Regenerative Medicine, Patellar Chondromalacia and Patellofemoral Pain Syndrome

 
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Introduction. Patellar chondromalacia represents a degenerative process of the hyaline cartilage coating the posterior patella as it articulates with hyaline cartilage of the femoral groove. It is often termed patellofemoral pain syndrome (PFP) or runner's knee. The term patellofemoral pain syndrome generally refers to anterior knee pain and is more of a “catch all” term that is not specific to chondromalacia, however the terms are frequently used interchangeably.

Clinically, we all have patients asking about regenerative medicine and we see tons of patients with knee pain, many of whom have chondromalacia or patellofemoral pain. Many clinics are offering some form of regenerative medicine. But… does it work?

Etiology. The etiology of chondromalacia is typically multifactorial. Post-traumatic injuries, microtrauma wear and tear, and iatrogenic injections of medication can lead to the development of chondromalacia [1]. Other risk factors include female gender, abnormal Q angle, weak knee extensor strength, shortened quadriceps muscle, an altered vastus medialis obliquus muscle reflex response time, a decreased explosive strength, and a hypermobile patella [3, 4]. Among athletes, patellofemoral pain is common in jumping, cutting and pivoting sports.

Epidemiology. Patellofemoral pain is a very common cause of knee pain. Patellofemoral pain was diagnosed between 1.5% and 7.3% of all patients seeking medical care within the United States [2]. It is estimated that up to 40% of visits to clinics for knee pain is attributable to PFP [5]. A prevalence rate of between 13% and 26% is reported in females participating in soccer, volleyball, running, fencing and rock climbing [6].

Pathophysiology. Hyaline cartilage represents a highly organised extracellular matrix composed of fibrillar collagen, hydrated proteoglycans, and hyaluronic acid designed to facilitate frictionless motion in joints. The pathophysiology is likely multifactorial as a result of both biochemical and mechanical degradation. Primarily, trauma is thought to be repetitive microtrauma however acute injuries such as an ACL tear may result in a cartilage insult. Biochemically, the cytokine cascade and proteolytic enzymes contribute to breakdown.

History and Physical Exam. The diagnosis of PFP is primarily clinical. The most important component of the history and physical is considering and then excluding other diagnosis before settling on chondromalacia. The most commonly reported symptom is anterior knee pain.  Exacerbating factors typically involve sitting for a long period of time, stairs, lunges, and running or other activities that load the patellofemoral joint.

Generally, there should not be an effusion. Patients will have tenderness with manipulation of the patella and resisted knee extension, particularly when the knee is fully flexed. There is no pathognomonic tests for PFP. Patellar tilt, patellar compression (also known as grind or clarks test) and squat test can all be used to aid in diagnosis, although there is a lack of evidence of superiority of any one exam finding [7].

Evaluation. Imaging studies are not generally required to diagnose chondromalacia and PFP, although they may be useful to exclude other etiologies of pain. Radiographs can be considered as an adjunct to history and physical exam. In cases of recent trauma or if the patient is not improving with initial therapy and activity modification, radiographs should be obtained. If there is concern for non-osseous structural deficit, MRI should be considered. Ultrasound can also be used to exclude other etiologies.

The Outerbridge Classification of chondromalacia is the most commonly accepted classification system for describing the severity of disease. Grade 0 reflects normal cartilage while Grade 4 reflects a full thickness defect, with grades 1 to 3 describing intermediate injuries. These grades can be assigned based on MRI, arthroscopy or, less commonly, macroscopy. This classification system is considered reliable and can be used to help predict the need for surgical management [8, 9].

Differential diagnosis. The differential diagnosis includes hoffa fat pad syndrome, patella alta, patella baja, patella instability, bipartite patella, plica syndrome, patellar or quadriceps tendinopathy, IT band syndrome, osteochondritis dissecans, rheumatological disease among others. In patients reporting trauma, suspicion should increase for meniscus or ligamentous injuries or patellar subluxation.

Management. There is no specific or best management of chondromalacia and it remains a challenging spectrum of illness for patients. The cornerstone of medical management is physical therapy focused on strengthening quadriceps, vmo, hip, core and back. Patellar stabilizing braces may play a role in select patients. In patients with foot and ankle disease, proper footwear and orthotics may aid in symptom relief. Analgesia, including oral NSAIDS and topical medications can be used to help reduce symptoms. Surgical management is reserved for patients with refractory to conservative therapy. Surgical intervention can include debridement of diseased cartilage, plica release, lateral retinacular release, and re-alignment procedures. One of the challenges of surgical management is patients have a widely variable response.

Regenerative Medicine. An area of significant interest in the management of patellar chondromalacia (and degenerative joint disease in general) are intra-articular injections, particularly regenerative therapies. Some examples of regenerative medicine include prolotherapy, platelet rich plasma (PRP) and stem cell therapy. There are many offices and clinics around the US and worldwide offering these therapies for the treatment of many musculoskeletal illnesses, including chondromalacia, with few well designed studies evaluating their efficacy. Regardless of the evidence, motivated patients can find someone to provide the treatment of choice they are interested in. This article aims to focus specifically on the evidence behind these therapies and help guide decision making in patients considering or actively pursuing these therapies.

One of the challenges when evaluating these regenerative medicine for chondromalacia is that many studies do not distinguish between chondropathies, degenerative joint disease and osteoarthritis. If one thinks of these pathologies as existing upon a spectrum of a diseased joint, extrapolation of results may be reasonable. However, it is important to distinguish that many patients with chondromalacia or patellofemoral pain have normal knee radiographs. Additionally, there is not an established protocol for prolotherapy, PRP or stem cell therapies and the implementation  of these therapies can vary wildly between physicians.

Prolotherapy. There are few studies evaluating prolotherapy and chondromalacia. Hauser et al studied 69 patients receiving prolotherapy experienced patients experienced statistically significant decreases in pain at rest, during ADL, and exercise [10]. The average length of time from last prolotherapy was 14 months. It is worth noting this study did not have a control arm. Several studies have found prolotherapy to be beneficial for osteoarthritis, of which chondromalacia can be thought of as a precursor [11, 12]. The patients with OA who benefited the most were younger and with mild OA. Patients with more advanced OA did not do as well.

Platelet Rich Plasma. PRP represents a novel approach to treating chondromalacia and there is very little research evaluating PRP and chondromalacia specifically. Hart et al conducted a pilot study 50 patients with outerbridge grade II or III chondromalacia who underwent 9 injections of PRP over 1 year [13]. Patients improved in all measures of function and pain however no differences in cartilage were noted on repeat MRI.

A 2016 systematic review evaluating PRP for degenerative cartilage disease concluded “Current clinical evidence supports the benefit in PRP treatment... proven to temporarily relieve pain and improve function of the involved joint” [17]. The authors do note that some studies found hyaluronic acid to be superior to PRP, there were widely varied injection protocols and that there was a trend towards younger patients with early knee OA.

A systematic review by Filardo et al included 59 articles and concluded “the preclinical literature shows an overall support toward this PRP application... An intra-articular injection does not just target cartilage; instead, PRP might influence the entire joint environment” [14]. A 2018 systematic review found some short term relief but no long term statistically significant improvements from PRP in patients with OA (and also those undergoing TKA for OA) [18].

Stem Cell Therapy. Stem cell therapy represents another regenerative approach to treating chondromalacia. There are various sources and modalities of stem cell therapy which will not be reviewed in detail here.

In a 3 patient case series by Pak et al, adipose tissue derived stem cells provided relief up to a year and repeat MRI showed improvement of the damaged cartilage [15]. Borakati et al performed a meta-analysis of mesenchymal stem cell therapy for cartilage repair, and although they noted significant heterogeneity among studies, there was a significant reduction in pain compared to controls [16]

Summary and Future. Regenerative medicine has made significant strides recently in the treatment of chondromalacia. Many variables might influence the clinical outcome and all of these have to be studied to determine which, if any, regenerative approach is best for the treatment of chondromalacia and other forms of cartilage degeneration. Challenges remain in identifying the best approach including which type of PRP to inject, how much, and how often. Thus, it can be stated with confidence that more research is needed to tease out the minutiae of regenerative medicine and chondromalacia. Finally, therapy will need to be tailored to individual patients and their goals.

References.

[1] Habusta SF, Griffin EE. Chondromalacia Patella. 2019 Feb 24. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK459195/ PubMed PMID: 29083563.

[2] Glaviano NR, Kew M, Hart JM, Saliba S. DEMOGRAPHIC AND EPIDEMIOLOGICAL TRENDS  IN PATELLOFEMORAL PAIN. Int J Sports Phys Ther. 2015 Jun;10(3):281-90.

[3] Lankhorst NE, Bierma-Zeinstra SM, van Middelkoop M. Risk factors for patellofemoral pain syndrome: a systematic review. J Orthop Sports Phys Ther. 2012 Feb;42(2):81-94.

[4] Witvrouw, E., Lysens, R., et al. (2000). Intrinsic Risk Factors for the Development of Anterior Knee Pain in an Athletic Population: A Two-Year Prospective Study. The American Journal of Sports Medicine, 28(4), 480–489.

[5] Baquie P, Brukner P. Injuries presenting to an Australian sports medicine centre: a 12-month study. Clin J Sport Med. 1997;7(1):28–31.

[6] Patellofemoral pain syndrome in Iranian female athletes. Nejati P, Forogh B, Moeineddin R, Baradaran HR, Nejati M. Acta Med Iran. 2011; 49(3):169-72.

[7] Nunes GS, Stapait EL, Kirsten MH, de Noronha M, Santos GM. Clinical test for diagnosis of patellofemoral pain syndrome: Systematic review with meta-analysis.  Phys Ther Sport. 2013 Feb;14(1):54-9.

[8] Cameron ML, Briggs KK, Steadman JR. Reproducibility and reliability of the outerbridge classification for grading chondral lesions of the knee arthroscopically. Am J Sports Med. 2003 Jan-Feb;31(1):83-6.

[9] Rodríguez-Merchán EC, Gómez-Cardero P. The outerbridge classification predicts the need for patellar resurfacing in TKA. Clin Orthop Relat Res. 2010 May;468(5):1254-7. doi: 10.1007/s11999-009-1123-0. PubMed PMID: 19844770;

[10]   Hauser, R. A., & Sprague, I. S. (2014). Outcomes of Prolotherapy in Chondromalacia Patella Patients: Improvements in Pain Level and Function. Clinical Medicine Insights: Arthritis and Musculoskeletal Disorders.

[11] Farpour HR, Fereydooni F. Comparative effectiveness of intra-articular prolotherapy versus peri-articular prolotherapy on pain reduction and improving function in patients with knee osteoarthritis: A randomized clinical trial. Electron Physician. 2017 Nov 25;9(11):5663-5669. doi:

[12] Hung CY, Hsiao MY, Chang KV, Han DS, Wang TG. Comparative effectiveness of dextrose prolotherapy versus control injections and exercise in the management of osteoarthritis pain: a systematic review and meta-analysis. J Pain Res. 2016 Oct  18;9:847-857.

[13] Hart R, Safi A, Komzák M, Jajtner P, Puskeiler M, Hartová P. Platelet-rich plasma in patients with tibiofemoral cartilage degeneration. Arch Orthop Trauma Surg. 2013 Sep;133(9):1295-301.

[14] Filardo, G., et al. "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 23.9 (2015): 2459-2474.

[15] Pak J, Lee JH, Lee SH. A novel biological approach to treat chondromalacia patellae. PLoS One. 2013 May 20;8(5):e64569.

[16] Borakati A, Mafi R, Mafi P, Khan WS. A Systematic Review And Meta-Analysis of  Clinical Trials of Mesenchymal Stem Cell Therapy for Cartilage Repair. Curr Stem Cell Res Ther. 2018 Feb 23;13(3):215-225.

[17]   Laver, L., Marom, N., Dnyanesh, L., Mei-Dan, O., Espregueira-Mendes, J., & Gobbi, A. (2017). PRP for Degenerative Cartilage Disease: A Systematic Review of Clinical Studies. CARTILAGE, 8(4), 341–364.

[18] Muchedzi TA, Roberts SB. A systematic review of the effects of platelet rich plasma on outcomes for patients with knee osteoarthritis and following total knee arthroplasty. Surgeon. 2018 Aug;16(4):250-258.