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Complication rates of bone marrow aspirate concentrate injections versus other injectable therapies for knee osteoarthritis: A systematic review and meta-analysis
⁎Corresponding author: Matthew J. Salzler. Msalzler@tuftsmedicalcenter.org
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Received: ,
Accepted: ,
This article was originally published by Reed Elsevier India Pvt. Ltd. and was migrated to Scientific Scholar after the change of Publisher.
Abstract
Abstract
Complications of bone marrow aspirate concentrate (BMAC) injections for knee osteoarthritis (OA) are not well known and were investigated through comparison to other injections.
PubMed, Embase, Cochrane, and Web of Science databases were searched for randomized controlled trials (RCTs) comparing isolated BMAC injections to other injectables for knee OA. Demographics, complications, and comparator injectable treatments were collected. Complication rates and number needed to harm (NNH) were calculated for BMAC. DerSimonian-Laird random-effects models evaluated differences in pooled early (≤7 days) and late (>7 days) complication rates using odds ratios.
Six RCTs were identified with 860 patients, 334 of whom received BMAC injections. The mean follow-up was 13 months. The overall complication rates among BMAC and comparison groups were 41.91 % and 41.25 %, respectively (p = 0.85). The NNH for BMAC was 152. Knee effusion was the most common complication of BMAC (18.26 %). Early and late complication rates for BMAC were not significantly different from other injectables (hyaluronic acid [HA], steroids, platelet-rich plasma, stromal vascular fraction, mesenchymal stromal cells, or saline) (early p = 0.09, I2 = 0; late p = 0.46, I2 = 0), nor specifically compared to HA (early p = 0.76, I2 = 0; late p = 0.66, I2 = 0).
Complication rates of BMAC injections are not significantly different from other injectables, nor specifically from HA for knee OA. Compared to other injections, 152 patients would need to receive a BMAC injection for one additional patient to experience a complication.
Keywords
Bone marrow aspirate concentrate
BMAC
Injection
Complications
Knee osteoarthritis
2 Introduction
Osteoarthritis (OA) is a leading global cause of health care expenditure and disability, with osteoarthritis of the knee being especially debilitating and diminishing to patient quality of life.1,2 Recent years have seen expanding investigation of cell based therapies in orthopaedics, with bone marrow aspirate concentrate (BMAC) 11BMAC = Bone marrow Aspirate Concentrate. being an appealing option due to its anti-inflammatory benefits and regenerative properties via stem cells and growth factors.1,3 The efficacy of this therapy has been widely debated, however, the application of BMAC continues to expand with literature detailing its use in fracture non-unions, rotator cuff repairs, osteoarthritis, osteochondral lesions, and chondral lesions.1,3–5 While BMAC becomes more frequently employed in clinical settings, there remains a paucity of summative research detailing associated risk22NNH = Number needed to harm..
Other systematic reviews investigating the efficacy of BMAC have outlined complication rates of injectable therapies to be anywhere from 0 % to 50 %, however this is a wide range and provides little detail on specific complications.1,4 Understanding procedural risk is important for informed consent and is an essential component of shared decision making; a detailed description and scoping review of complications following BMAC injections is critical to guide clinicians when caring for patients.
The aim of this systematic review and meta-analysis is to investigate the complications of BMAC injections compared with other injectable therapies when utilized to treat osteoarthritis of the knee. We hypothesize that patients receiving BMAC injections will not demonstrate a higher rate of complications than other injectable therapies, such as saline, cortisone, hyaluronic acid, stromal vascular fraction, platelet-rich plasma (PRP), and mesenchymal stem cells33HA = Hyaluronic Acid..
3 Methods
3.1 Article Query
This study was registered with PROSPERO prior to commencement (Prospero #: CRD42022346873). Following The 2020 Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, a systematic review of PubMed Central, Embase, Web of Science Core Collection, and Cochrane Library Databases was conducted (Fig. 1).6 All studies discussing the utilization of BMAC in treatments for knee OA and its associated complications published prior to March 2024, were queried using the search phrase “((bone marrow) AND (aspirate OR “concentrate”)) OR (BMAC) AND (Orthopaedic OR orthopaedic)).” Furthermore, the references of these studies were further screened to ensure inclusion of all applicable studies.
3.2 Study Selection
Two reviewers (J.B. and M.F.) reviewed all abstracts of identified articles for agreement with the following inclusion criteria: 1) utilized isolated bone marrow aspirate concentrate in the treatment of knee osteoarthritis not related to a surgical procedure; 2) administered a comparator group injectable treatment; 3) mentioned any complications associated with injectable use in both groups; 4) was a randomized controlled trial (RCT). Exclusion criteria consisted of: 1) systematic reviews; 2) meta-analysis; 3) review articles; 4) technique papers; 5) commentary/editorial articles; 6) abstracts only; 7) animal studies; 8) non-English studies; 9) not utilizing BMAC as a treatment for knee OA; 10) redacted articles; 11) basic science studies; 12) case reports; 13) no mention of complications; 14) not describing an orthopaedic population; 15) combination treatment with non-injectable therapies. The review was conducted independently by two reviewers (J.B. and M.F.) and any disagreements between the reviewers were resolved by a third, more senior author (L.K.). There was no minimum time required for follow-up.
3.3 Data Extraction
The data was recorded in a custom spreadsheet using an information extraction table. Two reviewers (J.B. and M.F.) extracted the data independently and compared their findings. Data extraction included title, year of publication, journal of publication, the condition studied, the site of the injection, the number of patients treated, demographic data for patients (Body Mass Index, age, gender), the number and type of complications, follow-up duration, and the complication outcomes. For trials assessing multiple study arms, only data related to the assessment of BMAC and the control group were collected. Early complications were defined as those that were noted within seven days of injection, and late complications were defined as those occurring greater than one week following injection.
3.4 Quality Assessment
The quality of these articles was assessed utilizing the Consolidated Standards of Reporting Trials (CONSORT) criteria for randomized controlled trials. Two reviewers (J.B. and M.F.) scored the studies based on these criteria independently and a kappa coefficient was determined for inter-rater reliability. If there were discrepancies in the score assigned between the reviewers, a consensus score was assigned. Kappa coefficient for inter-rater reliability was calculated using Stata/SE (College Station, Tx).
3.5 Statistical Analysis
Summary statistics, tests of significance, rates, and number needed to harm of the included studies were tabulated and analyzed in Microsoft Excel (v16.0 Redmond, WA). For the purposes of this study, other injectables were used as the control group given the lack of a placebo treatment in the included studies and the absence of a gold standard injectable. The number needed to harm (NNH) was calculated by dividing 1 by the absolute risk increase, which was determined by the absolute value of subtracting the risk of complications with BMAC by the risk of complications with the comparison group. DerSimonian-Laird binary random-effects models were created to evaluate differences in early and late complication rates between injectables, with odds ratios (OR) representing pooled estimates.7,8 Heterogeneity was evaluated using I2 statistics.9 The p-value was set at p < 0.05. All analysis was performed using Stata/SE (version 18, College Station, Tx).
4 Results
4.1 Study Characteristics
A total of six randomized controlled trials were included in this review, all of which reported treatment-related adverse events (Fig. 1). A total of 860 patients were included, 334 of whom received BMAC injections. The mean follow-up time was 13 months (range: 6–24 months). Two studies compared BMAC injections to hyaluronic acid injection (HA), one study compared BMAC to saline injections, and one study compared BMAC injections to injections containing a combination of BMAC and PRP. Two studies had more than two study arms, one of which had a HA group and a third group with PRP. The remaining study compared BMAC to injections of corticosteroids, stromal vascular fraction, and umbilical cord tissue-derived mesenchymal stromal cells. All injections were intraarticular. The average CONSORT score was 21.2 ± 1.5 (κ = 0.81). Additional study characteristics can be found in Table 1.
| Author | Study Design | Journal (year) | Number of Patients (Number of Patients per Group BMAC/Comparison) | Follow-up (months) | Comparison Group | Age of BMAC Group | Age of Comparison Group | Sex in BMAC Group (M:F) | Sex in Comparison Group (M:F) | Consort Score |
| Shapiro10 | RCT | AJSM (2017) | 50 (25/25) | 6 | Saline | 60 | 60 | 7:18 | 7:18 | 21 |
| Bastos11 | RCT | Knee (2018) | 18 (9/9) | 12 | PRP combined with BMAC | 54.7 ± 7.2 | 60.4 ± 11.3 | 5:4 | 4:5 | 22 |
| Mautner12 | RCT | Nature Medicine (2023) | 475 (118/357) | 12 | Corticosteroid Injection, Stromal Vascular Fraction, or Umbilical Cord Tissue-derived Mesenchymal Stromal Cells (4 arm study) | 56.6 ± 7.3 | 58.3 ± 8.1 | 56: 62 | 49: 71 | 23 |
| Boffa13 | RCT | KSSTA (2021) | 112 (56/56) | 24 | Hyaluronic Acid Injection | 57.8 ± 8.9 | 57.8 ± 8.9 | 35:21 | 35:21 | 22 |
| Dulic14 | RCT | Medicina (2021) | 175 (111/64) | 12 | Hyaluronic acid or PRP (3 arm study) | 56.9 ± 10.8 | HA: 59.4 ± 14.0PRP: 58.5 ± 11.2 | 57:54 | HA: 13:17PRP: 15:19 | 20 |
| Vega15 | RCT | Transplantation (2015) | 30 (15/15) | 12 | Hyaluronic Acid Injection | 56.6 | 57.3 | 6:9 | 5:10 | 19 |
4.2 Complications
There was a total of 140 complications in the BMAC group and 217 complications in the comparison group. The overall complication rate was 41.91 % in the BMAC group compared to 41.25 % in the comparison group (p = 0.85). The number needed to harm one patient following an injection of BMAC was 152 compared to all other injectables.
Of all reported complications, post-injection pain was the most common comprising 43.13 % (154/357) of all adverse events. This was followed by effusion, which accounted for 38.38 % (137/357) of all complications. The rate of post injection pain in the BMAC group was 15.27 % (51/334) and it was 19.58 % (103/526) in the comparison group (p = 0.11). In the BMAC group, the rate of effusion was 18.26 % (61/334), and in the comparison group, the rate effusion rare was 14.45 % (76/526) (p = 0.13) (Table 2). There were no reports of infections in either group.
| Complication | Number in BMAC Group | Number in Comparison Group | Rate of Complication for BMAC | Rate of Complication for Comparison | ARR | NNH | P value |
| Effusion | 61 | 76 | 18.26 % | 14.45 % | 3.81 % | 26 | 0.13 |
| Pain | 51 | 103 | 15.26 % | 19.58 % | 4.31 % | 23 | 0.11 |
| Inflammation | 7 | 5 | 2.10 % | 0.95 % | 1.15 % | 87 | 0.16 |
| Joint stiffness | 13 | 22 | 3.89 % | 4.18 % | 0.29 % | 345 | 0.83 |
| Othera | 8 | 11 | 2.40 % | 2.09 % | 0.31 % | 333 | 0.77 |
| Total | 140 | 217 | 41.91 % | 41.25 % | 0.66 % | 152 | 0.85 |
4.3 Complication Severity
With the exception of three patients who experienced moderate to intense knee pain (two in BMAC group and one in comparison group) that required pharmacological treatment, all other complications were defined by the studies as mild or not serious.11 In five studies, pain resolved by seven days following the injection and was treated with non-steroidal anti-inflammatories (NSAIDs) or physical therapy.10,11,14,15 One additional study reported resolution of almost every adverse event by the one-week follow-up.12 Alternatively, one study found that 12 % and 8 % of effusions persisted in the BMAC and comparison group, respectively, at six month follow-up.10 All studies noted that complications did not have any deleterious effects at final follow-up (range 6–24 months) and none required further treatments or hospitalization, though only one study explicitly reported this information.13
4.4 Meta-Analysis
Six studies reported early complications of BMAC compared to other injectables.10–15 Using a random-effects model, the meta-analysis resulted in an odds ratio of 1.35 (95 % CI 0.96–1.90), p = 0.09, I2 = 0, indicating that there was no significant difference in early complications between BMAC and other injectables (Fig. 2).
Four studies reported on late complications of BMAC compared to other injectables, excluding those complications that were self-limiting.10,13–15 Random-effects modeling revealed an odds ratio of 1.49 (95 % CI 0.51–4.36), p = 0.46, I2 = 0. Again, this model indicated no significant difference in late complications between BMAC and other injectables (Fig. 3).
When comparing BMAC specifically to hyaluronic acid, both early and late complications were found to have no significant difference using a random-effects modeling (early OR: 1.14 [95 % CI 0.48–2.74], p = 0.76, I2 = 0; late OR: 1.34 [95 % CI 0.36–4.95], p = 0.66, I2 = 0) (Figs. 4 and 5).13–15
Only one study investigated conversion to surgery or need for additional injection as an outcome; thus, a meta-analysis was unable to be performed for this outcome.13
5 Discussion
This study found that the complication rate of BMAC injections used for knee osteoarthritis was 41.91 % in the BMAC group and 41.25 % in the comparison group. Knee effusion was the most common complication in the BMAC group, with post injection pain being the most frequently reported complication in the comparison group. There were no infections in any study in any group. The number needed to harm was 152 patients, indicating that 152 patients would need to be injected with BMAC to result in one complication over a comparison treatment. In most cases, the adverse event was resolved within a week following the injection; in instances where this was not the case, meta-analyses indicated no significant difference between late complications of BMAC or other injectables. This study suggests that BMAC injections are a safe therapeutic intervention with minor complications that are self-limiting.
Bone marrow aspirate concentrate contains stem cell precursors as well as growth factors that stimulate the production of anti-inflammatory macrophages that direct tissue healing and remodeling.16 The appeal of having a nonsurgical method to potentially treat osteoarthritis of the knee is an exciting possibility for the field of regenerative medicine. However, to date few other studies have discussed complication rates of BMAC in a systematic way for treatment of knee OA. Existing studies that have discussed complications are mixed, with some finding no complications, and others report a complication rate of up to 50 % following injections of BMAC for knee OA.1,4 This present study presents a complication rate within these published values at 45.91 %, while also providing a detailed breakdown of the complications with classification based on severity and detailed analyses of specific complication rates.
The most common complications identified in this review were pain followed by effusion and joint stiffness. Defined by Clavien as “any deviation or alteration from the ideal course”, procedure-related complications may have significant consequences for patients, and clinicians should therefore have a deep understanding of these adverse events and their physical and psychological repercussions.17 However, this is not always the case. For example, while studying surgical patients, it was found that there was a discordance in beliefs of complication severity between patients and providers, with some patients highlighting pain as an important complication.18 Additionally, studies have found that anxiety and fear of pain can lead to patients reducing the acceptability of a particular treatment or avoiding it all together.19,20 To this point, there were only six studies included in this review, despite there being many more RCTs comparing BMAC to other injectables. Many studies were excluded due to lack of mention or reporting of complications in these trials, even with inclusion of this endpoint in the CONSORT statement.21 While the grading of complication severity remains an ongoing topic of debate and research, future studies comparing therapeutic injectables should aim for more strict adherence to reporting guidelines to ultimately improve patient counseling for new procedures.22–24
Previous literature has demonstrated that complications related to BMAC generally arise from harvest of the material, administration, or reaction to the product.25 Of note, this study did not specifically investigate the complications related to harvest, despite all included studies harvesting BMAC from the patients directly. As pain was the most common complication, included studies that did not classify complications, such as those that listed “pain or arthralgia” rather than “knee pain” or “hip pain” specifically, may have included events related to the harvest procedure rather than administration of the injectate. Furthermore, while bone marrow aspiration to obtain BMAC solution is a relatively safe procedure, there have been isolated reports of deep hematomas, iliac wing fractures, and gluteal compartment syndrome.26,27 These major complications were either a result of technical error or patient factors such as hematologic malignancy. One systematic review even noted a risk of rupturing the external iliac artery, harming the sciatic nerve, and gluteal vessel injury along with a risk of infection, chronic pain, and pathologic fractures.5 However, data from this review suggests that the majority of complications were minor in nature, as most complications resolved within one week following injection, which speaks to the overall safety of BMAC injections for treating knee osteoarthritis.
It is also important to note that effusion was common, and this could be due to the injection of fluid into the joint. Shapiro et al. used the largest volume of injectate at 15 mL relative to other studies described in this review.10 Previous studies have reported that there is anywhere from 0.5 to 4.0 mL of synovial fluid contained within the knee joint, however, pathologic conditions such as osteoarthritis can lead to a greater fluid collection.28,29 This is an important consideration when injecting substances into a closed area such as the joint, which not only can lead to effusions but also pain and patient discomfort following the injection. Investigators in a prior study simulated effusions in patient's knees, finding that higher volumes led to more discomfort as a result of stretch receptor activation.30
There were no reported infectious complications included in this review. In a separate systematic review of the clinical applications of BMAC, infection and fat embolism were noted as two severe complications clinicians should be most concerned about.5 Indeed there is risk of infection from both the harvesting of BMAC and injection, both of which violate the skin barrier. However, among included studies, four described the harvesting of BMAC cells occurring in procedure rooms or operating rooms with sterile technique in order to minimize the risk of infection.11,13–15 Additionally, fat emboli and respiratory complications were not mentioned in any of the studies included in this review, however it should be noted that all of the studies utilized BMAC intra-articularly, and thus these complications were unlikely.10–15 There is also concern that BMAC administration could lead to local tumorigenesis due to undifferentiated stem cells.31,32 However, in a study of over 1500 patients and in the present review of RCTs, this was not found to be the case.31 The results of this current review alternatively suggest that although clinicians should be aware of possible infection or fat embolism, other complications such as pain, effusion, and joint stiffness are far more prevalent, and patients should be counseled accordingly.
This study provides a summative analysis of the ever-expanding literature surrounding the use and risk profile of BMAC, and more specifically, its therapeutic use for knee osteoarthritis. To date, no study has investigated the complications of BMAC compared to other injectable therapeutics for knee OA; by doing so, this study provides clinicians a guide when counseling patients regarding the safety of these procedures, most notably when compared to alternative injectable regimens. Additionally, by only including RCTs in the analysis, direct comparisons between the treatment groups were able to be made and data was able to be pooled to allow for a meta-analysis of studies investigating BMAC and HA usage. While many studies use BMAC as an adjunct to surgical management, the exclusion of those investigations allows for the removal of confounding from operative intervention as it affects patient outcomes.
The findings of this systematic review should be taken in context of the limitations that follow. The first being that this study only included RCTs and did not include cohort studies, case reports, case series, or additional studies in the analysis. While including only comparative studies allows for higher quality analysis of therapeutic injectables with fewer confounding factors, the exclusion of lower quality study designs may lead to potential complications of BMAC injection therapy being underreported in this review. Additionally, in order to calculate a number needed to harm, the control group used included all other injectables. It was felt that this was warranted, as there is no true gold standard injectable, and this technique allows for direct comparison of BMAC to other therapies that are commonly employed in the clinical setting. Another important limitation to consider is that only one study reported on a need for operative intervention or further treatment, which precluded a meta-analysis to be performed on this endpoint. This would be an important outcome to study as it not only increases the risk for the patient but also costs to the healthcare system. A final note is that injectate volume was not controlled for in this meta-analysis, and while unlikely to have a momentous impact on outcomes, is an area for further consideration with respect to injectate risk profile.
6 Conclusions
Complication rates of BMAC injections are not significantly different from other injectables, nor specifically from HA for knee OA. Compared to other injections, 152 patients would need to receive a BMAC injection for one additional patient to experience a complication.
CRediT authorship contribution statement
Stephen Fucaloro: Methodology, Formal analysis, Investigation, Visualization. Jack T. Bragg: Methodology, Investigation, Writing – original draft, Validation. Matthew W. Feldman: Data curation, Methodology, Investigation, Writing – original draft, Validation. Laura Krivicich: Methodology, Formal analysis, Investigation, Writing – original draft. Matthew J. Salzler: Supervision.
Patient consent
This manuscript is a systematic review of available published literature. No new patient data was collected from patients, and no procedures were performed on human subjects.
1 Declarations
This research did not receive any specific grant form funding agencies in the public, commercial or non-profit sectors.
Principal investigator Matthew J. Salzler is on the editorial board for Arthroscopy.
Ethical statement
This manuscript is a systematic review of available published literature. All human subjects data in this manuscript was attained from previously published works, and IRB approval was not required.
Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Funding statement
No relevant sources of funding were procured for the production of this manuscript.
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