The Challenging Problem Of Knee Osteoarthritis

Osteoarthritis (OA) is a common condition, typically discovered in middle age. The prevalence of symptomatic knee OA is as high as 13% in women and 10% in men older than 60 years.¹ It is significantly higher in the population 65 years and older and is one of the top five causes of disability.¹ Direct healthcare costs of knee OA are significant. For example, estimated hospital expenditures for total knee joint replacements are around $10 billion a year in the United States alone.² However, this figure likely represents only a small portion of the economic impact of this condition: Likely to increase this cost estimate substantially are the global economic impact of knee OA on work performance, absenteeism, required assistance within households, and the negative impact of decreased physical activity on mental health as well as cardiovascular, endocrine, and other organ systems.³

Current evidence suggests that managing pain and other problems associated with knee OA via physical rehabilitation, manipulation therapy, and pharmacotherapy remain unsatisfactory.⁴ Corticosteroids and hyaluronic acid are the most commonly used agents for intra-articular knee injections.⁴ Despite their widespread use, corticosteroid injections appear to be appropriate predominantly for knee OA with synovitis.⁴ The duration of clinical effects for corticosteroid injections is usually only a few weeks, according to the majority of studies.⁴ Viscosupplementation with hyaluronic acid has been considered a safe and useful treatment for symptomatic knee OA in many studies, including a recent systematic review of high-quality, placebocontrolled trials.⁵ However, other systematic reviews have reported contradictory conclusions, including that viscosupplementation has no or minimal benefit, any benefits that occur last for less than 6 months after injection, and the therapy is associated with adverse effects.⁶

Analgesic outcomes of arthroscopic surgery for knee OA are unclear and, even if present, last less than 2 years.⁷ The definitive treatment for knee OA remains knee replacement, which is not without its own adverse effects and limitations.⁴ The current published causes of death secondary to knee OA do not include the complications of treatment with opioids, nonsteroidal antiinflammatory drugs (NSAIDs), or other drugs used to treat knee OA.⁴

A Search For Novel Management Tools

 Disappointing treatment outcomes have prompted a rigorous search for agents that will result in restorative reactions in the knee while maintaining a balance between degenerative and regenerative processes in the joint tissues.^4,7,8 Platelet-rich plasma (PRP) therapy involves the use of a patient’s own growth factors contained in platelet alpha-granules in supraphysiologic concentrations.⁹ Experimental studies have suggested that PRP injections may stimulate regeneration of the bone, cartilage, and synovia. Initial clinical studies assessing the feasibility of using PRP injections for knee pathology, published more than 7 years ago, showed that PRP might be a viable treatment option to address the pain and functional disability accompanying knee OA.¹⁰ The number of publications in this area has grown significantly since the initial investigations. Various reviews have assessed pain, function, and quality of life for knee OA patients treated with PRP. More recent studies and reviews of the clinical evidence suggest that PRP could be a reasonable management option for temporarily alleviating pain and improving function as well as improving quality of life. However, the current literature does not systematically assess the duration of clinical benefit of PRP and recounted autologous products. We have recently reviewed these studies with our colleagues, Dr. Samer Narouze and Dr. Aaron Calodney, in an attempt to answer this important question.¹⁰

Platelet-Rich Plasma Injections For Knee Osteoarthritis: Duration Of Clinical Effect

Using a systematic review approach, we analyzed published clinical reports on the duration of therapeutic effect of PRP in patients with knee OA. We searched primarily for randomized controlled studies (RCTs). If high-quality RCTs were not available, we included retrospective studies and other clinical reports. The gathered literature focused on PRP and related autologous products for treatment of knee OA and chondropathy.

A total of 24 relevant studies encompassing 2,315 patients were included in the analysis. The investigations addressed the duration of clinical effects of injected PRP or recounted autologous products for knee OA. The outcome measurements in the studies employed conventional pain and function scales. The methodology for PRP preparation, volume of patient’s blood obtained, type of anticoagulant, number and timing of knee injections, and other options varied significantly between studies. However, there was a consistent and clinically significant improvement in pain scores and functional indexes for at least 6 months in all included studies (Table 1).

Nine of the studies reported decreased therapeutic effect at 12 months after the start of injection therapy; however, in most of the studies, the pain and functional status scores increased but not to baseline lvels before PRP treatment. Authors of one of the recent RCTs stated that the outcomes were further improved at 18 months by annual repetition of the PRP treatment.¹¹ Variables possibly affecting the duration of clinical effects are related to the variety of study designs and variability of autologous agent preparations (eg, methods of PRP preparation, white blood cell count in the injectate, volume of blood used for PRP preparations, type of anticoagulant used). Substantial variability in treatment strategies was also noted (number of PRP injections; timing of injections; patients’ use of opioids, NSAIDs, or other pharmacologic agents; and concomitant use of physical rehabilitation or other treatment modalities). The duration of clinical benefit depended on variabilities in patient selection, including age, sex, and comorbidities (eg, obesity, depression, disability, worker compensation status) that were not routinely presented in the reports.

Summary

Dissatisfaction with the results of available injectable agents for management of pain and dysfunction associated with knee OA has led to explorations of newer options, including PRP, platelet lysates, conditioned serum, alpha-2-macroglobulin, isolated growth factors, and mesenchymal stem cells. Regenerative medicine agents are used with the intention of shifting the balance toward reparative processes in the knee joint affected by the degenerative process or injury. Results of robust experimental studies, widespread use in sports medicine, and simplicity of preparation of PRP have contributed to its popularity for the treatment of symptoms associated with knee OA. Analysis of existing clinical studies suggests that the duration of therapeutic benefits of PRP or recounted autologous products injection—including decreased pain and improved functional status—for patients with knee OA and chondropathy lasted up to 6 months from the time of injection. Pain and functional scores decreased after 12 months of followup but were still superior to pre-injection scores in most of the publications. The analysis is limited by the significant variability of the studies.

References

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2. Cram P, Lu X, Kates SL, Singh JA, Li Y, Wolf BR. Total knee arthroplasty volume, utilization, and outcomes among Medicare beneficiaries, 1991–2010. JAMA. 2012;308(12):1227–1236.

3. Losina E, Burbine SA, Suter LG, et al. Pharmacologic regimens for knee osteoarthritis prevention: can they be cost-effective? Osteoarthritis Cartilage. 2014;22(3):415–430.

4. Cheng OT, Souzdalnitski D, Vrooman B, Cheng J. Evidence-based knee injections for the management of arthritis. Pain Med. 2012;13(6):740–753.

5. Strand V, McIntyre LF, Beach WR, Miller LE, Block JE. Safety and efficacy of US-approved viscosupplements for knee osteoarthritis: a systematic review and meta-analysis of randomized, saline-controlled trials. J Pain Res. 2015;8:217– 228.

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7. Thorlund JB, Juhl CB, Roos EM, Lohmander LS. Arthroscopic surgery for degenerative knee: systematic review and meta-analysis of benefits and harms. BMJ. 2015;350:h2747.

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9. LaPrade CM, James EW, LaPrade RF, Engebretsen L. How should we evaluate outcomes for use of biologics in the knee? The Journal of Knee Surgery. 2015;28(1):35–44.

10. Souzdalnitski D, Narouze SN, Lerman IR, Calodney A. Platelet-rich plasma injections for knee osteoarthritis: systematic review of duration of clinical benefit. Tech Reg Anesth Pain Manag. 2015;19(1-2):67–72.

11. Gobbi A, Lad D, Karnatzikos G. The effects of repeated intra-articular PRP injections on clinical outcomes of early osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc. 2015;23(8):2170–2177.