Stem Cell Therapy

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What are the effects of osteoarthritis in Australia?

Osteoarthritis (OA) is a leading cause of pain and disability in adults and affects 15% of the Australian population (March & Bagga, 2004). It is characterised by a progressive loss of cartilage within the joint, with the knee being the most commonly affected joint (Bennell & Hinman, 2011). The pain and disability of OA seriously impacts the sufferer’s ability to perform everyday activities and impairs their ability to work. As a consequence, OA has a significant personal burden on the individual and large financial burden to the Australian economy, with estimated costs totalling $23.9 billion in 2007 (Arthritis Australia, 2007).

What are the treatment options for Osteoarthritis?

With the Australian population aging, OA is becoming more common. Despite this there are few treatment options to slow the progression of disease, and no therapy that effectively reverses the process.

Currently available treatments:

The basics

  • Weight loss
  • Exercise

Oral pain relief

  • Paracetamol
  • Anti-inflammatories
  • Glucosamine/chondroitin
  • Fish Oil

Injectable pain relief

  • Cortisone
  • Hyaluronic acid (most common brands are Synvisc or Osteoartz)
  • Platelet Rich Plasma

Surgical interventions

  • Arthrocsopy – the “clean up”
  • Joint re-alignment surgery
  • Joint replacement.

Weight loss and exercise are the mainstay of all treatments of osteoarthritis. All therapies for the treatment of osteoarthritis should be combined with a weight loss and exercise program, wherever possible. However, although exercise therapy has short-term benefits for pain and physical function in patients with knee OA, effectiveness has been shown to decline over the longer term due to poor adherence (Pisters et al, 2007).

Oral pain relieving therapies, such as paracetamol and anti-inflammatory medication aim to minimise the pain of the disease, but do not address the underlying processes driving OA (Sampson et al, 2010). Not surprisingly therefore, these treatments have poor long-term success and are associated with side effects that increase with long-term use (Bjordal, Ljunggren, Klovning, & Slørdal, 2004). In addition, the recently highlighted increase heart attack and stroke risk associated with the use of anti-inflammatories, significantly decreases their previous appeal (Fosbøl et al, 2010).

The injectable pain relief options include cortisone, Hyaluronic acid and platelet rich plasma. Cortisone is a well accepted means of controlling the pain of osteoarthritis, and although its big brother prednisone, gives it a bad name, it has quite a low side effect profile and is good especially during periods of acute pain. The problem is that is wears off relatively quickly and only gives on average 3 weeks pain relief when used for knee osteoarthritis (Habib et al, 2010). Hyaluronic acid is known as viscosupplementation. It acts as a local anti-inflammatory for the joint and settles pain. Its pain relieving effect come on over 3 months and will generally last 6 or more months. People with lower degrees of osteoarthritis do better than those with severe disease. It has been extensively researched with varying results.

The final injectable option is platelet rich plasma (PRP). There is currently 4 scientific papers that support its’ use in osteoarthritis. Two papers have followed patients up to 2 years with positive results (Baltzer et al, 2009, Filado et al, 2010), and 2 papers have compared it to hyaluronic acid and shown platelet rich plasma to have greater pain relieving effects (Baltzer et al, 2009, Sanchez et al, 2008). PRP requires on average 3 injections to have a significant effect with a gradually increasing effect after each injection. The pain relieving effect anecdotally lasts for about 11 months. PRP does hold some promise as a new therapy for osteoarthritis but is still considered experimental.

Surgical intervention is common given the progressive nature of the disease; however, a recent review of the literature concluded that there was no benefit from arthroscopic debridement for osteoarthritis (Laupattarakasem et al, 2008).  The final surgical step is joint replacement. The increase in demand for this treatment has resulted in a significant burden on the healthcare system (March & Bagga, 2004). Consequently, there is a pressing need for novel and effective therapies to treat OA.

Before considering any stem cell therapy we strongly recommend you consider the above treatment options as suited to your condition.


Where do the stem cells come from?

The stem cells used in the process are from your own body, these are known as autologous adult stem cells. The cells are harvested and then injected into the area being treated on the same day.  As adult stem cells are derived from the patients’ own body, they thus lack the ethical concerns associated with embryonic stem cells. Currently, adult stem cells are most commonly derived from bone marrow or adipose tissue (fat), with fat providing either a similar (De Ugarte et al, 2003) or a higher yield of stem cells (Kern et al, 2006). Further to this the mini-liposuction technique required to harvest the cells is less invasive and less painful than the bone marrow biopsy required to harvest bone marrow.

What benefit may stem cells have?

Recent work has demonstrated that adipose derived stem cells can differentiate into cartilage and bone supporting their potential in the treatment in osteoarthritis (Diekman et al, 2010; Kern et al 2006). Indeed, the use of adipose derived stem cells has shown cartilage regrowth  in rabbits (Dragoo et al, 2007, Cui et al, 2009), and significantly improve function in dogs (Black et al, 2007, Black et al, 2008). Bone marrow derived stem cells have been shown stimulate cartilage regeneration in dogs (Mokbel et, al 2010), and Pigs (Zhou et al, 2006).

There have been 11 studies in humans looking at the use of stem cells to treat cartilage defects or osteoarthritis. These studies are all small case series and provide only limited evidence for the efficacy. Below is a quick summary.

11 studies with between 1 and 180 patients in each study

  • Studies have used bone marrow, blood and fat derived stem  cells
  • The have treated knees and hips
  • These have been in various degrees of osteoarthrits
  • They have all found improvement in patients pain and function
  • Cartilage regeneration shown on MRI and second look arthroscopy

The below tables give you a little more information about each study. How many patients, how long the follow up has been and whether they have been able to find cartilage regeneration.


The above pre-human data shows some promise in stem cells either adipose derived or bone marrow derived, being a new therapy for osteoarthritis . To date however there are no randomised controlled trials investigating the effect of intra-articular injections of stem cells for the treatment of knee osteoarthritis.

Are stem cells safe?

Stem cell therapy is in a development phase. The total safety of the therapy is yet to be elucidated. Preliminary use in humans has been shown to be safe with the local injection of bone marrow derived stem cells in 339 patients (Centeno et al, 2011). Similarly bone marrow derived stem cells injected to treat knee osteoarthritis and followed up for 11 years was also shown to be safe in all 41 patients in the trial (Wakitani et, al, 2010). The use of adipose derived stem cells in humans has demonstrated its safety and efficacy in phase I and II clinical trials of up to two years (Garcia-Olmo et al, 2005; Garcia-Olmo et al, 2008; Garcia-Olmo et al, 2009). Intravenous administration of adipose derived stem cells has also been shown to be safe in mice and humans (ra et al 2011).

However, the effect on cancer has been varied. For example, a recent study reported that adipose-derived stem cells can promote the spread and invasion of breast cancer (Muehlberg et al, 2009). It should be noted that this research was performed using murine (mouse) breast cancer cells in a petrie dish, and that other studies have shown that adipose derived stem cells may inhibit breast cancer metastases and invasion in mice (Sun et al, 2009). Importantly, as stated above, phase I and II safety trials in humans injected with adipose-derived stem cells demonstrated no adverse effects, including tumor growth, in a two year follow up clinical trial.

The safety of stem cell therapy is still to be fully determined. If you are considering entering into a trail or stem cell therapy you should discuss the treatment thoroughly with your doctor.


Where is the technology at?

To date, at Lakeside Sports Medicine we have treated a number of patients and followed their results for over 12 months. Our first patient was treated in 2010 with adipose derived stem cells. This patient had a large hole in the cartilage of his left knee known as a chondral defect. He had a single injection of stem cells and has been followed with MRI’s at 7 weeks and 5 months and 12 months. He was featured on George Negus as part of Stem cell awareness day then report can be seen on this link http://www.youtube.com/watch?v=8N2QT4AKpXM.

The pictures of how his knee progressed are below.

As you can see in the final picture there is complete coverage of the defect that has lasted out to 12 months.  The patient has been pain free from 2 weeks after the procedure. He has returned to boxing and has lost 10Kg, which has undoubtedly played an important role in his pain control.

The issues with these results:

  • It is only 1 patient
  • We do not know how long this will last
  • We do not know if it is high quality cartilage or poor quality cartilage
  • The above results are not peer reviewed in a journal

We have also treated 3 patients (4 knees) with osteoarthritis of their knees. Each of these patients received a single injection of adipose derived stem cells and has been followed for over 12 months. All patients had an improvement in pain and function but none demonstrated cartilage regeneration on MRI. A graph of their outcomes based on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is below.

We interpret the combination of the cartilage defect case and osteoarthritis results in a number of ways.

  1. We may be able to improve pain and function suffered by patients with osteoarthritis and cartilage defects with adipose derived stem cells
  2. We may be able to regenerate cartilage defects in joints, however, the upper size is yet to be determined
  3. We are unlikely with the technology as it stands, to regenerate cartilage in severe osteoarthritis (Grade 4 – Bone on bone), but there should still be an improvement in pain and function
  4. We need multiple injections to get a prolonged effect

Off what we have done to date we have spent the last 12 months developing a clinic and laboratory structure to meet our needs to treat patients. The first of these will open on the Gold Coast in Australia in August 2012, and the second shortly after in Melbourne. We have formed a strong relationship with Monash Immunology and Stem cell Laboratories and Australian Catholic University and have the below study commencing in September 2012.

Is there further research in progress?

We have designed a case series of 60 patients with all grades of cartilage defects and osteoarthritis. All patients will receive 4 injection and be followed for 12 months pain scales, outcome measures and MRI.

The total number of places are limited, however, we are able to offer treatment to patients. They will be treated as if in a trial and followed in the same way with pain scales, outcome measures and MRI. The results we gather will be published as a prospective case series.

Currently there is NO rebate from Medicare, Workcover, TAC or Private Health for this service. We intend the evidence we generate to go towards supporting a rebate in the future.

Where can I get more information on cell therapy?

For more information click here


References:

Arthritis Australia (2007). Painful realities: The economic impact of Arthritis in Australia in 2007. Report by Access Economics for Arthritis Australia, 31 July 2007, 1-71.

Baltzer, A.W.A., Moser, C.,Jansen, S.A., & Krauspe, R. (2009). Autologous conditioned serum (Orthokine) is an effective treatment for knee osteoarthritis. Osteoarthritis and Cartilage, 17, 152-160.

Bjordal, J.M., Ljunggren, A.E., Klovning, A,. & Slørdal, L. (2004). Non-steroidal anti-inflammatory drugs, including coxibs, in osteoarthritic knee pain: a meta-analysis of randomised placebo-controlled trials. British Medical Journal, 329:1317-20. BMJ, doi:10.1136/bmj.38273.626655.63 (published 23 November 2004).

Brazier, J.E., Harper, R., Jones, N et al. (1992). Validating the SF-36 health survey questionnaire: new outcome measure for primary care. British Medical Journal, 305(6846), 160–164.

Centeno CJKisiday JFreeman MSchultz JR. Partial regeneration of the human hip via autologous bone marrow nucleated cell transfer: A case study. Pain Physician. 2006 Jul;9(3):253-6.

Centeno CJBusse DKisiday JKeohan CFreeman MKarli D. Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells. Pain Physician. 2008 May-Jun;11(3):343-53.

Centeno CJBusse DKisiday JKeohan CFreeman MKarli D. Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells. Med Hypotheses. 2008 Dec;71(6):900-8. Epub 2008 Sep 10.

Centeno CJSchultz JRCheever MRobinson BFreeman MMarasco W. Safety and complications reporting on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther. 2010 Mar;5(1):81-93.

Dragoo JLCarlson GMcCormick FKhan-Farooqi HZhu MZuk PABenhaim P. Healing full-thickness cartilage defects using adipose-derived stem cells. Tissue Eng. 2007 Jul;13(7):1615-21.

Flandry, F., Hunt, J.P., Terry, G.C., Hughston, J.C. (1991). Analysis of subjective knee complaints using visual analog scales. American Journal of Sports Medicine, 19 (2), 112-8.

Filardo GKon EBuda RTimoncini ADi Martino ACenacchi AFornasari PMGiannini SMarcacci M. Platelet-rich plasma intra-articular knee injections for the treatment of degenerative cartilage lesions and osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2010 Aug 26. [Epub ahead of print]

Fosbøl ELFolke FJacobsen SRasmussen JNSørensen RSchramm TKAndersen SSRasmussen SPoulsen HEKøber LTorp-Pedersen CGislason GH Cause-specific cardiovascular risk associated with nonsteroidal antiinflammatory drugs among healthy individuals. Circ Cardiovasc Qual Outcomes. 2010 Jul;3(4):395-405. Epub 2010 Jun 8.

Habib GSSaliba WNashashibi M. Local effects of intra-articular corticosteroids. Clin Rheumatol. 2010 Apr;29(4):347-56. Epub 2010 Jan 26.

Laupattarakasem WLaopaiboon MLaupattarakasem PSumananont C. Arthroscopic debridement for knee osteoarthritis. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD005118.

.March, L.M. and Bagga, H (2004). Epidemiology of osteoarthritis in Australia. Medical Journal of Australia, 180(5), S6-10.

Mokbel AMEl-Tookhy OShamaa AASabry DRashed LMostafa A. Homing and efficacy of intra-articular injection of autologous mesenchymal stem cells in experimental chondral defects in dogs. Clin Exp Rheumatol. 2011 Mar 7.

Muehlberg FL, Song YH, Krohn A, Pinilla SP, Droll LH, Leng X, Seidensticker M, Ricke J, Altman AM, Devarajan E, Liu W, Arlinghaus RB, Alt EU. Tissue-resident stem cells promote breast cancer growth and metastasis. Carcinogenesis 30(4):589-597, 2009.

Pisters, M.F., Veenhof, C., van Meeteren, N.L., et al. (2007). Long-term effectiveness of exercise etherapy in patients with osteoarthritis of the hip or knee: A systematic review. Arthritis Rheum, 57(7), 1245-53.

Ra JCShin ISKim SHKang SKKang BCLee HYKim YJJo JYYoon EJChoi HJKwon E. Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. Stem Cells Dev. 2011 Feb 8. [Epub ahead of print]

Roos EM, Roos HP, Ekdahl C et al (1998). Knee injury and Osteoarthritis Outcomes Score (KOOS) -validation of a Swedish version. Scandinavian Journal of Medicine and Science in Sports, 8, 439-448.

Roos, E.M., Bremander, A.B., Englund, M., & Lohmander, L.S. (2007). Change in self-reported outcomes and objective physical function over 7 years in middle-aged subjects with or at high risk of knee osteoarthritis. Annals of Rheumatic diseases, 67, 505-510.

Sánchez MAnitua EAzofra JAguirre JJAndia I. Intra-articular injection of an autologous preparation rich in growth factors for the treatment of knee OA: a retrospective cohort study.  Clin Exp Rheumatol. 2008 Sep-Oct;26(5):910-3.

Salaffi, F, Carotti, M. and Grassi, W. (2005). Health-related quality of life in patients with hip or knee osteoarthritis: comparison of generic and disease-specific instruments. Clinical Rheumatology, 24(1), 29–37.

Sun B, Roh KH, Park JR, Lee SR, Park SB, Jung JW, Kang SK, Lee YS, Kang KS. Therapeutic potential of mesenchymal stromal cells in a mouse breast cancer metastasis model. Cytotherapy 11(3):289-298, 2009.

Tobita MOrbay HMizuno H. Adipose-derived stem cells: current findings and future perspectives. Discov Med. 2011 Feb;11(57):160-70.

Turner-Bowker, D.M., Bayliss, M.S., Ware, J.E. and Kosinski, M. (2003). Usefulness of the SF-8 Health Survey for comparing the impact of migraine and other conditions, Quality of Life Research, 12(8), 1003–1012.

Zhou GLiu WCui LWang XLiu TCao Y. Repair of porcine articular osteochondral defects in non-weightbearing areas with autologous bone marrow stromal cells. Tissue Eng. 2006 Nov;12(11):3209-21.

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