Biologic Therapies for the Treatment of Knee Osteoarthritis

doi:10.1016/j.arth.2018.12.001

The Journal of Arthroplasty

Volume 34, Issue 4, April 2019, Pages 801-813

https://doi.org/10.1016/j.arth.2018.12.001 Get rights and content

Abstract

Background

The use of biologic therapies for the management of knee osteoarthritis has increased, despite insufficient evidence of efficacy. Our aim was to complete a systematic review and analysis of reports utilizing the highest level-of-evidence evaluating: (1) platelet-rich plasma injections (PRPs); (2) bone marrow-derived mesenchymal stem cells (BMSCs); (3) adipose-derived mesenchymal stem cells (ADSCs); and (4) amnion-derived mesenchymal stem cells (AMSCs).

Methods

PubMed, Embase, and Cochrane Library databases were queried for studies evaluating PRP injections, BMSCs, ADSCs, and AMSCs in patients with knee osteoarthritis. Of 1009 studies identified within the last 5 years, 123 met inclusion criteria. A comprehensive analysis of all levels-of-evidence was performed, as well as separate analysis on level-of-evidence I studies. Level-of-evidence was determined by the American Academy of Orthopedic Surgeons classification system.

Results

Although the majority of PRP reports demonstrated improvements in pain and/or function, others revealed no substantial improvements. Similar findings were noted for BMSCs, ADSCs, and AMSCs. Assessments of BMSC studies yielded majority with positive clinical results, although short-lived. Studies on ADSCs revealed improved clinical outcomes, but equivocal radiographic outcomes. Studies evaluating AMSCs demonstrated improvements in pain and function, and decreased radiographic evidence of osteoarthritis.

Conclusion

Despite some promising early results for PRP, BMSC, ADSC, and AMSC therapies, the majority of level-of-evidence I studies have multiple problems: small sample sizes, potentially inappropriate control cohorts, short-term follow-up, and so on. Despite the limitations, there still appears to be evidence justifying their use for knee osteoarthritis management. More high-level, larger human studies utilizing standardized protocols are needed.

Section snippets

Methods

An electronic systematic review of the literature for biological therapies for OA of the knee was conducted utilizing the Embase, Cochrane Library, and PubMed databases. Reports published in the past 5 years (March 1, 2013 to March 31, 2018), evaluating PRP, BMSCs, ADSCs, and amniotic mesenchymal stem cells (MSCs) for the treatment of knee OA, were identified using various keyword combinations and Boolean operators. The queries were performed in March 2018. The following strings were utilized

Formulation and Procurement Protocols

PRP is an autologous concentration of platelets containing a variety of growth factors and cytokines postulated to aid in cellular anabolism and tissue healing. Formulation is based on centrifugation of whole blood products into component fractions, which are subsequently recentrifuged to prepare a final product. From the greater than 100 publications [7], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43],

Conclusion

Biologic therapies—including PRP, BMSCs, ADSCs, and AMSCs—are becoming increasingly prevalent as treatment strategies for knee OA management. This is largely due to the Public Health Service Act Section 361, which allows for the use of “minimally manipulated” autologous therapies to be marketed and administered in clinics across the United States. Of the studies reporting positive results, major limitations included varying study protocols, inconsistent formulations, and number of

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In fact, the growth of studies warrants an updated systematic review to adequately apprise current understanding from a previous review of 16 studies by Delanois et al [16], in 2019. Therefore, we sought to evaluate all level of evidence I-III studies (levels I and II for PRP) evaluating intra-articular biologic injections for knee OA in an update, with inclusion of eligible studies from the previous review [16]. Only 82 of the 644 (87.3%) studies screened met inclusion criteria.
Use of “orthobiologics” continues to expand for patients who have knee osteoarthritis (OA). We sought to perform a systemic review of biologic therapies relative to comparative groups, including the following: (1) platelet-rich plasma (PRP); (2) bone marrow–derived mesenchymal stem cells (BMSCs); (3) adipose-derived mesenchymal stem cells (ADSCs); and (4) amniotic-derived mesenchymal stem cells (AMSCs). We assessed the following: (1) study methodologies; (2) cell preparations and formulations; (3) patient-reported outcome scores (PROMs); and (4) structural changes.
PubMed, Cochrane Library, and Embase databases were queried (2013-2021) to conduct a systematic review of biologic therapies for knee OA, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eighty-two studies were included: PRP (51); BMSC (15); ADSC (11); and AMSC (5). Study evaluations were made using the Modified Coleman Methodology Score. PROMs included the Western Ontario and McMaster Universities Arthritis Index and the Visual Analog Scale. Structural change evaluations included ultrasounds, radiographs, or magnetic resonance imaging.
PRP comprised a majority of the studies (n = 51), most with “fair” to “good” Modified Coleman Methodology Score. Studies had variable cell preparations and formulations, with comparison study results leading to inconsistent PROMs, and structural changes. A limited number of studies were included for BMSC, ADSC, and AMSC, all with similar findings to PRP.
Available literature evaluating “orthobiologics” for knee OA remain nonsuperior to comparison cohorts. Higher level studies with larger sample sizes and improved methodologies are warranted to suggest differences. Despite a growth of “orthobiologics” in clinics, this updated systematic review highlights the uncertain efficacy for use in knee OA.
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The Efficacy of Platelet-Rich Plasma for the Treatment of Knee Osteoarthritis Symptoms and Structural Changes: A Systematic Review and Meta-Analysis
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Use of PRP to treat knee OA has rapidly expanded over the last decade with global estimated growth of up to 4.5 billion dollars over the next several years [10,45]. However, reports remain inconclusive and continue to demonstrate PRP’s non-superiority [8,13–15]. Knee structural changes have also been recently evaluated in high level reports, though a comprehensive review of this literature is lacking.
Platelet-rich plasma (PRP) usage in orthopedics continues to rise, despite guidelines suggesting non-superiority to comparative cohorts. Therefore, we performed a systematic review and meta-analysis on PRP efficacy using two clinical assessments: (1) Visual Analog Scale and (2) Western Ontario and McMaster Universities Osteoarthritis Index. We assessed consistency and clinical relevancy by determining study heterogeneity (eg, sample sizes, ages, body mass index, arthritic severities, etc.). Comparative cohorts were: (A) hyaluronic acid (HA); (B) corticosteroid (CS); (C) normal saline (NS); and (D) exercise therapy. We performed sub-analyses of structural changes assessed on ultrasound, radiograph, or magnetic resonance imaging .
We utilized PubMed, Cochrane Library, and Embase databases up to December 1, 2021, according to Preferred Reporting Items for Systematic-Reviews and Meta-Analyses guidelines. Twenty-four studies met criteria, with comparisons to: HA (n = 11); CS (n = 6); NS (n = 5); and exercise therapy (n = 3). Seven studies assessed structural changes. Evaluations utilized a methodological scoring system. I² statistics and forest plots pooled analyses and delineated study results.
PRP led to Visual Analog Scale and Western Ontario and McMaster Universities Osteoarthritis Index improvements in most studies when compared to HA, CS, and NS (P ≤ .05). Comparison to exercise therapy resulted in inconclusive findings (P ≥ .05). However, substantial heterogeneity (I² ≥ 76%) was reported due to study variability. No differences were found when assessing structural changes or cartilage thickness by magnetic resonance imaging (standardized mean difference −0.01 [−0.19, 0.18], P = .91).
PRP may be associated with pain and functional improvements but was not clinically relevant (inconsistent study- and patient-metrics). In addition, PRP did not confer superiority when assessing knee-related structural changes.
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: One or more of the authors of this paper have disclosed potential or pertinent conflicts of interest, which may include receipt of payment, either direct or indirect, institutional support, or association with an entity in the biomedical field which may be perceived to have potential conflict of interest with this work. For full disclosure statements refer to https://doi.org/10.1016/j.arth.2018.12.001.

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ReviewBiologic Therapies for the Treatment of Knee Osteoarthritis

Abstract

Background

Methods

Results

Conclusion

Section snippets

Methods

Formulation and Procurement Protocols

Conclusion

Stem cell industry update: 2012 to 2016 reveals accelerated investment, but market capitalization and earnings lag

Cytotherapy

The possible use of stem cells in regenerative medicine: dream or reality?

Langenbecks Arch Surg

Association between body mass index and thirty-day complications after total knee arthroplasty

J Arthroplasty

What influence does the time of year have on postoperative complications following total knee arthroplasty?

J Arthroplasty

[Obesity: risk factor and predictor of osteoarthritis]

Lijec Vjesn

Epidemiology of osteoarthritis

Clin Geriatr Med

Platelet-rich plasma for the treatment of knee osteoarthritis: a review

J Knee Surg

Microarray analysis of bone marrow lesions in osteoarthritis demonstrates upregulation of genes implicated in osteochondral turnover, neurogenesis and inflammation

Ann Rheum Dis

Native joint-resident mesenchymal stem cells for cartilage repair in osteoarthritis

Nat Rev Rheumatol

Correlations between serum adipocytokine concentrations, disease stage, radiological status and total body fat content in the patients with primary knee osteoarthritis

Int Orthop

Physical activity level and health-related quality of life in the general adult population: a systematic review

Prev Med

Regulatory considerations for human cells, tissues, and cellular and tissue-based products: minimal manipulation and homologous use. Guidance for Industry and Food and Drug Administration Staff

Stem cell therapies are still mostly theory, yet clinics are flourishing

Selling stem cells in the USA: assessing the direct-to-consumer industry

Cell Stem Cell

Stem cells in Texas: cowboy culture

Nature

FDA moves to crack down on unproven stem cell therapies

Marketing of unproven stem cell-based interventions: a call to action

Sci Transl Med

Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial

Stem Cells

Mesenchymal stem cell therapy for osteoarthritis: current perspectives

Stem Cells Cloning

AAOS bulletin

Platelet-rich plasma intra-articular knee injections show no superiority versus viscosupplementation

Am J Sports Med

Effect of leukocyte concentration on the efficacy of platelet-rich plasma in the treatment of knee osteoarthritis

Am J Sports Med

Platelet-rich plasma increases anti-inflammatory markers in a human coculture model for osteoarthritis

Am J Sports Med

Use of platelet-rich plasma in intra-articular knee injections for osteoarthritis: a systematic review

PM R

State-of-the-art management of knee osteoarthritis

World J Clin Cases

Role of platelet-rich plasma in articular cartilage lesions

Chin Med J (Engl)

Efficacy of platelet-rich plasma injections in osteoarthritis of the knee: a systematic review and meta-analysis

Br J Sports Med

Does intra articular platelet rich plasma injection improve function, pain and quality of life in patients with osteoarthritis of the knee? A randomized clinical trial

Orthop Rev (Pavia)

Intraarticular injections (corticosteroid, hyaluronic acid, platelet rich plasma) for the knee osteoarthritis

World J Orthop

Update on biological therapies for knee injuries: osteoarthritis

Curr Rev Musculoskelet Med

The effects of platelet-rich plasma in the treatment of large-joint osteoarthritis: a systematic review

Phys Sportsmed

A comparison between platelet-rich plasma (PRP) and hyaluronate acid on the healing of cartilage defects

PLoS One

Knee osteoarthritis: hyaluronic acid, platelet-rich plasma or both in association?

Expert Opin Biol Ther

The effect of platelet-rich plasma on pain, function, and quality of life of patients with knee osteoarthritis

Pain Res Treat

Comparative effectiveness of platelet-rich plasma injections for treating knee joint cartilage degenerative pathology: a systematic review and meta-analysis

Arch Phys Med Rehabil

The efficacy of platelet-rich plasma in the treatment of symptomatic knee osteoarthritis: a systematic review with quantitative synthesis

Arthroscopy

Platelet-rich plasma: why intra-articular? A systematic review of preclinical studies and clinical evidence on PRP for joint degeneration

Knee Surg Sports Traumatol Arthrosc

Review
Biologic Therapies for the Treatment of Knee Osteoarthritis