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I'm 40 years old, and remember the years in my youth when stem cells were touted as the great new miracle discovery. And like most promising new discoveries I've seen the press quietly died away and we never heard about them again for whatever reason. I'm now seeing clinics popping up all over the country offering PRP (platelet rich plasma) and MSC (Mesenchymal Stem Cell) injections to treat a variety of issues, including bulging/turn discs and spinal arthritis, since around 2013ish.

However, I cannot tell if there is any real clinical evidence of efficacy. I have found studies that imply PRP treatments are showing promise, but are have several years old. I have found some press about clinical trials from 2017, but no follow up. I found one paper on animal studies that showed great results. And clinics like Regenexx say that they have data showing incredible effectiveness, but I haven't seen any analysis or corroboration of such data. Much of my Googling is coming up with out-of-date information, though.

As of 2020, is there any peer-reviewed clinical evidence (double blind studies preferred) that show efficacy (or lack thereof) of either PRP or MSC injections for back pain caused by disc herniations and/or arthritis? If not, is there any peer-reviewed clinical evidence of the efficacy of these treatments for any conditions? Or are these clinics just selling a new brand of pyramid power?

Some of the studies and (mutually inconsistent) information I've run across:

Per a comment suggesting I link some of the information I've come across that is confusing me:

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The question of the efficacy of stem cell treatments is a topic of great current (October 2020) interest with randomized clinical trials on-going or planned for a variety of conditions.

This 2020 publication is a systematic review of studies of mesenchymal stromal cell-based therapies for the treatment of osteoarthritis.

Maleitzke T, Elazaly H, Festbaum C, et al. Mesenchymal Stromal Cell-Based Therapy-An Alternative to Arthroplasty for the Treatment of Osteoarthritis? A State of the Art Review of Clinical Trials. J Clin Med. 2020;9(7):2062. Published 2020 Jun 30. doi:10.3390/jcm9072062 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409016/

The review provides a description of studies of mesenchymal stromal cell-based therapies for treatment of osteoarthritis that are registered at ClinicalTrials.gov and are currently recruiting along with their registration numbers. Review of these registered and recruiting trials gives an idea of the scope of interest in these therapies for one condition—osteoarthritis—as well as the diversity of approaches.

The review identified published randomized placebo-controlled trials of mesenchymal stromal cell treatments for osteoarthritis as well as randomized trials with an active treatment comparison and non-randomized studies (sometimes called trials but not really trials). These are described in Table 2 of the cited publication.

The authors do not try to meta-analyze data from these published studies. Nor do they draw conclusions about whether mesenchymal stromal cell treatments should or should not be used to treat osteoarthritis.

Two studies cited in this review (reference 83 and 103) seem to address the question of whether there are any randomized trials that show benefits of mesenchymal cell-based therapies for any condition. There are.

FREITAG, BATES, WICKHAM et al.

Reference 83 is a reference to a study of adipose-derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis.

Freitag J, Bates D, Wickham J, et a. Adipose-derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis: a randomized controlled trial. Regen Med. 2019;14:213-230. doi: 10.2217/rme-2018-0161. Epub 2019 Feb 14. PMID: 30762487.

The article is available in full-text form for free. The link is accessed from PubMed.

The trial was registered on the Australian and New Zealand Clinic Trial Registry (Trial ID: ACTRN12614000814673).

There were 30 patients in the trial. They were randomized to three groups with 10 patients in each group—a single intra-articular injection of 108 (100 million) mesenchymal cells, two injections of 108 (100 million) mesenchymal cells six months apart, and a control (ongoing conventional conservative management only). The mesenchymal cells were autologous—derived from the treated persons own adipose tissue. The participants were not blinded to their treatment assignment. Randomization was “prepared in advance using a random number generator.” However, researchers with direct involvement in participant recruitment and treatment were blinded to the randomization process.

In spite of random assignment, participants in the control group had a lower body mass index than participants in the treatment groups (25.2 for control compared with 31.6 in the group given 1 injection and 30.4 in the group given two injections).

Follow-up was done at 1, 3, 6 and 12 months.

Main results for pain and function were as follows:

“Pain, as measured by the NPRS [Numeric Pain Rating Scale], in the one-injection group and two-injection group improved from a mean (standard deviation) of 6.7 (1.7) and 6.5 (1.4) to 2.6 (1.8) and 2.3 (2) respectively at completion of the study. Within group improvement when compared with baseline was statistically significant (< 0.05) throughout all time points in both the single and two injection protocol treatment groups. Similarly, between group differences revealed that both the one-injection and two-injection groups had significantly less pain at 12 months compared with the Control group. No significant differences were found between the two treatment groups.”

“KOOS [Knee Injury and Osteoarthritis Outcome Score] subscale analysis showed consistent improvement in all subscales during follow-up and this was maintained until completion of follow-up at 12 months. There was no significant difference at 12 months in all subscales between the two treatment groups. All subscales displayed statistically significant improvement against control at 12 months of follow-up. The one-injection group had more consistent improvement against Control throughout the follow-up period.”

MATAS, ORREGO, AMENABAR et al.

Reference 103 is a reference to a study of adipose-derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis.

Matas J, Orrego M, Amenabar D, et al. Umbilical Cord-Derived Mesenchymal Stromal Cells (MSCs) for Knee Osteoarthritis: Repeated MSC Dosing Is Superior to a Single MSC Dose and to Hyaluronic Acid in a Controlled Randomized Phase I/II Trial. Stem Cells Transl Med. 2019;8(3):215-224. doi:10.1002/sctm.18-0053

The full-text can be accessed on PMC. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392367/

The study was registered at Clinical Trials.gov (NCT02589695). It was a randomized, double-blind study of a single versus repeated (two) injections of umbilical-derived mesenchymal stromal cells compared with compared with standard therapy--repeated (two) injections of intra‐articular hyaluronic acid—in patients with knee OA.

There were 29 patients in the trial. They were randomized to three groups—10 were allocated to receive a single intra-articular injection of 20 x 106 (20 million) umbilical-derived mesenchymal cells at baseline and a plasma/saline placebo injection at six month; 10 were allocated to receive a baseline intra-articular injection of 20 x 106 (20 million) umbilical-cord mesenchymal cells and another injection of 20 x 106 (20 million) cells at six months; 9 were allocated to receive two intra-articular injections of hyaluronic acid--one at baseline and another at six months. There was 1 drop-out in each of the three groups leaving 9 patients in the single injection group, 9 in the two injection group, and 8 in active treatment comparator.

The mesenchymal cells were allogenic—derived from the umbilical cords obtained from full‐term human placentas by cesarean section after informed consent.

The investigators and the participants were blinded to their treatment assignment. Randomization was described as being “by electronic data entry system.”

Follow-up was done at 1, 4, 8, 12, 24, 36, and 52 weeks.

Pain and function outcomes were assessed using a number of instruments-- the Western Ontario and Mc Master Universities Arthritis Index (WOMAC), the Pain Visual Analog scale (VAS), the Short‐form 36 (SF‐36) questionnaire, the Patient Global Assessment, and the Outcome Measures in Rheumatology Committee (OMERACT)‐Osteoarthritis Research Society International (OARSI) Responder Index Criteria .

Results were reported for the Western Ontario McMaster Universities Arthritis Index, the Pain Visual Analogue Scale, the SF-36, and Outcomes Measures in Rheumatology (OMERACT)-Osteoarthritis Research Society International (OARS) Responder Index.

Results were as follows:

At 12 months follow‐up, scores on the pain subscale of the WOMAC‐A were statistically lower [better] in the group treated with 2 mesenchymal stromal cell injections (1.1 ± 1.3) compared with the group treated with hyaluronic acid (4.3 ± 3.5). (Table 3) (p = 0.04 after correction for multiple comparison)

Considering the total WOMAC, at 12 months, the group treated with 2 mesenchymal stromal cell injections also had statistically significantly lower [better] scores than the group with hyaluronic acid at 12 months (4.2 ± 3.9 vs. 15.2 ± 11). (Table 3) (p = .05 after correction for multiple comparisons).

At 12 months, scores on the pain VAS were statistically significantly lower [better] in the group treated with two mesenchymal stromal cell injections compared with group treated with hyaluronic acid (2.4 ± 2.1 vs. 22.1 ± 9.8). (Table 3) (p = .03 after correction for multiple comparison).

There were no statistically significant differences between the three groups on functional component of the WOMAC or the SF-36.

The authors also reported that:

“When comparing how often patients in the trial would achieve responder status at study endpoint, as defined by the OMERACT‐OARSI responder index criteria, all individuals in the repeated MSC (two injections of mesenchymal stromal cell) group were found to be responders as opposed to 62.5% of patients in the control HA group, a tendency that did not reach significance (p = .08; Figure 3D).”

So the answer to your question is yes, there are randomized controlled trials—with one being blinded--that report benefits of mesenchymal stromal cell (stem cell) treatment for knee osteoarthritis.

Given the small number of patients in these two trials and the findings in other randomized trials, these findings should NOT be used as evidence that the treatments studied in these two trials, or any other stem cell treatment, are recommended for any patient with knee osteoarthritis (or any other condition).

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    Thank you. It's clear you put a LOT of time and effort into this answer and it's very useful information. You didn't reference any studies related to MSC injections for disc problems or back pain (only joints), and made no reference to PRP. Is this because there is no clinical support yet for either of those? – Nicholas Oct 27 '20 at 19:51
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    @Diana Petitti Is your question focused on the spine, rather than arthritis in general? If so, this article might be helpful. – Blue Various Oct 29 '20 at 5:24
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    @Blue Various The systematic review was about osteoarthritis. The clinical trials that were recruiting (Table 1) included 22 of them were of knee osteoarthritis. None were spine osteoarthritis. Both randomized trials discussed were knee osteoarthritis. The post was not about whether these treatments work....it is an answer to question are ANY randomized trials that show a statistically significant effect. With 25 recruiting trials, the jury is out on a true effect across trials, the size of effect (if any) and an effect (if any) worth the cost. – Diana Petitti Oct 29 '20 at 20:23
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    @Nicholas Right, the systematic review that is the source of my information only talks about osteoarthritis. All the completed trials in Table 2 except 1 involved only the knee. The meta-analysis identified by Blue Various in the comment should be looked at carefully. I haven't done this. No reference to PRP because I didn't look. Perhaps post a separate question about this. MSCs are being studied for stroke, spinal cord injury, myocardial infarction, heart failure, etc. etc. etc. It is very hard to keep up and to figure out what is proven not to work and what is still being studied. – Diana Petitti Oct 29 '20 at 20:36
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    @Blue Various Agree completely with your comment. – Diana Petitti Oct 30 '20 at 18:36
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Is your question focused on the clinical trial on the spine, rather than arthritis in general? If so, the following articles will be helpful.

As for the PRPs, how about this review?

They conclude that;

Clinical studies for evaluating the effects of the injection of PRP into degenerated IVDs for patients with discogenic LBP have been reviewed. Although there was only one double-blind randomized controlled trial, all the studies reported that PRP was safe and effective in reducing back pain. While the clinical evidence of tissue repair of IVDs by PRP treatment is currently lacking, there is a great possibility that the application of PRP has the potential to lead to a feasible intradiscal therapy for the treatment of degenerative disc diseases. Further large-scale studies may be required to confirm the clinical evidence of PRP for the treatment of discogenic LBP.

They say they need larger-scale trials, but remember that any small difference can be made statistically significant by increasing the sample size.

As for the MSCs, how about this review? They conclude that;

Treatment of LBP by implantation of MSCs is unlikely to effect a significant repair or relieve pain. <<omission of middle part>>
In addition clinical studies suggesting MSC injections as a possible treatment for LBP, all lack high patient numbers and long‐term results. As not all of them have controls, they are not able to rule out that the positive results reported could arise from a placebo effect. <<omission of middle part>>
Hence the treatment of the illustrated case through injection of MSCs cannot thus be recommended. MSC implantation is very unlikely to effect a clinically relevant repair and even if it could, it is unclear whether the patient would benefit from repair of her disc.

Note that, as you can see from other review review the spine is not a major target of the MSCs; you can see how many clinical trials on MSC are registered on clinicaltrials.gov.

From the above reviews, in general, one should conclude that the benefits of MSCs and PRP for arthritis or similar diseases on the spine have not been proven to be worth the cost. No credible evidence has yet been found to establish their effectiveness. Conducting larger sample size trials may lead to statistically significant differences in some surrogates, but I don't think that dramatic treatment exists as an extension of the current MSC and PRP;I think we need a radically improved MSC or PRP.

Recently, Mesoblast Group appears to have an MSC-based pipeline, MPC-25-Osteo, for the spine. There appears to be a Phase 3 clinical trial underway, so I suspect we'll know more about it when the results come in. (See this site). However, they say their target is opioid substitution; in other words, the goal might be pain relief rather than a cure for the root cause.

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