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February 2023, Volume 73, Issue 2

Review Article

Role of stem cells in the treatment of osteoarthritis- a review of literature

Authors: Mohammad Mustafa  ( Department of Orthopaedics, Liaquat National Hospital, Karachi, Pakistan. )
Arslan Ahmed Abro  ( Department. of Orthopaedics, Liaquat National Hospital, Karachi, Pakistan. )
Noman Khan  ( Department of Orthopaedics, Liaquat National Hospital, Karachi, Pakistan. )
Muhammmad Kazim Rahim Najjad  ( Department of Orthopaedics, Liaquat National Hospital, Karachi, Pakistan. )
Syed Shahid Noor  ( Department of Orthopaedics, Liaquat National Hospital, Karachi, Pakistan )

Abstract

The purpose of this review was to identify and assess the effectiveness of stem cells in the form of injectables in the treatment of joint osteoarthritis as published  in the literature. Studies were searched from multiple databases like Pubmed, Embase and Cochrane Library until June 2022 using multiple keywords. Randomized controlled trials of patients with osteoarthritis (OA) were included which compared the pain and functional outcomes for those getting Mesenchymal Stem Cells (MSCs) injectables as compared to those who received no MSCs injection. Twelve randomized controlled trials, assessing a total of 486 participants were identified and studied. Overall, stem cells injection has no significant effect on pain along with physical function. Stem cells injection could be effective in reducing pain and might also help in improving functional outcome in patients with OA. However, the findings are not yet significant and further clinical trials with larger samples are needed to come to a positive conclusion.

 

Keywords: Osteoarthritis, Pain, Injections.

 

DOI: 10.47391/JPMA.AKUS-15

 

Introduction

 

Osteoarthritis (OA) is among the most commonly occurring arthritis in adults and causes joint pain resulting in inability to function and subsequent disability. This condition is characterized by loss of the articular cartilage, destruction of the subchondral bone, thickening of synovium, disintegration of ligaments and hypertrophy of capsule1. Many treatment regimens have been proposed and marketed for OA, majority of which are modestly efficacious, but are often restricted by adverse events. The primary management of OA includes exercises, lifestyle modifications and pain medications.12-5 When such interventions are inadequate, many non-invasive therapies have been investigated and applied such as steroids,6 hyaluronic acid,7 platelet-rich plasma (PRP)8 and glucosamine9.

Total knee replacement (TKR) is the surgical treatment of choice for painful knee OA that is not controlled using conservative measures. Total knee replacements are associated with significant complications11,12. Many of the patients will continue to feel pain in the knee after TKR13. Many other complications can occur such as pulmonary embolism, infections and death in around 2 % of patients12.

The overall health and financial impact of OA has made it a liability which has resulted in working on alternative joint preservation strategies like stem cells. Stem cells have sprouted as a new modality for the management of OA.14,15 These pluripotent cells have the ability to divide into multiple cell lines.16 Mesenchymal stem cells (MSCs) are known owing to easy extraction,17 safety profile18,19 and ability to differentiate into chondral tissue.19 They help in immune-modulation by releasing growth factors and cytokines.20-22 All of these factors could help in the management of OA. These stem cells can be extracted from bone marrow or even adipose tissue and utilised in the form of injection in different joints for degenerative conditions. However, this aspect of stem cells for the management of OA is still open to discussion with no proven data stating its efficacy.23-25

Many case series have been identified which do point towards acceptable results of stem cell injections in cartilage disruption16-17, however, further review into literature is still required. We performed a literature search to evaluate the efficacy of injectable MSCs in reducing pain and enhancing function in advanced OA patients.

 

Methods

 

Literature Search: The current review included studies until July 2022. Electronic databases of Pubmed, Cochrane Library, Embase and MEDLINE were searched through the combination of keywords related to OA, stem cell therapy, mesenchymal stem cells and randomized controlled trials (RCT). 152 studies were reviewed initially by name of the title or abstract of the article to assess study inclusion based on criteria.

 

Study Selection: Studies which met the following criteria were included in the review: (1) RCTs; (2) patients with OA; (3) pain and functional outcome of patients with OA being reported; and (4) Non-human studies were excluded.

 

Outcome Measures: The primary goal of the study was to assess the efficacy of pain management and functional improvement by injecting stem cells in various joints. Outcomes assessed included outcomes reported by patients such as the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score,3 the visual analog scale (VAS) for pain, and the macroscopic International Cartilage Regeneration & Joint Preservation Society (ICRS) score.31  

 

Results

 

The search of electronic databases and other sources resulted in 152 articles. After removing duplicates, 42 full-text articles were chosen. 11 studies were excluded after reading the full text. Seven were excluded because they were not RCTs or CCTs. In total, 12 studies met the criteria.26-37 The trials were published between 2011 and 2022.

Nine  articles used the WOMAC score,5,6,9,24,33; 7 studies used the VAS;9,24,29,33 and 5 studies used the macroscopic ICRS score.6,29,33 The macroscopic ICRS score determines the final outcome of cartilage macroscopically. Grade 1 points towards normal cartilage whereas grade 4 indicates severely damaged cartilage.

Ten randomized controlled trials26,27,30–37 and two controlled clinical trials28,29 were included in this review. All the studies included patients with osteoarthritis and the average age of participants was over 55 years. Five studies27–31, 33 contrasted stem cells with placebo, which included other interventions as well, such as arthroscopy, rehabilitation regimes, PRP and hyaluronic acid. Two articles31,32 compared stem cells with HA excluding all other interventions.

 

Outcomes on Pain: Eight articles27,29–35 evaluated the impact of injectable stem cells on pain using a visual analog scale. Inconsistent data extracted showed that stem cells’ injection alone, or with other interventions, had an impact on pain in OA but not significantly.

However, when two low quality studies were removed from the review, it resulted in significantly decreased pain scores. Two studies reported that MSCs injection alone was as effective as hyaluronic acid (HA) in reducing pain in OA [30,31].

 

Outcomes on Function: Seven articles evaluated physical function. Review showed that stem cells alone or in combination with other therapies significantly improved various functional scores (Lysholm score, Lequesne index and OAOS). The Lysholm score of five articles showed significant results28–32 compared to control group. The rest of the studies utilised the Lequesne index for assessing function between experimental and control groups and showed significant differences31–33.  However , when six months post injection follow up was studied, neither of the studies showed significant difference between the two groups.

Four studies31,32,33,34 have been searched in this review which have compared stem cells injection with hyaluronic acid. Evaluation for function was done with Lequesne index and WOMAC at six months and 12 months post injection. The results indicated a significant difference in Lequesne index when the two groups were compared. On the other hand, WOMAC score showed no significant difference.

 

Discussion

 

Musculoskeletal conditions requiring alternative regenerative measures are increasing in popularity for treating injuries requiring bone augmentation. Stem cell therapy has sprouted as a fulfilling technique to support bone regeneration24. It was the pathologist Cohnheim who claimed that nonhematopoietic cells in the blood travel to injury sites and potentiate tissue regeneration.(Ref)

Frieden stein indicated that bone marrow contains stem cells many years after the discovery of similar cells in rabbits. The research on MSCs has since then resulted in many new researches on their potential for various therapeutic outcomes35.

MSCs are non haematopoietic stromal stem cells that can be extracted from many sources, like bone marrow, adipose tissue, periosteum, muscle, umbilical cord blood and other mesenchymal tissues as well. They are able to self-replicate themselves and are also able to differentiate into and help in the reproduction of various tissues like bone, cartilage, muscle and adipose tissue. They have been utilised to provide a scaffold for bone grafts using engineered tissues. All this information regarding stem cells paves way for further research and development of newer therapies for bone regeneration using MSCs38.

In recent years, multiple clinical trials have shown that injectable stem cells have been helpful in the pain management and function outcomes for patients with knee osteoarthritis30,39-42. However there are few RCTs describing osteoarthritis in various other joints. Therefore, the outcomes of stem cell therapy on patients of osteoarthritis haven’t had a conclusive outcome. Our review included twelve RCTs26–37, which fulfilled the inclusion criteria.

On the basis of Jadad scale evaluation, seven of these studies were categorized as high quality and the other five studies fell under low quality. Eight different studies39,29–35 used VAS for pain evaluation, however,  nonsignificant benefit came up of the stem cells injection on improving pain at the last followup. However, it should be noted that owing to the heterogeneity of these studies, the results should be dealt with caution. When two of the mentioned low quality studies were removed from the final results, the remaining high quality articles showed that the injection improved pain relief when compared with the control group. Therefore, this particular outcome of MSCs injection on pain in patients with osteoarthritis can not be significantly concluded.

All of the included studies evaluated the outcome of MSCs injection on the function of patients with OA. Even though a significant result was observed of stem cells injection as compared with the opposing group, the positive effect was not significant at six months post-injection. As there was a wide variance of these reported outcome measures, we utilized the Lysholm score and Lequesne index to portray the effect of stem cells injection. The final results showed that MSCs injection has had a significant effect on Lysholom score or Lequesne index when compared with the control therapeutic measures.

In order to highlight the comparison between stem cells and hyaluronic acid, four studies31- 34 were included. One article36 which studied VAS had a nonsignificant effect on pain reduction with the use of stem cells. When Lequesne index was compared in two studies, it indicated that stem cells were more effective than hyaluronic acid. However, when comparison was made using WOMAC, no significant difference could be associated between the two. However, owing to the limitation of sample size, our findings indicate that stem cells’ effect on pain and functional outcome compared with hyaluronic acid cannot be significantly concluded.

A notable limitation keeping this review in mind is that the findings studied and observed have a high risk of bias and being low quality on the basis of evidence studied. Moreover, the studies are limited in number included in this literature search. And even though various different outcome measures of pain and function have been studied in the articles, our main focus has been on Lysholm score and Lequesne index for comparing function between MSCs injection and the control groups. Throughout our review we assumed that no interaction between MSCs and other co-interventions like platelet-rich plasma (PRP) must have taken place without testing this assumption. This adds further limitation.

Finally, only a limited number of small trials have been studied and only twelve studies containing 486 participants in total were included, biases could not be completely appreciated. With such a

limited number of randomized control trials and the data published, only positive outcomes being published is at a high risk while the negative trials are disregarded. Therefore, with such limitations, confidence in the outcomes studied and observed in this literature review is reduced.

 

Conclusion

 

The current evidence shows and points out that there could be a potential positive effect of stem cells injection on pain in patients diagnosed with osteoarthritis. There could also be a significant potential positive outcome on physical function in patients with osteoarthritis after the injection. However, the evidence can be considered weak, with some studies being low quality, outcomes not being completely reported and small sample sized studies. Therefore, in conclusion, large sample sized studies and high quality RCTs need to be carried out to prevent such biases, which will evaluate and measure outcomes related to patients’ pain relief and functional improvement to support the role of stem cells injection for osteoarthritis patients.

 

Disclaimer: None to declare.

 

 

Conflict of Interest: None to declare.

 

Funding Disclosure: None to declare.

 

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