TARGET OSTEOARTHRITIS

– Written by Angelo Boffa, Stefano Zaffagnini, and Giuseppe Filardo, Italy

INTRODUCTION

Osteoarthritis (OA) is a common disease characterized by progressive deterioration and loss of articular cartilage with concomitant structural and functional changes in the entire joint, involving synovium, meniscus, periarticular ligaments, and subchondral bone. OA affects more than 10% of the world population aged 60 years or older and represents one of the major causes of disability worldwide, with a massive impact on society both in terms of quality of life for the individuals and high costs for the healthcare systems. Clinical features of OA are mostly characterized by signs and symptoms of inflammation, including pain, effusions, and loss of mobility, often associated with significant functional impairment and disability. 

Current strategies to manage OA include weight loss, physical treatments, oral medications such as non-steroidal anti-inflammatory drugs and acetaminophen, and intra-articular injection therapies with corticosteroids and hyaluronic acid (HA). These conservative therapies have modest and short-lasting efficacy and are not able to arrest the underlying disease process. Thus, the final treatment is often represented by joint replacement, which is invasive and not free from complications, especially in young and active patients. In this light, research efforts have been made to find new minimally invasive and potentially disease-modifying procedures to address patients with OA in order to delay or avoid surgery. Among these, orthobiologics are gaining increasing interest due to the availability of several promising products with a biologic potential in improving joint tissues healing, ranging from platelet concentrates to minimally manipulated mesenchymal stromal cells (MSCs) obtained from bone marrow or adipose tissue. The evidence for these approaches derives largely from their intra-articular applications to address degenerative joint disease, in particular for knee OA.

This article will describe rationale and clinical evidence of the most used orthobiologics for the management of OA. 

RATIONALE

The use of orthobiologic injectables is growing in the clinical practice with the aim to reduce symptoms, restore a satisfactory joint function, and possibly prevent OA progression delaying the need for surgery. These approaches exploit the high concentrations of growth factors, cytokines, and bioactive molecules of blood derivatives, as well as the presence of mesenchymal stromal cells (MSCs) in tissue derived concentrates. 

·       Platelet Rich Plasma (PRP) has gained increasing attention due to the high concentration of bioactive molecules stored in platelet α-granules, which showed to take part in the homeostasis of joint tissues, being involved in both healing process and immunoregulation. These biologically active proteins seem to be able to promote a positive joint environment, favoring the restoration of a homeostatic balance in OA joints. PRP showed different and heterogeneous mechanisms of action, including the increase of chondrocyte proliferation rate, matrix production stimulation, and inflammation modulation. PRP may also significantly enhance synoviocyte HA secretion and switch synovial angiogenesis to a more balanced status, as well as increase the expression of biglycan and decorin in meniscal cells. Pre-clinical evidence further supports the role of PRP in modulating the intra-articular environment by counteracting inflammation in degenerative joint diseases. PRP injections showed disease-modifying effects in experimental animal studies, attenuating the progression of cartilage tissue damage and reducing the inflammatory reaction of the synovial membrane in OA joints¹.

·       Bone Marrow Aspirate Concentrate (BMAC) has been proposed as a promising option for the treatment of cartilage lesions and OA, being a combination of biologically active proteins and cells obtained through a mini-invasive and technically easy procedure. The rationale for the use of BMAC relies on the transplantation of the entire bone marrow niche which contains MSCs, hematopoietic precursors, monocytes, and endothelial cells, as well as a great array of soluble factors. All these are involved in several pathways crucial for cell maintenance and function, differentiation, extracellular matrix production, and for the regulation of cell catabolic/anabolic activities. Bone marrow MSCs showed the ability to differentiate toward several lineages (i.e., chondrocytes, osteoblasts) and to produce growth factors, which may positively affect joint homeostasis and eventually contribute to relief pain and to improve joint function². Accordingly, this combination of cells and bioactive proteins makes BMAC a unique product among currently available orthobiologics, with the rationale of potentially altering OA course. 

·       Adipose-derived products have been recently proposed as promising alternatives for the management of OA, thanks to the advantages provided by adipose tissue over other MSCs sources. In fact, adipose tissue is easily accessible, abundant, and obtainable with a mini-invasive procedure offering a high number of cells and pericytes (MSCs precursors). Adipose tissue contains approximately 500–2500 times more MSCs compared to the same volume of bone marrow³. Moreover, while the number of MSCs contained in bone marrow decreases with age, the available in the adipose tissue is quite stable during life, representing an aspect that is very beneficial for an elderly population⁴. Adipose tissue can be processed at the point of care into cell suspensions, producing the Stromal Vascular Fraction (SFV), or as microfragments, producing the Micro Fragmented Adipose Tissue (MF-AT). Compared with bone marrow-derived MSCs, adipose-derived MSCs showed to be more genetically stable, with higher proliferative and differentiation capacity, longer telomere length, and lower senescence ratio⁵.

CLINICAL EVIDENCE

Platelet Rich Plasma (PRP)

PRP is gaining a large interest in the clinical practice as a minimally invasive injective OA treatment thanks to its safety, low costs, and simple preparation technique to obtain its biologically active content (Figure 1). Since the first clinical applications, several studies supported the safety and effectiveness of PRP for the treatment of knee OA, demonstrating satisfactory results in terms of reduction of pain-related symptoms and functional improvement up to 12 months. These benefits have been observed especially in young patients and early OA stages. Despite the large placebo effect ascribed to intra-articular injections, in particular when dealing with new products such as PRP, a recent meta-analysis on 34 randomized controlled trials (RCTs) showed that PRP injections provided a statistically and clinically significant improvement in patients with knee OA compared to saline injections at 6 and 12 months of follow-up, without increasing the risk of adverse events⁶. Moreover, PRP injections provided better clinical results than other commonly used injective strategies such as corticosteroids or HA at 6 and 12 months of follow-up⁶. Some studies suggest that the clinical improvement provided by PRP can be perceived by patients also beyond 24 months, with a subsequent gradual reduction over time⁷. A recent retrospective study and survival analysis also showed that PRP may delay the need for total knee arthroplasty (TKA) with a median of 4 years and with a survival rate of 85% at 5 years of follow-up⁸.

Recently, some researchers investigated the effectiveness of subchondral injections of PRP to address patients with knee OA. Sànchez et al analyzed the combined use of subchondral and intra-articular PRP injections reporting the safety of this strategy, with rare and mild adverse events, and supporting its effectiveness in improving functional status and reducing pain, with a relatively low rate of conversion to TKA⁹. More recently, the same group observed better clinical results at 6 and 12 months in favor of the combination of subchondral and intra-articular PRP injections compared to intra-articular injections alone in 60 patients with a prevalent grade 3 knee OA according to the Ahlbäck scale, confirming the importance of directly targeting also the subchondral bone area¹⁰. The biological effects of subchondral PRP injections have been evaluated by Lychagin et al through the measurement of the levels of the serum cartilage oligomeric matrix protein (COMP), an early biomarker for the remodeling of articular cartilage, in OA patients treated with subchondral PRP injections¹¹. They found a consistent increase of serum COMP levels after the procedure, which in the authors conclusions could reflect the effects on cartilage turnover resulting from the subchondral treatment.

Despite the promising clinical results, no consensus or guidelines still exist among the scientific societies of orthopedic surgeons, rheumatologists, and physiatrists, on the most suitable indications for the use of PRP in the treatment of OA. This is likely due to the relatively new evidence as well as the lack of a standardized protocol and to the wide availability of different PRP preparation methods. These can yield products with different composition and characteristics in terms of number of platelets and leukocytes, volume of whole blood harvested or PRP obtained, storage procedures, activation method of platelets, formation of a fibrin matrix, etc... Many questions remain open, and all this makes it very difficult to merge and analyze clinical results of different studies and to gain a full understanding of the real benefits of this biological approach. Further studies will have to investigate all these aspects to better understand the potential and limitations of PRP for the treatment of joints affected by OA.

Bone Marrow Aspirate Concentrate (BMAC)

BMAC has been widely applied in the clinical practice for the treatment of cartilage lesions first and, more recently, it has been proposed as a promising mini-invasive approach to treat degenerative orthopedic conditions like knee OA (Figure 2). Only a few pre-clinical studies analyzed the effects of BMAC injections to address OA joints. In vivo OA models reported that BMAC provided better results in terms of macroscopic, histological, radiological, and immunohistochemical findings compared with control groups (saline, HA, or PRP)¹². The available clinical studies investigating the use of BMAC to address OA evaluated mainly the knee injective treatment, while only few studies focused on shoulder, hip, or ankle OA¹². Despite an overall poor methodology and a significant heterogeneity, these preliminary trials reported promising results for OA in terms of safety and effectiveness for symptoms management of this intra-articular approach, which led to pain relief and knee function improvement. Nevertheless, the few comparative studies available in the literature did not show BMAC superiority over the other intra-articular options, and the only placebo-blinded RCT was not able to prove BMAC superiority over saline at 12 months of follow-up¹³.

A new application of BMAC has been recently suggested to further exploit its potential by targeting the subchondral bone, which is commonly involved in the OA processes. The subchondral BMAC administration demonstrated promising clinical results in preliminary reports on knee OA. The first evidence has been reported in an RCT by Hernigou et al, which evaluated 30 young patients with bilateral knee OA secondary to osteonecrosis and treated with subchondral BMAC injections on one side, and with TKA on the other side. BMAC injections provided similar clinical outcomes compared with TKA, but a lower complication rate and a quicker recovery¹⁴. The same authors analyzed 140 patients with medial knee OA planned to undergo bilateral TKA and treated with subchondral BMAC injections on one side and with TKA on the other side. Subchondral BMAC injections provided an effect on pain that allowed to postpone or avoid TKA up to 15 years of follow-up, with only 25 patients requesting TKA in the knee treated with BMAC¹⁵. Hernigou et al also described the superiority of subchondral BMAC injections over intra-articular BMAC injections in an RCT on 60 patients with bilateral knee OA, showing in the subchondral group a lower yearly arthroplasty incidence (1.3% versus 4.6%) and higher clinical and magnetic resonance imaging (MRI) improvements at 2 years of follow-up¹⁶. A recent prospective multi-centric study of Kon et al evaluated the combined approach of subchondral and intra-articular BMAC injections to address 30 patients with symptomatic knee OA with associated subchondral bone alterations. The authors documented a significant clinical improvement up to 12 months of follow-up, while the MRI evaluation showed a reduction of bone marrow edema, suggesting that targeting with BMAC both subchondral bone and joint environment can provide promising results to treat knee OA¹⁷.

Still, the application of BMAC to address patients with OA joints has a limited scientific support and more high-level studies are needed to understand if this product could represent a valid option among the different biological treatment strategies. Moreover, many aspects remain to be clarified to optimize the potential of BMAC, including methods of harvest and centrifugation, timing of injection, and application modality, and to provide a standardized method targeted to the OA treatment.

Adipose-derived products

Adipose tissue can be obtained with a minimally invasive procedure and processed at the point of care into cell suspensions, producing SVF or MF-AT (Figure 3). SVF is generally obtained with an enzymatic method, which consists of digesting the lipoaspirate with collagenase to break down the matrix and release MSCs and other cells. Subsequently, the collagenase is removed by dilution and washing, followed by centrifugation¹⁸. SVF application showed safety, feasibility, and effectiveness for the treatment of joints affected by degenerative cartilage lesions and OA in pre-clinical studies, improving of the quality of the cartilage with respect to control groups¹⁸. Several trials analyzed SVF injections in the clinical practice, reporting a low rate of adverse events and improvement in pain and functional outcome scores in patients with knee OA, although most studies are case series without a comparative arm¹⁹. A recent double-blind placebo-controlled RCT on 39 patients with knee OA showed a statistically significant improvement in the SVF group compared to the control group up to 12 months of follow-up, although MRI did not reveal changes in cartilage thickness after treatment²⁰. Moreover, intra-articular SVF demonstrated better clinical and imaging findings at 12 months compared to HA in an RCT on 32 patients with knee OA²¹. Despite these promising findings, these studies analyzed only small sample sizes and thus further high-level studies are needed to clarify the real therapeutic potential of SVF.

MF-AT treatment is also gaining interest in clinical practice, since it is obtained through a simple, minimal mechanical manipulation that leads to a progressive reduction in the size of adipose tissue clusters with the elimination of oil and blood residue. MF-AT approach has the advantage of preserving cell integrity and tissue microarchitecture, providing a high number of cells and growth factors, without the need for enzymatic or expansion treatment²². The benefits of this products were observed in in vitro studies, reporting a better (qualitatively and quantitatively) secretion of growth factors and cytokines involved in tissue repair compared to the enzymatic methods²³. Moreover, MF-AT contains a significantly higher concentration of exosomes secreted by MSCs compared to the enzymatic method, suggesting a better preservation of the paracrine potential of adipose MSCs and thus their efficacy²⁴. To this regard, a recent in vivo pre-clinical study reported better results in terms of protection of the articular surface from the joint degenerative OA processes in rabbits treated with MF-AT compared to those treated with SVF or expanded adipose-derived MSCs²⁵. MF-AT injections showed promising results also in the clinical practice in patients with knee OA, with a low number of adverse events and a significant improvement in pain, function, and quality of life^26,27. Despite the growing number of clinical studies focusing on intra-articular MFAT injections for knee OA, high-level studies comparing the effectiveness of this product with other injectables are still limited. Therefore, further studies are needed to clarify the potential of MF-AT and the advantages versus other injective options to treat OA joints.

CONCLUSIONS

The management of OA remains an important challenge for physicians, and orthobiologic approaches can play a key role thanks to their potential in modulating the articular environment. Several products ranging from PRP to minimally manipulated MSCs strategies are frequently performed in patients with symptomatic OA, although their indications and guidelines are not always clear. Despite the increasing use in the clinical practice, evidence on these injective approaches is still limited and not able to guide clinicians in choosing the best product, indication, formulation, injections schedule, as well as many other aspects related to both products and patient management. Further research efforts are needed to define potential and limitations of each biological strategy for the conservative treatment of joints affected by OA.

Acknowledgements

Silvia Bassini for the graphical contribution.

Angelo Boffa M.D. 

Doctor 

Clinica Ortopedica e Traumatologica 

IRCCS Istituto Ortopedico Rizzoli 

Bologna, Italy

Stefano Zaffagnini M.D. 

Professor

Director

Clinica Ortopedica e Traumatologica 

IRCCS Istituto Ortopedico Rizzoli 

Bologna, Italy

Giuseppe Filardo M.D., Ph.D.

Professor

Applied and Translational Research (ATR) center

IRCCS Istituto Ortopedico Rizzoli,

Bologna, Italy

Orthopaedic and Traumatology Unit, 

Ospedale Regionale di Lugano, EOC 

USI - Università della Svizzera Italiana,

Facoltà di Scienze Biomediche,

Lugano, Switzerland

Contact: angeloboffa@libero.it

References

1. Filardo G, Kon E, Roffi A, Di Matteo B, Merli ML, Marcacci M. Platelet-rich plasma: why intra-articular? A systematic review of preclinical studies and clinical evidence on PRP for joint degeneration. Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA. 2015;23(9):2459-74. Epub 2013/11/28.
2. Fortier LA, Strauss EJ, Shepard DO, Becktell L, Kennedy JG. Biological Effects of Bone Marrow Concentrate in Knee Pathologies. The journal of knee surgery. 2019;32(1):2-8. Epub 2018/12/01.
3. Aust L, Devlin B, Foster SJ, Halvorsen YD, Hicok K, du Laney T, et al. Yield of human adipose-derived adult stem cells from liposuction aspirates. Cytotherapy. 2004;6(1):7-14. Epub 2004/02/27.
4. Usuelli FG, D'Ambrosi R, Maccario C, Indino C, Manzi L, Maffulli N. Adipose-derived stem cells in orthopaedic pathologies. British medical bulletin. 2017;124(1):31-54. Epub 2017/12/19.
5. Strioga M, Viswanathan S, Darinskas A, Slaby O, Michalek J. Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem cells and development. 2012;21(14):2724-52. Epub 2012/04/04.
6. Filardo G, Previtali D, Napoli F, Candrian C, Zaffagnini S, Grassi A. PRP Injections for the Treatment of Knee Osteoarthritis: A Meta-Analysis of Randomized Controlled Trials. Cartilage. 2020:1947603520931170. Epub 2020/06/20.
7. Di Martino A, Di Matteo B, Papio T, Tentoni F, Selleri F, Cenacchi A, et al. Platelet-Rich Plasma Versus Hyaluronic Acid Injections for the Treatment of Knee Osteoarthritis: Results at 5 Years of a Double-Blind, Randomized Controlled Trial. The American journal of sports medicine. 2019;47(2):347-54. Epub 2018/12/14.
8. Sanchez M, Jorquera C, Sanchez P, Beitia M, Garcia-Cano B, Guadilla J, et al. Platelet-rich plasma injections delay the need for knee arthroplasty: a retrospective study and survival analysis. International orthopaedics. 2021;45(2):401-10. Epub 2020/07/06.
9. Sanchez M, Delgado D, Sanchez P, Muinos-Lopez E, Paiva B, Granero-Molto F, et al. Combination of Intra-Articular and Intraosseous Injections of Platelet Rich Plasma for Severe Knee Osteoarthritis: A Pilot Study. BioMed research international. 2016;2016:4868613. Epub 2016/07/28.
10. Sanchez M, Delgado D, Pompei O, Perez JC, Sanchez P, Garate A, et al. Treating Severe Knee Osteoarthritis with Combination of Intra-Osseous and Intra-Articular Infiltrations of Platelet-Rich Plasma: An Observational Study. Cartilage. 2019;10(2):245-53. Epub 2018/02/17.
11. Lychagin A, Lipina M, Garkavi A, Islaieh O, Timashev P, Ashmore K, et al. Intraosseous injections of platelet rich plasma for knee bone marrow lesions treatment: one year follow-up. International orthopaedics. 2021;45(2):355-63. Epub 2020/04/06.
12. Cavallo C, Boffa A, Andriolo L, Silva S, Grigolo B, Zaffagnini S, et al. Bone marrow concentrate injections for the treatment of osteoarthritis: evidence from preclinical findings to the clinical application. International orthopaedics. 2021;45(2):525-38. Epub 2020/07/15.
13. Shapiro SA, Arthurs JR, Heckman MG, Bestic JM, Kazmerchak SE, Diehl NN, et al. Quantitative T2 MRI Mapping and 12-Month Follow-up in a Randomized, Blinded, Placebo Controlled Trial of Bone Marrow Aspiration and Concentration for Osteoarthritis of the Knees. Cartilage. 2019;10(4):432-43. Epub 2018/08/31.
14. Hernigou P, Auregan JC, Dubory A, Flouzat-Lachaniette CH, Chevallier N, Rouard H. Subchondral stem cell therapy versus contralateral total knee arthroplasty for osteoarthritis following secondary osteonecrosis of the knee. International orthopaedics. 2018;42(11):2563-71. Epub 2018/03/29.
15. Hernigou P, Delambre J, Quiennec S, Poignard A. Human bone marrow mesenchymal stem cell injection in subchondral lesions of knee osteoarthritis: a prospective randomized study versus contralateral arthroplasty at a mean fifteen year follow-up. International orthopaedics. 2021;45(2):365-73. Epub 2020/04/24.
16. Hernigou P, Bouthors C, Bastard C, Flouzat Lachaniette CH, Rouard H, Dubory A. Subchondral bone or intra-articular injection of bone marrow concentrate mesenchymal stem cells in bilateral knee osteoarthritis: what better postpone knee arthroplasty at fifteen years? A randomized study. International orthopaedics. 2021;45(2):391-9. Epub 2020/07/04.
17. Kon E, Boffa A, Andriolo L, Di Martino A, Di Matteo B, Magarelli N, et al. Subchondral and intra-articular injections of bone marrow concentrate are a safe and effective treatment for knee osteoarthritis: a prospective, multi-center pilot study. Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA. 2021. Epub 2021/03/28.
18. Perdisa F, Gostynska N, Roffi A, Filardo G, Marcacci M, Kon E. Adipose-Derived Mesenchymal Stem Cells for the Treatment of Articular Cartilage: A Systematic Review on Preclinical and Clinical Evidence. Stem cells international. 2015;2015:597652. Epub 2015/08/05.
19. Shanmugasundaram S, Vaish A, Chavada V, Murrell WD, Vaishya R. Assessment of safety and efficacy of intra-articular injection of stromal vascular fraction for the treatment of knee osteoarthritis-a systematic review. International orthopaedics. 2021;45(3):615-25. Epub 2021/01/13.
20. Garza JR, Campbell RE, Tjoumakaris FP, Freedman KB, Miller LS, Santa Maria D, et al. Clinical Efficacy of Intra-articular Mesenchymal Stromal Cells for the Treatment of Knee Osteoarthritis: A Double-Blinded Prospective Randomized Controlled Clinical Trial. The American journal of sports medicine. 2020;48(3):588-98. Epub 2020/02/29.
21. Hong Z, Chen J, Zhang S, Zhao C, Bi M, Chen X, et al. Intra-articular injection of autologous adipose-derived stromal vascular fractions for knee osteoarthritis: a double-blind randomized self-controlled trial. International orthopaedics. 2019;43(5):1123-34. Epub 2018/08/16.
22. Tremolada C, Colombo V, Ventura C. Adipose Tissue and Mesenchymal Stem Cells: State of the Art and Lipogems(R) Technology Development. Current stem cell reports. 2016;2:304-12. Epub 2016/08/23.
23. Vezzani B, Gomez-Salazar M, Casamitjana J, Tremolada C, Peault B. Human Adipose Tissue Micro-fragmentation for Cell Phenotyping and Secretome Characterization. Journal of visualized experiments : JoVE. 2019(152). Epub 2019/11/05.
24. D'Arrigo D, Roffi A, Cucchiarini M, Moretti M, Candrian C, Filardo G. Secretome and Extracellular Vesicles as New Biological Therapies for Knee Osteoarthritis: A Systematic Review. Journal of clinical medicine. 2019;8(11). Epub 2019/11/07.
25. Filardo G, Tschon M, Perdisa F, Brogini S, Cavallo C, Desando G, et al. Micro-fragmentation is a valid alternative to cell expansion and enzymatic digestion of adipose tissue for the treatment of knee osteoarthritis: a comparative preclinical study. Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA. 2021. Epub 2021/01/20.
26. Heidari N, Noorani A, Slevin M, Cullen A, Stark L, Olgiati S, et al. Patient-Centered Outcomes of Microfragmented Adipose Tissue Treatments of Knee Osteoarthritis: An Observational, Intention-to-Treat Study at Twelve Months. Stem cells international. 2020;2020:8881405. Epub 2020/08/25.
27. Hudetz D, Boric I, Rod E, Jelec Z, Kunovac B, Polasek O, et al. Early results of intra-articular micro-fragmented lipoaspirate treatment in patients with late stages knee osteoarthritis: a prospective study. Croatian medical journal. 2019;60(3):227-36. Epub 2019/06/13.

Header image by Sangudo (Cropped)