Introduction

The promise of biologic therapies is to provide natural growth factors or stem cells early in the disease process in hopes of ameliorating treatment regiments. To date, many therapies have fallen short of that promise often because they are used in all indications, in all types of patients, and have little level I clinical evidence supporting their benefit. The next generation of biologics developed must be designed for specific indications and specific patient populations. While at first glance this limits their use, this approach will vastly expand the level I evidence demonstrating a clear benefit for the patients in select indications.

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Japan is on the forefront of Regenerative Medicine. The Japanese Society for Regenerative Medicine (JSRM) has worked closely with the Japanese government for creation of a new law for regenerative medicine treatment. With passage of the Regenerative Medicine Law (The Act on the Safety of Regenerative Medicine; The Act on Pharmaceuticals and Medical Devices; passed in 2014) allows for clinicians to utilize Regenerative Medicine products under ethics approval much earlier in the development timeline compared to the United States. Often, these products are approved without specific indication and the evidence must be reviewed by the government for each facility wanting to use one of these products.

One such product approved through this pathway in Japan is Autologous Protein Solution (APS, Zimmer Biomet). APS is a biologic designed specifically to counteract the inflammatory proteins found inside an osteoarthritic knee while simultaneously providing anabolic proteins to stimulate chondrocyte proliferation(1). Unlike biologic therapies that preceded APS, evidence to support the potential mechanism of action has been demonstrated (1,2)

Inflammatory proteins interleukin-1 (IL-1) and tissue necrosis factor alpha (TNFα) work together to stimulate chondrocytes to produce the enzyme MMP-13 which breaks down cartilage matrix. APS has been shown to inhibit MMP-13 production from IL-1 and TNFα stimulated chondrocytes in a culture dish and then consequently to reduce matrix release from IL-1 and TNFα stimulated cartilage explants (1,2). Additionally, chondrocyte proliferation is observed in the chondrocyte treated explants, suggesting a potential mechanism of repair (1). APS has also demonstrated pain reduction in both large animal (3;4) and in clinical trials (5-7). This summary will review the initial experience of APS in patients with OA in Japan. It will be one of the first reports of real world evidence for this product outside of the control of a clinical trial.

References

(1) Matuska A, O'Shaughnessey KM, King WJ, Woodell-May JE. Autologous solution protects bovine cartilage explants from IL-1a and TNFa induced cartilage degradation. J Orthop Res 2013;31(12):1929-35.
(2) Woodell-May J, Matuska A, Oyster M, et al. Autologous protein solution inhibits MMP-13 production by IL-1beta and TNFalpha-stimulated human articular chondrocytes. J Orthop Res 2011 Sep 15;29:1320-6.
(3) Bertone AL, Ishihara A, Zekas LJ, et al. Evaluation of a single intra-articular injection of autologous protein solution for treatment of osteoarthritis in horses. Am J Vet Res 2014 Feb 1;75(2):141-51.
(4) Wanstrath AW, Hettlich BF, Su L, et al. Evaluation of a Single Intra-Articular Injection of Autologous Protein Solution for Treatment of Osteoarthritis in a Canine Population. Vet Surg 2016 Jul 8;45(6):764-74.
(5) Hix J, Klaassen M, Foreman R, et al. An Autologous Anti-Inflammatory Protein Solution Yielded a Favorable Safety Profile and Significant Pain Relief in an Open-Label Pilot Study of Patients with Osteoarthritis. Biores Open Access 2017 Dec 1;6(1):151-8.
(6) Kon E, Engebretsen L, Verdonk P, Nehrer S, Filardo G. Clinical outcomes of an Autologous Protein Solution Injection for Knee Osteoarthritis: A 1-year Pilot Double-Blinded Randomized Controlled Trial. American Journal of Sports Medicine 2018;46(1):171-80.
(7) van Drumpt RA, van der Weegen W, King WJ, Toler K, Macenski M. Safety and treatment effectiveness of a single autologous protein solution injection in patients with knee osteoarthritis. BioResearch Open Access 2016;5.1:261-8.

Introduction

Osteoarthritis (OA) of the knee is the leading indication for joint replacement surgery, with the incidence of OA in the US expected to rise to rise to 67 million by 2030¹. There is a need for earlier intervention procedures and therapies to slow the progression of OA and delay more invasive procedures.

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While the loss of articular cartilage is the hallmark pathological change in OA, there is evidence to suggest an important role of abnormal subchondral bone in the early stages of disease, such as bone marrow lesions. Bone marrow lesions (BML) were initially described as bone marrow edema due to the appearance as bright signal on fluid sensitive MRI sequences. However, histopathology of BMLs suggests that there is minimal true edema. Instead, findings show abnormal bone spicules with excessive fibrosis and extensive bony remodeling; essentially the pattern often seen after fatigue fractures in bone². Felson first explored the relationship between the presence of these lesion on MRI in knee osteoarthritis with pain symptoms and progression of OA³.

In another study, Wluka et al. performed a longitudinal cohort study to assess the relationship between the presence of a BML at baseline and change in cartilage defects and cartilage volume in healthy adults, without knee pain or a history of significant knee trauma. The study found that BMLs, present in healthy asymptomatic individuals with no history of significant knee pain or trauma, are associated with an increased risk of cartilage defect progression and loss of cartilage volume⁴. This suggests that either BMLs or a factor associated with their presence may be important as a target for preventive measures for the clinical sequelae associated with progression of cartilage damage and knee OA.
Current methods of treating patients with symptomatic knee osteoarthritis include non-pharmacological options, such as physical therapy and unloader bracing, pharmacological treatments including pain medication (NSAIDs, opioids and acetaminophens, etc.), and viscosupplementation or corticosteroid injections. For patients with mild to moderate knee pain, these techniques provide temporary (< 6 months) pain relief⁵. More invasive surgical options include arthroscopic debridement to total or unicompartmental knee arthroplasty. Total knee arthroplasty (TKA) is an end-stage surgical procedure with a high rate of success but requires in-patient surgery and several months recovery time. There is a clinical need for an intermediate safe and reliable technique which can provide sustained pain relief for patients with knee pain.

The Subchondroplasty (SCP) procedure was first described by Sharkey (2012) as a minimally invasive treatment option for painful bone marrow lesions, which preserves the native joint⁶. Previous publications on SCP include retrospective case studies and case examples^7,8. Cohen and Sharkey retrospectively reviewed 66 patients that underwent SCP for the treatment of bone defects associated with osteoarthritis of the knee and demonstrated and improvement in pain and function scores with 70% of patients avoiding arthroplasty through 2 years⁷. This summary will review 2 year outcomes and conversion rates from the first prospective study of SCP for the knee. It will also provide an overview of indications including other joints currently under study.

References

Control CfD, Prevention. Prevalence and most common causes of disability among adults--United States, 2005. MMWR: Morbidity and Mortality weekly report. 2009;58(16):421-426.

Zanetti M, Bruder E, Romero J, Hodler J. Bone marrow edema pattern in osteoarthritic knees: correlation between MR imaging and histologic findings. Radiology. 2000;215(3):835-840.

Felson DT, Chaisson CE, Hill CL, et al. The association of bone marrow lesions with pain in knee osteoarthritis. Paper presented at: Annals Internal Medicine; 4/3/2001, 2001.

Wluka A, Wang Y, Davies-Tuck M, English D, Giles G, Cicuttini FM. Bone marrow lesions predict progression of cartilage defects and loss of cartilage volume in healthy middle-aged adults without knee pain over 2 yrs. Rheumatology. 2008;47(9):1392-1396.

Crawford DC, Miller LE, Block JE. Conservative management of symptomatic knee osteoarthritis: a flawed strategy? Orthopedic reviews. 2013;5(1).

Sharkey PF, Cohen SB, Leinberry CF, Parvizi J. Subchondral bone marrow lesions associated with knee osteoarthritis. American Journal of Orthopedics (Belle Mead, NJ). 2012;41(9):413-417.

Cohen SB, Sharkey PF. Subchondroplasty for Treating Bone Marrow Lesions. Knee Surg. 2016;29(7):555-563.

Nevalainen MT, Sharkey PF, Cohen SB, Roedl JB, Zoga AC, Morrison WB. MRI findings of subchondroplasty of the knee: a two-case report. Clinical imaging. 2016;40(2):241-243.