Key messages
• Compared with placebo injection, stem cell injection for people with knee osteoarthritis may slightly improve pain and function.
• We are uncertain whether stem cell injection slows down the progression of the disease, improves quality of life or the chance of treatment success, or whether stem cell injections are safe.
What is osteoarthritis?
Osteoarthritis is a disease of the joints. The joint loses cartilage and other changes to the structure of the joint may occur. This can lead to pain and reduced ability to use the joint.
How is osteoarthritis treated?
Most treatments aim to relieve symptoms, although few are effective. Joint replacement surgery is the only definitive treatment, and is reserved for people with severe disease who have not experienced any benefit from other treatments.
Stem cells are a special type of cell that can develop into mature cells in different parts of the body, including cells that produce cartilage, bone and fat tissue. Thus, in theory, these stem cells could lead to regrowth of damaged cartilage in the joint, which has led to their use as a treatment for osteoarthritis.
What did we want to find out?
We wanted to find out if stem cell injections improve pain, function, treatment success and quality of life, slow down disease progression or lead to harm in people with knee osteoarthritis.
What did we do?
We searched for studies that investigated stem cell injection compared with placebo, no treatment or usual (routine) care, or other treatments in knee osteoarthritis.
We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as variability in the stem cell injections, completeness of the evidence and study size.
What did we find?
We found 25 studies (1341 participants), including 8 studies (459 participants) that compared stem cell injection into the knee with a placebo injection. The remaining studies compared stem cell injection with no treatment or usual care (2 studies, 30 participants), intra-articular glucocorticoid injection (1 study, 33 participants), hyaluronic acid injection (7 studies, 429 participants), platelet-rich plasma injection (2 studies, 142 participants), oral acetaminophen (paracetamol; 1 study, 51 participants), NSAIDs (non-steroidal anti-inflammatory drugs) plus physical therapy plus hyaluronic acid injection (1 study, 57 participants) and stem cell injection plus intra-articular co-intervention versus co-intervention alone (3 studies, 140 participants). Studies were conducted worldwide, including Europe, the Middle East, Asia, the USA, South America, the United Kingdom and Australia.
Main results
Compared with placebo injections, stem cell injections may improve pain and function slightly.
Pain measured on a 0 to 10 scale (0 is no pain) at six months was 1.2 points better with stem cell injection.
• People who had stem cell injection rated their pain as 3.3 points.
• People who had placebo injection rated their pain as 4.5 points.
Function measured on a 0 to 100 scale (0 is best function) at six months was 14.2 points better with stem cell injection.
• People who had stem cell injection rated their function as 32.1 points.
• People who had placebo injection rated their function as 46.3 points.
Quality of life measured on a 0 to 100 scale (0 is best function) at six months was 22.8 points better with stem cell injection.
• People who had stem cell injection rated their quality of life as 68.1 points.
• People who had placebo injection rated their quality of life as 45.3 points.
After stem cell injection, 153 more people per 1000 rated their treatment a success at 12 months.
• 683 per 1000 reported treatment success with stem cell injection.
• 530 per 1000 reported treatment success with placebo injection.
After stem cell injection, seven fewer people per 1000 had serious adverse events at 12 months.
• 16 per 1000 people experienced a serious adverse event with stem cell injection.
• 23 per 1000 people reported a serious adverse event with placebo injection.
No withdrawals from the study due to harms from stem cell or placebo injections were reported.
Disease progression was not assessed in any study.
What are the limitations of the evidence?
Our confidence in the estimates for pain and function is low, as the optimal preparation and dose of stem cells is unknown, and varied across studies. Further, up to three larger studies could not be included, as they were conducted but withdrawn by their investigators before reporting results.
We are uncertain whether more people report treatment success, or improvement in quality of life. We are uncertain of the risk of serious harms and harms leading to treatment discontinuation because, in addition to the variation in stem cells used across studies and missing results from larger studies, there were a very small number of events.
How up-to-date is this evidence?
The evidence is up-to-date to 15 September 2023.
Editorial note: This is a living systematic review. We search for new evidence every three months and update the review when we identify relevant new evidence. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.
Compared with placebo injections and based upon low-certainty evidence, stem cell injections for people with knee osteoarthritis may slightly improve pain and function. We are uncertain of the effects of stem cell injections on quality of life or the number who report treatment success. Although the putative benefits of stem cell therapies for osteoarthritis include potential regenerative effects on damaged tissues, particularly articular cartilage, we remain uncertain of the effect of stem cell injections on structural progression in the knee (measured by radiographic appearance). There is also uncertainty regarding the safety of stem cell injections. Serious adverse events were infrequently reported, although all invasive joint procedures (including injections) carry a small risk of septic arthritis. The risk of other important harms, including potential concerns related to the use of a therapy with the theoretical capacity to promote cell growth, or to the use of allogeneic cells, remains unknown.
Stem cells are specialised precursor cells that can replace aged or damaged cells and thereby maintain healthy tissue function. Stem cell therapy is increasingly used as a treatment for knee osteoarthritis, despite the lack of clarity around the mechanism by which stem cell therapy may slow down disease progression in osteoarthritis, and uncertainty regarding its benefits and harms.
To assess the benefits and harms of stem cell injections for people with osteoarthritis of the knee. A secondary objective is to maintain the currency of the evidence, using a living systematic review approach.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase on 15 September 2023, unrestricted by date or language of publication. We also searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) for relevant trial protocols and ongoing trials.
We included randomised controlled trials (RCTs), or trials using quasi-randomised methods of participant allocation, comparing stem cell injection with placebo injection, no treatment or usual care, glucocorticoid injection, other injections, exercise, drug therapy, surgical interventions, and supplements and complementary therapies in people with knee osteoarthritis.
Two review authors selected studies for inclusion, extracted trial characteristics and outcome data, assessed risk of bias and assessed the certainty of evidence using the GRADE approach. The primary comparison was stem cell injection compared with placebo injection. The primary time point for pain, function and quality of life was three to six months, and the end of the trial period for participant-reported success, joint structure changes and adverse event outcomes. Major outcomes were pain, function, quality of life, global assessment of success, radiographic joint progression, withdrawals due to adverse events and serious adverse events.
We found 25 randomised trials (1341 participants) comparing stem cell injections with placebo injection (eight trials), no treatment or usual care (analgesia, weight loss and exercise) (two trials), glucocorticoid injection (one trial), hyaluronic acid injection (seven trials), platelet-rich plasma injections (two trials), oral acetaminophen (paracetamol) (one trial), non-steroidal anti-inflammatory drugs plus physical therapy plus hyaluronic acid injection (one trial) and stem cell injection plus intra-articular co-intervention versus co-intervention alone (three trials) in people with osteoarthritis of the knee. Trials were predominantly small, with sample sizes ranging from 6 to 252 participants, with only two trials having more than 100 participants. The average age of participants across trials ranged from 51 to 66 years, and symptom duration varied from one to 10 years.
Placebo-controlled trials were largely free from bias, while most trials without a placebo control were susceptible to performance and detection biases. Here, we limit reporting to the main comparison, stem cell injection versus placebo injection.
Compared with placebo injection, stem cell injection may slightly improve pain and function up to six months after treatment. Mean pain (0 to 10 scale, 0 no pain) was 4.5 out of 10 points with placebo injection and 1.2 points better (2.5 points better to 0 points better) with stem cell injection (I2 = 80%; 7 studies, 445 participants). Mean function (0 to 100 scale, 0 best function) was 46.3 points with placebo injection and 14.2 points better (25.3 points better to 3.1 points better) with stem cell injection (I2 = 82%; 7 studies, 432 participants). We are uncertain whether stem cell injections improve quality of life or increase the number of people who report treatment success compared to placebo injection, because the certainty of the evidence was very low. Mean quality of life was 45.3 points with placebo injection and 22.8 points better (18.0 points worse to 63.7 points better) with stem cell injection (I2 = 96%; 2 studies, 288 participants) at up to six months follow-up. At the end of follow-up, 89/168 participants (530 per 1000) in the placebo injection group reported treatment success compared with 126/180 participants (683 per 1000) in the stem cell injection group (risk ratio (RR) 1.29, 95% CI 1.10 to 1.53; I2 = 0%; 4 trials, 348 participants).
We downgraded the evidence to low certainty for pain and function due to indirectness (as the source, method of preparation and dose of stem cells varied across studies), and suspected publication bias (up to three larger RCTs have been conducted but withdrawn prior to reporting of results). For quality of life and treatment success, we further downgraded the evidence to very low certainty due to imprecision in addition to indirectness and suspected publication bias.
We are uncertain of the potential harms associated with stem cell injection, as there were very low event rates for serious adverse events. At the end of follow-up, 5/219 participants (23 per 1000) in the placebo injection group experienced serious adverse events compared with 4/242 participants (16 per 1000) in the stem cell injection group (RR 0.72, 95% CI 0.20 to 2.64; I2 = 0%; 7 trials, 461 participants) and there were no reported withdrawals due to adverse events. We downgraded the evidence to very low certainty due to indirectness, suspected publication bias and imprecision.
Radiographic progression was not assessed in any of the included studies.