Marc Darrow, MD, JD
Marc Darrow MD,JD

In this article I will present research on the use of stem cell therapy treatments for knee osteoarthritis. I will discuss published research by the Darrow Stem Cell Institute on the use of bone marrow derived stem cells. I also invite you to ask your questions using the form below about your knee pain.

Stem Cells Instead of Knee Replacement?

Over the years it became clear to many researchers that knee replacement had to be redefined and disputed as the gold standard of knee osteoarthritis, “bone-on-bone,” treatment. Other doctors, however, had already decided to abandon joint replacement and explore growing tissue as the new standard of care. The thinking was simple—why remove bone and tissue when these could be repaired and rejuvenated?

What was found in the initial research was startling. Doctors discovered that one type of stem cell (mesenchymal stem cells found in bone marrow) could morph into bone cells and cartilage cells when injected into a joint. The ramifications for the treatment of osteoarthritis or “bone-on-bone” joints were enormous. Stem cell injections showed that cartilage could be regrown, something that doctors had previously thought impossible because of the cartilage’s limited blood supply within the joint. Most recently, doctors announced that they had confirmed successful regeneration of cartilage tissue in the knee through simple Stem Cell Therapy injection.(1,2)

Before we get to new updates, let’s review the research we conducted at the Darrow Stem Cell Institute in Los Angeles, California on patients with knee osteoarthritis.

Short-Term Outcomes in Treatment of Knee Osteoarthritis With 4 Bone Marrow Concentrate Injections

Brent Shaw, Marc Darrow, MD JD : Darrow Stem Cell Institute, Los Angeles, CA, USA
Armen Derian : Mayo Clinic, Phoenix, AZ, USA
Clinical Medicine Insights: Arthritis and Musculoskeletal Disorders June 18, 2018 (3)
Study synopsis
Preliminary research suggests that bone marrow concentrate (BMC), which contains mesenchymal stem cells and platelets, is a promising treatment for knee osteoarthritis. The aim of this study was to build on this preliminary research by reporting the short-term progress of 15 patients (20 knees) with knee osteoarthritis through 4 BMC (bone marrow derived stem cell treatments.)

The timetable of the four treatments:

  • First treatment
  • Second treatment approximately 14 days after first treatment.
  • Third treatment, approximately 21 days after second treatment, 35 days after first treatment
  • Fourth treatment, approximately 34 days after the third treatment. Approximately 69 days on average after first treatment
  • The last follow-up was conducted a mean 86 days after the first treatment.

What we measured: Overall improvement percentage was compared after each treatment for the following:

  • pain at rest
  • pain during activity
  • functionality scale scores

What we found:

  • Patients experienced statistically significant improvements in active pain and functionality score after the first treatment.
  • Additionally, patients experienced a mean decrease in resting pain after the first treatment, yet outcomes were not statistically significant until after the second treatment.
  • On average, patients experienced:
    • an 84.31% decrease in resting pain,
    • a 61.95% decrease in active pain,
    • and a 55.68% increase in functionality score at the final follow-up.
  • Patients also reported a mean 67% total overall improvement at study conclusion. Outcomes at the final follow-up after the fourth treatment were statistically significant compared to outcomes at baseline, after first treatment, after second treatment, and after third treatment.

In this study we concluded: “These results are promising, and additional research with a larger sample size and longer follow-up is needed to further examine the treatment effectiveness of multiple BMC injections for knee osteoarthritis.”

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Recent research on bone marrow derived stem cells

A February 2021 study, (4) citing our above research, among other research studies investigated the available literature on the use of bone marrow aspirate concentrate (BMAC) and summarize the current evidence supporting its potential for the injective treatment of joints affected by osteoarthritis. They noted that the “publication trend (of bone marrow aspirate concentrate research) remarkably increased over time. A total of 22 studies were included in the qualitative data synthesis: four preclinical studies and 18 clinical studies, for a total number of 4626 patients. Safety was documented by all studies, with a low number of adverse events. An overall improvement in pain and function was documented in most of the studies.” This study team concluded: “There is a growing interest in the field of bone marrow aspirate concentrate injections for the treatment of osteoarthritis, with promising results in preclinical and clinical studies in terms of safety and effectiveness. Nevertheless, the current knowledge is still preliminary. Preclinical research is still needed to optimize bone marrow aspirate concentrate use, as well as high-level large controlled trials to better understand the real potential of bone marrow aspirate concentrate injections for the treatment of patients affected by osteoarthritis.”

In the above study, the authors noted that there is a significant increase in the number of papers being produced. They like other researchers are looking for more because the treatment seems to work.

An August 2019 study, (5) which also cited our research paper said: “The available literature is undermined by both the lack of high-quality studies and the varied clinical settings and different protocols reported in the few random clinical trials presently published. . . Nevertheless, the use of (bone marrow aspirate concentrate) has been shown to be safe and have some short-term beneficial effects.” The treatment seems to work.

Regeneration of cartilage

A January 2020 (6) study from Loughborough University in the United Kingdom suggests:

“Pre-clinical studies have demonstrated successful, safe and encouraging results for articular cartilage repair and regeneration (with intra-articular injections of bone marrow derived mesenchymal stem cells). This is concluded to be due to the multilineage differential potential, immunosuppressive and self-renewal capabilities of bone marrow derived mesenchymal stem cells, which have shown to augment pain and improve functional outcomes.

Subsequently, clinical applications of intra-articular injections of bone marrow derived mesenchymal stem cells are steadily increasing, with most studies demonstrating a decrease in poor cartilage index, improvements in pain, function and Quality of Life; with moderate-to-high level evidence regarding safety for therapeutic administration . . .

Overall, the benefits of intra-articular injections of bone marrow derived mesenchymal stem cells were deemed to outweigh the adverse effects; thus, this treatment be considered as a future therapy strategy. To realize this, long-term large-scale randomized clinical trials are required to enable improved interpretations, to determine the validity of efficacy in future studies.”

A study published in the Archives of orthopaedic and trauma surgery (7) in August 2019 offered these observations on improved outcomes after mesenchymal stem cells injections for knee osteoarthritis: results at 12-months follow-up. This was a systematic review of 18 medical studies and 1069 knees offered treatment.

  • 72% of the included studies harvested the stem cells from the iliac crest (bone marrow-derived MSCs),
  • the remaining 28% from the adipose tissue (adipose-derived MSCs).

The investigators wrote: “According to the current evidences and the main findings of this systematic review, we reported that MSC infiltrations for knee osteoarthritis can represent a feasible option, leading to an overall remarkable improvement of all clinical and functional considered outcomes, regardless of the cell source. Patients treated at earlier-degeneration stages reported statistically significant greater outcomes. The pain and function scores were improved considerably, thus, leading to a significant improvement of patient participation in recreational activities and quality of life.”

A study in the journal Cytotherapy (8) , examined the injection of mesenchymal stromal cells (bone marrow derived stem cells) as a treatment for knee osteoarthritis.

The study subjects were randomized into two groups:

  • A single injection of stem cells, or
  • A placebo injection of saline solution

Patients were followed up for 6 months after the injection.

Scores were recorded for :

  • Pain level and function improvements to include: walking distance, painless walking distance, standing time and knee flexion compared with the placebo group at 3 and 6 months

The conclusion of this research was the bone marrow derived stem cell injection demonstrated safety and effectiveness. However more research would be needed to confirm this.

Research: Bone marrow derived stem cell injection provided significant and clinically relevant pain relief over 6 months versus placebo.

In their 2016 study published in the journal Clinical and translational medicine,(9) researchers at Georgia Regents University wrote: “Current pharmacological treatment strategies are ineffective to prevent the osteoarthritic progression; however, cellular therapies have the potential to regenerate the lost cartilage, combat cartilage degeneration, provide pain relief, and improve patient mobility.” They add that among the cellular therapies, bone marrow-derived stem cells which have been shown to have a higher chondrogenic capability (the ability to make cartilage) than adipose (fat) derived stem cells, and they have been studied more extensively than the fat derived stem cells.

They also note that: “Due to the increasing incidence and prevalence of osteoarthritis, more innovative and effective therapeutic modalities need to be investigated, including MSCs. More randomized clinical trials need to be completed in order to demonstrate the efficacy, safety, and benefits of MSCs in treating patients with osteoarthritis.”

Doctors suggest that patients may experience benefits for at least two years

This is from a recent study published in the journal Experimental and therapeutic medicine. (10)

“MSC treatment in patients with knee osteoarthritis showed continual efficacy for 24 months compared with their pretreatment condition. Effectiveness of MSCs was improved at 12 and 24 months post-treatment, compared with at 3 and 6 months. . .  MSC application ameliorated the overall outcomes of patients with knee osteoarthritis, including pain relief and functional improvement from basal (base) evaluations, particularly at 12 and 24 months after follow-up.

This was after a single treatment only.

A July 2021 review study on Bone Marrow Aspirate Concentrate for the Treatment of Knee Osteoarthritis

A July 2021 paper (11) gave this assessment of Bone marrow aspirate concentrate (BMAC) for symptomatic knee osteoarthritis. They have good things to say and not so good things. First, how was the study conducted?

The study authors reviewed previously published research and found eight studies met their inclusion criteria, including a total of 299 knees with an average follow-up of 12.9 months.

  • Of all patient-reported outcomes assessed across studies, 34 of 36 patient reported (94.4%) demonstrated significant improvement from baseline to latest follow-up.
  • Five studies evaluating numerical pain scores (visual analog scale and Numeric Rating Scale) reported significant improvements in pain level at final follow-up.
  • However, 3 comparative studies evaluating Bone marrow aspirate concentrate in relation to other therapeutic injections failed to demonstrate the clinical superiority of Bone marrow aspirate concentrate.

Conclusion: “The Bone marrow aspirate concentrate injection is effective in improving pain and patient-reported outcomes in patients with knee osteoarthritis at short- to midterm follow-up. Nevertheless, Bone marrow aspirate concentrate has not demonstrated clinical superiority in relation to other biologic therapies commonly used in the treatment of osteoarthritis, including platelet-rich plasma and microfragmented adipose tissue, or in relation to placebo. The high cost of the Bone marrow aspirate concentrate injection in comparison with other biologic and nonoperative treatment modalities may limit its utility despite demonstrable clinical benefit.”

Stem cell therapy, PRP therapy and a hyaluronate

In some practices stem cell therapy and PRP therapy are given at the same time. This is something that we typically do not do because of the platelets already present in the bone marrow concentrate. There is also extra cost involved to the patient that many times we do see as being justified. Many people however, do get great benefit from this combined treatment. Let’s explore a comparative study published in January 2021.(12)

The study aimed to determine the clinical response to an autologous bone marrow aspirate concentrate (BMAC) and platelet-rich plasma (PRP) intra-articular injection compared to an active comparator  (Gel-One® crosslinked hyaluronate (HA)).

  • Participants with diagnosed knee osteoarthritis were divided into one of two treatment groups.
    • One group will receive bone marrow aspirate concentrate immediately followed by a PRP injection or a single injection of Gel-One® crosslinked hyaluronate (HA).
    • Outcomes were assessed at three, six, and 12 months post-treatment.
  • Results: Significant improvements were observed in both treatment groups for all Knee Injury and Osteoarthritis Outcome Score (KOOS) subscales with the exception of the symptoms assessment at 12 months in the hyaluronate group. Results demonstrate that both treatment groups experienced clinically and statistically significant improvement across the KOOS subscales. While BMAC has shown promise in the treatment of knee osteoarthritis, there is a need for multi-center investigations with larger sample sizes, an extended follow-up, and placebo-based control.

Our conclusions about bone marrow derived stem cells for knee osteoarthritis

Returning to our own published research cited above, I would like to recap the learning points:

  • We found that in the short-term, receiving multiple injections may be more effective than receiving a single Bone Marrow Concentrate stem cell injection.
    • Outcomes at the final follow-up after the fourth treatment were statistically significant compared with outcomes at baseline, after first treatment, after second treatment, and after third treatment.
  • Functionality score increased after first treatment, illustrating that patients experienced an immediate benefit in performing everyday activities with less difficulty.
  • By the second injection, patients began to report improvement with pain at rest. Patients then experienced additional decreases in resting pain with each treatment thereafter.
  • The increase in mean functionality score with successive BMC treatments shows that increasing the number of BMC treatments improves patient performance in daily activities.

The present findings may provide new clinical insights into treating osteoarthritis with Bone Marrow Concentrate. If Bone Marrow Concentrate treatments become more affordable or covered by insurance companies, there could be an increase in the number of patients receiving multiple Bone Marrow Concentrate treatments for osteoarthritis. If patients who reported improvement to a single injection received multiple, they may experience increased symptomatic relief such as the patients in our study. An additional finding illustrated that patients experienced a greater pain relief when injected with a high-nucleated cell count compared to a lower dose. Our study demonstrates that gradual increase in BMC injections in a short time period may be more effective than a single injection.

We do call on more research to help validate our findings as our small sampling case studies are not definitive.

Do you have questions? Ask Dr. Darrow

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A leading provider of stem cell therapy, platelet rich plasma and prolotherapy
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PHONE: (800) 300-9300 or 310-231-7000

Stem cell and PRP injections for musculoskeletal conditions are not FDA approved. We do not treat disease. We do not offer IV treatments. There are no guarantees that this treatment will help you. Prior to our treatment, seek advice from your medical physician.

Neither Dr. Darrow, nor any associate, offer medical advice from this transmission. This information is offered for educational purposes only. The transmission of this information does not create a physician-patient relationship between you and Dr. Darrow or any associate. We do not guarantee the accuracy, completeness, usefulness or adequacy of any resource, information, product, or process available from this transmission. We cannot be responsible for the receipt of your email since spam filters and servers often block their receipt. If you have a medical issue, please call our office. If you have a medical emergency, please call 911.

References

1 Anderson JA, Little D, Toth AP, Moorman CT 3rd, Tucker BS, Ciccotti MG, Guilak F. Stem cell therapies for knee cartilage repair: the current status of preclinical and clinical studies. Am J Sports Med. 2014 Sep;42(9):2253-61. doi:10.1177/0363546513508744. Epub 2013 Nov 12.
2 Vangsness Jr CT, Jack Farr II, Boyd J, Dellaero DT, Mills CR, LeRoux-Williams M. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: a randomized, double-blind, controlled study. JBJS. 2014 Jan 15;96(2):90-8.
3 Shaw B, Darrow M, Derian A. Short-Term Outcomes in Treatment of Knee Osteoarthritis With 4 Bone Marrow Concentrate Injections. Clin Med Insights Arthritis Musculoskelet Disord. 2018 Jun 18;11:1179544118781080. doi: 10.1177/1179544118781080. PMID: 29977117; PMCID: PMC6024328.
4 Cavallo C, Boffa A, Andriolo L, Silva S, Grigolo B, Zaffagnini S, Filardo G. Bone marrow concentrate injections for the treatment of osteoarthritis: evidence from preclinical findings to the clinical application. International Orthopaedics. 2020 Jul 13:1-4.
5 Di Matteo B, Vandenbulcke F, Vitale ND, Iacono F, Ashmore K, Marcacci M, Kon E. Minimally manipulated mesenchymal stem cells for the treatment of knee osteoarthritis: a systematic review of clinical evidence. Stem cells international. 2019 Aug 14;2019
6 Doyle EC, Wragg NM, Wilson SL. Intraarticular injection of bone marrow-derived mesenchymal stem cells enhances regeneration in knee osteoarthritis [published online ahead of print, 2020 Jan 31]. Knee Surg Sports Traumatol Arthrosc. 2020;10.1007/s00167-020-05859-z. doi:10.1007/s00167-020-05859-z
7 Migliorini F, Rath B, Colarossi G, Driessen A, Tingart M, Niewiera M, Eschweiler J. Improved outcomes after mesenchymal stem cells injections for knee osteoarthritis: results at 12-months follow-up: a systematic review of the literature. Archives of orthopaedic and trauma surgery. 2019 Aug 27:1-6.
8 Emadedin M, Labibzadeh N, Liastani MG, Karimi A, Jaroughi N, Bolurieh T, Hosseini SE, Baharvand H, Aghdami N. Intra-articular implantation of autologous bone marrow-derived mesenchymal stromal cells to treat knee osteoarthritis: a randomized, triple-blind, placebo-controlled phase 1/2 clinical trial. Cytotherapy. 2018 Oct 11. pii: S1465-3249(18)30605-4. doi: 10.1016/j.jcyt.2018.08.005. PubMed PMID: 30318332.
9 Burke J, Hunter M, Kolhe R, Isales C, Hamrick M, Fulzele S. Therapeutic potential of mesenchymal stem cell based therapy for osteoarthritis. Clinical and Translational Medicine. 2016;5:27. doi:10.1186/s40169-016-0112-7.
10 Cui G-H, Wang YY, Li C-J, Shi C-H, Wang W-S. Efficacy of mesenchymal stem cells in treating patients with osteoarthritis of the knee: A meta-analysis. Experimental and Therapeutic Medicine. 2016;12(5):3390-3400. doi:10.3892/etm.2016.3791.
11 Keeling LE, Belk JW, Kraeutler MJ, et al. Bone Marrow Aspirate Concentrate for the Treatment of Knee Osteoarthritis: A Systematic Review [published online ahead of print, 2021 Jul 8]. Am J Sports Med. 2021;3635465211018837. doi:10.1177/03635465211018837
12 Ruane JJ, Ross A, Zigmont V, McClure D, Gascon G. A Single-Blinded Randomized Controlled Trial of Mesenchymal Stem Cell Therapy for the Treatment of Osteoarthritis of the Knee with Active Control. Journal of Stem Cells & Regenerative Medicine. 2021;17(1):3.

 

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