective trials, preferably randomized controlled trials, are the preferred evidence standard for efficacy; document availability of RCT-level data if relying on published evidence.
- Efficacy: preference for comparative controlled prospective trials (RCTs)
- Long‑term outcomes and safety: single‑arm longer follow‑up studies are acceptable
References only — no authorization steps here
No authorization or documentation instructions appear in these reference sections of the policy.
- Reference lists and citations are provided but do not contain procedural authorization instructions
Report appropriate procedure and diagnosis codes
Use appropriate CPT, HCPCS, revenue, and ICD diagnosis codes to report provider services; failure to report proper codes may cause processing issues or denial.
- Report services with appropriate CPT/HCPCS and ICD codes
- Representative unlisted and Category II/III codes are listed elsewhere in the policy
Claims for MSC therapy/allograft with viable stem cells risk denial
Claims for mesenchymal stem cell therapy and allograft bone products containing viable stem cells for orthopedic indications are considered investigational and therefore risk denial as not medically necessary.
- Policy statement: MSC therapy investigational for all orthopedic applications
- Allograft bone products containing viable stem cells (eg, DBM with stem cells) are investigational
Regulatory non‑homologous use may prompt denial or additional authorization
Because the FDA does not consider stem cell use for orthopedic procedures to be homologous use, HCT/Ps that do not meet the FDA criteria may be subject to regulation as drugs/devices/biologics and could be denied coverage if not properly authorized.
- FDA criteria for section 361 HCT/Ps must be met to avoid premarket regulation
- Non‑homologous use for orthopedic procedures may trigger additional regulatory requirements
Lack of FDA approval may trigger additional review or denial
FDA approval for the described MSC methods has not been obtained; lack of FDA approval is a basis for additional review or potential denial of coverage.
- Multiple phase trials cited, but FDA approval for these MSC methods is lacking
- Absence of FDA approval may lead to case‑by‑case review or denial
Limited evidence may prompt additional review
Because much of the literature is early‑phase, nonrandomized, and heterogeneous in methods, claims may be subject to additional review or denial where evidence is limited.
- Evidence for many orthopedic MSC uses is limited and primarily from early‑phase or industry‑sponsored studies
- Limited evidence quality may prompt additional utilization review
Insufficient high‑quality evidence for osteonecrosis may lead to denial
Evidence for stem cell therapies in osteonecrosis is based on small, short‑term RCTs with heterogeneity; insufficient high‑quality evidence may lead to denial for this indication without stronger RCT support.
- Li et al (2021) systematic review included mostly small, short‑term RCTs with heterogeneity
- Although pooled results favored stem cells for Harris hip score and VAS, study limitations reduce certainty
References only — no provider action required here
These reference fragments do not include explicit provider action instructions; they are citations and bibliographic entries only.
- Reference sections list studies and trials but do not specify procedural requirements or authorization steps
Ensure correct coding to avoid claim processing issues
Failure to report appropriate CPT, HCPCS, revenue, and/or ICD diagnosis codes for provider services may result in claim processing issues or denial; ensure billing uses codes listed in the policy when applicable.
Background and Rationale
Mesenchymal stem cells (MSCs) are multipotent stromal cells capable of differentiating into bone, cartilage, tendon, ligament, muscle, and fat. They are present in bone marrow, adipose tissue, synovium, and muscle. The investigational rationale for MSC therapy in orthopedics is based on their potential to provide osteogenic and chondrogenic cells and paracrine effects that may promote tissue repair; however, harvest methods, cell processing, dosing, and delivery techniques vary and optimal approaches remain uncertain.
Definitions and Product Examples
Policy Revision History
Evidence review created in June 2014 to evaluate MSC therapies for orthopedic indications; policy established investigational stance for MSC therapy and related allograft products.
Annual review performed (policy history shows March 2025 annual review/renewal).
Annual review and policy renewal completed (policy history: March 2026 annual review; policy renewed).
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