A specific protocol of autologous bone marrow concentrate and platelet products versus exercise therapy for symptomatic knee osteoarthritis: a randomized controlled trial with 2 year follow-up

Osteoarthritis (OA) is one of the most common causes of chronic joint pain. In the United States, symptomatic OA affects more than 50 million adults, resulting in annual costs due to medical expenses and lost wages exceeding $100 billion [1, 2].

Conservative treatment options for painful knee OA aimed at controlling pain and improving function, are often unsatisfactory. Treatment modalities include pharmacologic agents, physical therapy, and injections. The most common pharmaceutical therapies for knee OA include non-steroidal anti-inflammatory drugs (NSAIDs), which are not curative and associated with side effects when used long term, including upper gastrointestinal complications and increased risk of cardiovascular events [3]. Exercise or physical therapy including aerobic walking and strengthening exercises has been shown to improve function and reduce pain compared to control groups [4, 5], while aquatic therapies provide short term benefits [6]. Minimally invasive injection procedures for OA such as corticosteroid injections only demonstrate modest clinical benefits without altering disease progression and may increase the rate of cartilage loss [7].

The only definitive treatment option for end-stage knee OA is arthroplasty. Post-operative complications include deep vein thrombosis and neuropathy, and up to 34% of patients report persisting moderate-to-severe pain [8, 9]. Hence, cell-based therapy including platelet rich plasma (PRP) and bone marrow concentrate (BMC) [10, 11] have been discussed as less invasive options. Autologous BMC contains mesenchymal stem cells (MSCs), platelets, and other cells with healing and regeneration potential (e.g. hematopoietic stem cells and macrophages) [12, 13]. Multiple studies have demonstrated encouraging results for the use of BMC for OA in human populations, although few controlled trials exist [14, 15].

In the present investigation we describe a randomized controlled trial of a specific protocol of image guided percutaneous injection of a combination of BMC and platelet products versus an exercise therapy regimen among patients with moderate knee osteoarthritis. We hypothesized that a specific protocol of BMC and platelet products would improve clinical outcomes more than exercise therapy alone.

Patients who received a specific protocol of BMC and platelet products improved significantly in activity levels (shown by LEAS), as well as pain, ROM and stability as assessed by the KSS-knee score compared to patients who underwent a home exercise therapy program for 3 months for the treatment of moderate knee OA. Pain decreased for both the exercise therapy and the BMC groups, and function increased for the BMC group (KSS-function), although did not differ significantly between the 2 groups. Exercise therapy provided significant improvements in ROM and activity levels at 3-months compared to baseline, albeit a lower activity level than the BMC treatment produced.

All individuals in the exercise therapy groups chose to crossover and receive BMC treatment. Since this crossover group did not differ significant from the BMC only group, data was combined to determine long-term efficacy throughout the 2-year study duration. Significant improvements in pain and functionality were maintained through 2 years follow-up after receiving BMC treatment. These findings are in-line with several previous studies that suggest BMC as an alternative treatment for knee osteoarthritis [17, 23].

To our knowledge, this is the first prospective randomized controlled trial comparing the use of autologous BMC and exercise therapy for knee OA. A primary objective for this investigation was to determine how a cross-section of patients who present with knee OA, including patients with varying degrees of pain and functional levels, respond to a specific protocol of BMC and platelet product treatment. The most frequently reported side effect of treatment was temporary pain and swelling, which may be explained by the release of trophic factors associated with the intra-articular injection of MSCs, a phenomenon observed in animal models [24]. It is important to highlight that even though 52% of patients were classified as K-L grade 3 and deemed total knee arthroplasty candidates, only 3 patients received TKA during the study follow-up period, and no other surgeries were reported.

Only one other randomized trial investigating the use of BMC for knee OA has been published. Shapiro et al. described a trial of BMC in one knee compared to saline placebo in the contralateral knee in bilateral knee OA patients and concluded that BMC was no more effective than saline [14]. Several factors may account for the differences in the present study versus the Shapiro et al. study. It appears that the cell counts were substantially (~ 75%) lower than in the present investigation, and likely fell below a previously published threshold needed to produce significant symptom improvement [25]. Additionally, Shapiro and colleagues’ injectate consisted of 33% BMC, which was less than half the proportion used in the present investigation (which was 75%). The remaining volume of injectate used by Shapiro et al. consisted of platelet poor plasma (PPP), compared to the PRP and PL in present study, which contain greater quantities of platelet-derived growth factors compared to PPP [26].

The exact properties responsible for the beneficial effects of treatment with BMC for knee OA are currently unknown. The pathogenesis of OA is associated with an alteration in the repair and breakdown of the articular cartilage, which is believed to be influenced by multiple factors including the depletion of healthy MSCs in the microenvironment [27]. BMC contains MSCs and other regenerative factors including hematopoietic stem cells (i.e. pluripotent cells), platelets containing over 1500 growth factors, white blood cells, macrophages, and several different cytokines (e.g. interleukin 1-receptor antagonist protein and alpha-2-macroglobulin) [12]. Hence, the anti-inflammatory and immunomodulatory effects of BMC may lead to the regeneration of damaged tissue, modification of the microenvironment to aid in cartilage regeneration, and/or simply pain and inflammatory modulation. Paracrine factors may also play a role in potential therapeutic mechanisms [28].

In the present investigation, we used a pre- and post-injection protocol to prime the knee before receiving the BMC as well to aid in proliferation of MSCs after receiving the BMC. The rationale for an inflammatory pre-injection was to stimulate local MSCs. For example, MSCs have been found in higher concentrations in the synovial fluid in an acutely injured knee compared to a normal knee [29]. Doxycycline was added to the injectate because as it has been shown to decrease catabolic cytokines (matrix metalloproteinases) and improve MSC induced chondrogenesis [30]. Nanogram dosing of corticosteroids has been previously shown to promote chondrogenesis with limited systemic response [31]. The addition of autologous PRP and PL for the post-injection is primarily to aid in the proliferation of both native MSCs and those contained in the BMC. The benefits of PL as a culture medium for MSCs and its effects on cellular proliferation have also been widely reported [32].

There are several potential limitations of the present study to consider. First, there were 17 patients that received PRP injections after undergoing the BMC treatment protocol for recurrent pain. PRP used alone has been previously shown to have a limited effect on moderate OA [33]. Second, doxycycline and ultra-low dose corticosteroid used in post-injection protocol theoretically may have contributed to the observed effects via their mechanisms of decreasing matrix metalloproteinases and aid in local chondrocyte proliferation, respectively, although is unlikely to account for the observed results [30, 34]. A third limitation is the relatively short duration of the exercise therapy group and the allowance of those in the exercise group to crossover and receive BMC treatment. This was designed to aid in study participant recruitment and retention. Statistically, the crossover group did not improve more than the BMC only treatment group. A final limitation is missing data at some follow-up time points due to being lost to follow-up as well as patients that were removed for receiving treatments outside of the study protocol. Approximately 20% of patients received outside treatment (hyaluronic acid injections or TKA) during the study, suggesting that a portion of the study sample did not achieve the desired clinical response after the BMC and platelet product treatment. Since we believe that these outside treatments would affect clinical outcomes, we did not include data at subsequent follow-up time points for a patient after the time of the outside intervention. Further research focused on identifying good or poor candidates for this treatment is needed. Future investigations should also include patients that completed physical therapy for 6–12 months.

To our knowledge, the present study is the first randomized trial comparing a specific protocol of BMC with platelet products to exercise therapy for the treatment of knee osteoarthritis. While exercise therapy helped knee OA symptoms and function, this specific protocol of intra-articular injection of BMC with platelet products had a greater impact on patients. The results of our study warrant expanded investigation.