Osteoarthritis of the Knee: Selected Treatments

Number: 0673

Policy

Aetna considers arthroscopic debridement medically necessary for persons presenting with mild-to-moderate (Outerbridge classification I and II) osteoarthritis with knee pain plus mechanical symptoms due to loose bodies and/or meniscal tears.

Aetna considers arthroscopic partial meniscectomy medically necessary for traumatic meniscal tears. Aetna considers arthroscopic partial meniscectomy experimental and investigational for degenerative meniscal tears.

Aetna considers the following interventions experimental and investigational because the effectiveness of these approaches has not been established:

  • Arthroscopic debridement for persons with osteoarthritis presenting with knee pain only or with severe osteoarthritis (Outerbridge classification III or IVFootnotes for outerbridge scale.*)
  • Arthroscopic lavage
  • Balneotherapy
  • Bone marrow aspirate concentrate
  • Combination of high tibial osteotomy and autologous bone marrow derived cell implantation
  • Cryotherapy
  • Extracorporeal shock wave therapy
  • Intra-articular injections of autologous conditioned serum
  • Patellar denervation
  • Patellofemoral replacement (arthroplasty)
  • Percutaneous autologous fat injections
  • Percutaneous calcium phosphate injections
  • Stem cell therapy (e.g., intra-articular injections of adipose tissue-derived stem cells, bone marrow-derived mononuclear cell, infra-patellar fat pad-derived mesenchymal stem cell or pre-cartilaginous stem cells)

Aetna considers extended-release triamcinolone acetonide injectable suspension (Zilretta) not medically necessary because it has not demonstrated a significant improvement in osteoarthritis pain compared with the immediate-release formulation of triamcinolone acetonide.  

Notes:

Footnotes for outerbridge scale.*The most commonly used instrument to classify the severity of osteoarthritis in study patients was the Outerbridge scale.  The Outerbridge scale classifies the articular degeneration of the knee by compartment in four grades.  Grade I refers to softening or blistering of the articular cartilage.  Grade II describes fragmentation or fissuring in an area less than 1 cm, while those with an area greater than 1 cm are considered Grade III.  Finally, Grade IV refers to cartilage erosion down to the bone.

Background

Osteoarthritis (OA) is a non-inflammatory degenerative joint disease that occurs mainly in middle-aged and older individuals.  Osteoarthritis of the knee occurs when the elastoviscous properties of the synovial fluid in the knee joint becomes diminished, resulting in less protection and shock absorption.  Osteoarthritis of the knee is often characterized by pain that frequently requires medical and/or surgical intervention.  In general, the pain associated with OA develops gradually, although sudden onset is also possible.  The joint may become stiff and swollen, making it difficult to bend or straighten the knee.  Pain and swelling are worse in the morning or after a period of inactivity.  Pain may also increase after activities such as walking, stair climbing or kneeling.  The pain may often cause a feeling of weakness in the knee, resulting in a "locking" or "buckling".  Many arthritic patients note that changes in the weather also affect the degree of pain from arthritis.

Based on the criteria of the American College of Rheumatology (Altman et al, 1986), a diagnosis of OA of the knee can be rendered if patients experience knee pain and at least 5 of the following:

  • Bony enlargement
  • Bony tenderness
  • Crepitus (noisy, grating sound) on active motion
  • Erythrocyte sedimentation rate (ESR) less than 40 mm/hr
  • Less than 30 minutes of morning stiffness
  • No palpable warmth of synovium
  • Over 50 years of age
  • Rheumatoid factor less than 1:40 titer (agglutination method)
  • Synovial fluid signs.
The severity of OA is often described according to the Outerbridge scale, which classifies the articular degeneration of the knee by compartment in 4 grades:
  1. Grade I refers to softening or blistering of the articular cartilage,
  2. Grade II describes fragmentation or fissuring in an area less than 1 cm,
  3. Grade III describes fragmentation or fissuring in an area greater than 1 cm, and
  4. Grade IV refers to cartilage erosion down to the bone.

Treatment of mild symptomatic OA entails patient education, non-pharmacological approaches such as exercises, lifestyle modifications, and use of supportive devices, as well as pharmacotherapies including non-opioid oral and topical analgesics.  In patients who are unresponsive to this regimen, the use of non-steroidal anti-inflammatory drugs (NSAIDs) is appropriate.  Intra-articular injections of steroids or viscosupplementation may be used for patients who fail conservative management.  Patients with severe symptomatic OA of the knee may require surgical intervention, e.g., arthroscopic surgery, osteotomy, abrasion arthroplasty, subchondral penetration procedures, and laser/thermal chondroplasty.

Arthroscopy involves direct visualization of the joint by a videofiberoptic device.  Arthroscopic lavage and/or debridement is often recommended when medical therapy fails to reduce osteoarthritic knee pain and improve functioning.  Lavage entails either large or small volume saline irrigation of the knee.  Debridement covers many types of arthroscopic surgery and may include but is not limited to variable amounts of the following treatments: partial synovectomy, decompression and resection of plicae/adipose tissue, partial menisectomy, chondroplasty, loose body removal, and/or osteophyte removal.  In clinical practice, debridement is generally performed with low volume lavage or washout.  The available evidence supporting the use of arthroscopic surgery for the treatment of symptomatic OA of the knee is largely retrospective and lacks validated health-related quality-of-life measures.  In this regard, the reports by Baumgaertner and colleagues (1990), Ogilvie-Harris and Fitsialos (1991), Yang and Nisonson (1995), as well as Jackson and Dieterichs (2003) were case series studies, while that by Fond et al (2002) was a cohort observational study. 

In contrast, findings of many randomized controlled studies indicate that arthroscopic lavage and/or debridement did not result in pain relief and improvement of functioning.  Gibson et al (1992) studied the effect of arthroscopic lavage and debridement of the osteoarthritic knee.  A total of 20 patients were randomly assigned to receive
  1. lavage, or
  2. debridement.
The primary outcome was objective evaluation of thigh muscle function in the affected quadriceps compared to that of the non-affected quadriceps before and after operation.  There was some improvement in quadriceps isokinetic torque at 6 and 12 weeks after joint lavage but not after debridement.  However, neither method significantly relieved patients' symptoms.
In a multi-center, randomized, controlled study, Ravaud et al (1999) assessed the effectiveness of joint lavage and intra-articular steroid injection, alone and in combination, in the treatment of patients with symptomatic knee OA.  A total of 98 patients were randomly assigned to 4 treatment groups:
  1. intra-articular placebo (1.5 ml of 0.9 % normal saline),
  2. intra-articular corticosteroids (3.75 mg of cortivazol in 1.5 ml),
  3. joint lavage and intra-articular placebo, and
  4. joint lavage and intra-articular corticosteroid.
Outcome measures including severity of pain (100-mm visual analog scale [VAS]), global status (100-mm VAS), and Lequesne's functional index were evaluated at baseline, week 1, week 4, week 12, and week 24.  There was no interaction between steroid injection and joint lavage.  Patients who had undergone joint lavage had significantly improved pain VAS scores at week 24 (p < 0.020).  In contrast, corticosteroid injection had no long-term effect (p < 0.313); corticosteroid injection was associated with a decrease in pain only at week 1 (p < 0.003) and week 4 (p < 0.020).  However, there was no significant improvement in function at week 4 regardless of the assigned treatment as indexed by Lequesne's functional index.
In a multi-center, randomized, controlled study, Kalunian and associates (2000) examined if visually-guided arthroscopic irrigation is an effective therapeutic intervention in patients with early knee OA.  A total of 90 patients were randomly assigned in a double-blind fashion to receive
  1. arthroscopic irrigation with 3,000 ml of saline (treatment group), or
  2. the minimal amount of irrigation (250 ml) needed to perform arthroscopy (placebo group).
The primary outcome variable was aggregate Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score.  The study did not demonstrate an effect of irrigation on arthritis severity as measured by aggregate WOMAC scores, the primary outcome variable.  The mean change in aggregate WOMAC score at 12 months was 15.5 (95 % confidence interval [CI]: 7.7 to 23.4) for the full irrigation group compared to 8.9 (95 % CI: 4.9 to 13.0) for the minimal irrigation group (p < 0.10).

In a prospective, randomized, placebo-controlled trial to determine whether a placebo effect might play a role in arthroscopic treatment of OA of the knee (Moseley et al, 1996), 5 subjects were randomized to a placebo arthroscopy group, 3 subjects were randomized to an arthroscopic lavage group, and 2 subjects were randomized to a standard arthroscopic debridement group.  Patients who received the placebo surgery reported decreased frequency, intensity, and duration of knee pain.  They also thought that the procedure was worthwhile and would recommend it to family and friends.  Thus, there may be a significant placebo effect for arthroscopic treatment of osteoarthritis of the knee.  The authors concluded that a larger study is needed to evaluate fully the effectiveness of an arthroscopic procedure for this condition.  Recent evidence published in the New England Journal of Medicine (Moseley et al, 2002) confirms this earlier finding that arthroscopic lavage and/or debridement in patients with OA of the knee without other specific indications is no better than placebo surgery.

Moseley and colleagues (2002) carried out a randomized, placebo-controlled study to examine the effectiveness of arthroscopy for OA of the knee.  A total of 180 patients with knee OA were randomly assigned to receive
  1. arthroscopic debridement,
  2. arthroscopic lavage, or
  3. placebo surgery.
Patients in the placebo group received skin incisions and underwent a simulated debridement without insertion of the arthroscope.  Patients and assessors of outcome were blinded to the treatment-group assignment.  Outcomes were assessed at multiple points over a 24-month period with the use of 5 self-reported scores -- 3 on scales for pain and 2 on scales for function -- and 1 objective test of walking and stair climbing.  A total of 165 patients completed the trial.  At no point did either of the intervention groups report less pain or better function than the placebo group.  For example, mean (+/- standard deviation [SD]) scores on the Knee-Specific Pain Scale (range of 0 to 100, with higher scores indicating more severe pain) were similar in the placebo, lavage, and debridement groups: 48.9 +/- 21.9, 54.8 +/- 19.8, and 51.7 +/- 22.4, respectively, at 1 year (p < 0.14 for the comparison between placebo and lavage; p < 0.51 for the comparison between placebo and debridement) and 51.6 +/- 23.7, 53.7 +/- 23.7, and 51.4 +/- 23.2, respectively, at 2 years (p < 0.64 and p < 0.96, respectively).  Furthermore, the 95 % CIs for the differences between the placebo group and the intervention groups exclude any clinically meaningful difference.  These researchers concluded that for patients with OA of the knee, the outcomes after arthroscopic lavage or arthroscopic debridement were no better than those after a placebo procedure.

In view of the findings of Moseley and associates, advocates of arthroscopic lavage and debridement suggest that may be these procedures are effective in subgroups of patients with knee OA including those at the early stages of OA, those with normal alignment as well as those with mechanical symptoms.  However, Moseley and co-workers stated that they have performed an extensive subgroup analysis and did not find any differences to support the claim that outcomes of arthroscopic surgery for OA of the knee may be related to the severity of arthritis or alignment (Wray et al, 2002).

In a sham-controlled, randomized, double-blinded study, Bradley et al (2002) evaluated the effectiveness of tidal irrigation (TI) in comparison with a well-matched sham irrigation (SI) procedure as a treatment for OA of the knee.  A total of 180 patients with knee OA were randomized to receive TI or SI, with clinical follow-up over the ensuing 12 months.  The primary outcomes of interest were changes in pain and function, as measured by the WOMAC.  Patients and the nurse assessor were blinded, and success of blinding was assessed.  Although the study groups were otherwise comparable, the baseline WOMAC pain and physical functioning scores were higher (worse) in the SI group.  After adjustment for baseline, there were no differences between the effects of SI and TI.  Blinding was successful with approximately 90 % of SI and TI patients stating that they had received the TI procedure.  The authors concluded that the improvement of these patients with knee OA following TI was due to a placebo effect.

Dervin and colleagues (2003) prospectively evaluated a cohort of patients (n = 126) with OA of the knee who were selected for arthroscopic debridement and determined which clinical criteria favor a sustained improvement in health-related quality of life after 2 years of follow-up.  These researchers found that the prospectively evaluated quality-of-life benefit from arthroscopic debridement of the osteoarthritic knee is less than that reported in previous retrospective surveys on satisfaction.  Additionally, clinical variables were only partially helpful for predicting a successful result after arthroscopic debridement.

The American College of Rheumatology (ACR) (2000) guidelines on OA of the hip and knee has concluded that “[n]o well-controlled trials of arthroscopic debridement with or without arthroplasty have been conducted, and the utility of this intervention for the treatment of knee osteoarthritis is unproven.”  The ACR guidelines state that routine arthroscopic lavage with or without debridement should not be routinely recommended to patients with knee OA who have failed medical therapy.  Arthroscopic removal of debris may, however, be useful for relief of pain and improvement in joint function in patients with mechanical symptoms due to loose bodies and meniscal tears.  However, further studies in these types of patients are needed. 

An assessment of arthroscopic lavage for knee osteoarthritis conducted by the Wessex Institute for Health Research and Development (Algood, 2002) summarized the evidence on arthroscopic lavage and debridement for osteoarthritis: "We found evidence from one good quality RCT [randomized controlled trial] that arthroscopic debridement or lavage did not improve patient reported pain and function at 2 years compared with sham arthroscopy for men with osteoarthritis of the knee.  Two other, weaker, RCTs found that debridement and lavage did not improve symptoms compared with non-arthroscopic lavage.  Another RCT found that arthroscopic lavage with 3,000 ml saline slightly improved pain compared with arthroscopic lavage with 250 ml saline.  Another RCT found that arthroscopic debridement improved pain relief compared with arthroscopic lavage in people with isolated degenerative disease on the medial femoral condyle.  We found no evidence that arthroscopic debridement or lavage improves symptoms compared with non-arthroscopic treatments."

In the Patient-Oriented Evidence that Matters (POEMs) of the Journal of Family Practice, Bailey (2002) stated that arthroscopy does not provide any benefit over sham surgery in reducing pain or physical functioning of patients with knee OA.  In the Interpreting Key Trials section of the Cleveland clinic Journal of Medicine, Bernstein and Quach (2003) stated that the value of arthroscopy in treating patients with arthritic joints must be proved.  Furthermore, in the American College of Physicians Journal Club, Gillespie (2003) stated that the study by Moseley et al (2002) made a case for questioning the value of arthroscopic lavage and debridement in active men younger than 65 years of age with OA of the knee.  In addition, the Centers for Medicare and Medicaid Services (2003) will be issuing a national non-coverage determination stating that arthroscopic lavage alone is not reasonable and necessary for patients with OA of the knee; and that arthroscopic debridement is not reasonable and necessary for patients presenting with knee pain only or with severe OA (Outerbridge classification III or IV).

An assessment of arthroscopic lavage and debridement by the Medical Advisory Secretariat of the Ontario Ministry of Health and Long-term Care (2005) concluded: "Arthroscopic debridement of the knee has thus far only been found to be effective for medial compartmental OA.  All other indications should be reviewed with a view to reducing arthroscopic debridement as an effective therapy.  Arthroscopic lavage of the knee is not indicated for any stage of OA.  There is very poor quality evidence on the effectiveness of debridement with partial meniscectomy in the case of meniscal tears in OA of the knee."

A randomized study by Kirkley et al (2008) published in the New England Journal of Medicine found that arthroscopic lavage and debridement for OA of the knee provided no additional benefit to optimized physical and medical therapy.  The investigators conducted a single-center, randomized, controlled trial of arthroscopic surgery in patients with moderate-to-severe OA of the knee.  Patients were randomly assigned to surgical lavage and arthroscopic debridement together with optimized physical and medical therapy or to treatment with physical and medical therapy alone.  The primary outcome was the total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score at 2 years of follow-up.  Secondary outcomes included the Short Form-36 (SF-36) Physical Component Summary score.  Of the 92 patients assigned to surgery, 6 did not undergo surgery.  Of the 86 patients assigned to control treatment, all received only physical and medical therapy.  After 2 years, there were no statistically significant differences in WOMAC scores or the SF-36 Physical Component Summary scores for the surgery group as compared with the control group.  Analyses of WOMAC scores at interim visits and other secondary outcomes also failed to show superiority of surgery.

An accompanying study published in the New England Journal of Medicine found that incidental meniscal findings on magnetic resonance imaging (MRI) of the knee are common in the general population and increase with increasing age (Englund et al, 2008).  MRI of the knee is often performed in patients who have knee symptoms of unclear cause.  When meniscal tears are found, it is commonly assumed that the symptoms are attributable to them.  However, there is a paucity of data regarding the prevalence of meniscal damage in the general population and the association of meniscal tears with knee symptoms and with radiographical evidence of osteoarthritis.  Englund et al (2008) studied persons from Framingham, Massachusetts, who were drawn from census-tract data and random-digit telephone dialing.  Subjects were 50 to 90 years of age and ambulatory; selection was not made on the basis of knee or other joint problems.  The investigators assessed the integrity of the menisci in the right knee on 1.5-tesla MRI scans obtained from 991 subjects (57 % of whom were women).  Symptoms involving the right knee were evaluated by questionnaire.  The investigators found that the prevalence of a meniscal tear or of meniscal destruction in the right knee as detected on MRI ranged from 19 % among women 50 to 59 years of age to 56 % among men 70 to 90 years of age; prevalences were not materially lower when subjects who had had previous knee surgery were excluded.  Among persons with radiographical evidence of OA, the prevalence of a meniscal tear was 63 % among those with knee pain, aching, or stiffness on most days and 60 % among those without these symptoms.  The corresponding prevalences among persons without radiographical evidence of OA were 32 % and 23 %.  Sixty-one percent of the subjects who had meniscal tears in their knees had not had any pain, aching, or stiffness during the previous month.

An accompanying editorial by Marx (2008) in the New England Journal of Medicine concluded that the study by Kirkley et al (2008), combined with other evidence, indicates that OA of the knee (in the absence of a history and physical examination suggesting meniscal or other findings) is not an indication for arthroscopic surgery and indeed has been associated with inferior outcomes after arthroscopic knee surgery.  The editorialist stated, however, that OA is not a contraindication to arthroscopic surgery, and arthroscopic surgery remains appropriate in patients with arthritis in specific situations in which OA is not believed to be the primary cause of pain.

In a systematic review of outcomes of 3 treatments for OA of the knee:
  1. intra-articular viscosupplementation,
  2. oral glucosamine, chondroitin or the combination, and
  3. arthroscopic lavage or debridement,
Samson et al (2007) concluded that these 3 interventions are widely used in the treatment of OA of the knee, yet the best available evidence does not clearly demonstrate clinical benefit.  Uncertainty regarding clinical benefit can be resolved only by rigorous, multi-center randomized controlled trials.  Furthermore, a Cochrane review on arthroscopic debridement for knee OA, Laupattarakasem et al (2008) concluded that there is "gold" level evidence that arthroscopic debridement has no benefit for undiscriminated OA (mechanical or inflammatory causes).

In a review on surgical options for patients with OA of the knee, Lützner and colleagues(2009) stated that surgical treatments for knee OA include arthroscopy, osteotomy and knee arthroplasty; determining which of these procedures is most appropriate will depend on several factors, including the location and severity of OA damage, patient characteristics and risk factors.  Arthroscopic lavage and debridement do not alter disease progression, and should not be used as a routine treatment for the osteoarthritic knee.

The American Association of Orthopaedic Surgeons’ clinical practice guideline on the treatment of OA of the knee (AAOS, 2008) does not recommend performing arthroscopy with debridement or lavage.  Furthermore, it does not recommend performing needle lavage.  Also, a recent Agency for Healthcare Research and Quality's (AHRQ, 2009) report summarized the evidence on the safety and effectiveness of 3 treatments for OA of the knee:
  1. use of the supplements glucosamine hydrochloride, chondroitin sulfate, or combination of both;
  2. viscosupplementation; and
  3. arthroscopic lavage and debridement of the knee joint.
The evidence evaluated comes mainly from comparisons of each therapeutic approach with a placebo.  The AHRQ guideline concluded that glucosamine and chondroitin, viscosupplementation, as well as arthroscopic lavage with or without debridement do not lead to clinically meaningful improvement.

In a Cochrane review, Reichenbach and colleagues (2010) compared joint lavage with sham intervention, placebo or non-intervention control in terms of effects on pain, function and safety outcomes in patients with knee OAs.  These investigators searched CENTRAL, MEDLINE, EMBASE, and CINAHL up to August 3, 2009, checked conference proceedings, reference lists, and contacted authors.  They included studies if they were randomized or quasi-randomized trials that compared arthroscopic and non-arthroscopic joint lavage with a control intervention in patients with OA of the knee.  Two independent review authors extracted data using standardised forms.  They contacted investigators to obtain missing outcome information, and calculated standardized mean differences (SMDs) for pain and function, and risk ratios for safety outcomes.  They combined trials using inverse-variance random-effects meta-analysis.  These researchers included 7 trials with 567 patients; 3 trials examined arthroscopic joint lavage, 2 non-arthroscopic joint lavage and 2 tidal irrigation.  The methodological quality and the quality of reporting was poor and these investigators identified a moderate-to-large degree of heterogeneity among the trials (I(2) = 65 %).  They found little evidence for a benefit of joint lavage in terms of pain relief at 3 months (SMD -0.11, 95 % CI: -0.42 to 0.21), corresponding to a difference in pain scores between joint lavage and control of 0.3 cm on a 10-cm VAS.  Results for improvement in function at 3 months were similar (SMD -0.10, 95 % CI: -0.30 to 0.11), corresponding to a difference in function scores between joint lavage and control of 0.2 cm on a WOMAC disability sub-scale from 0 to 10.  For pain, estimates of effect sizes varied to some degree depending on the type of lavage, but this variation was likely to be explained by differences in the credibility of control interventions: trials using sham interventions to closely mimic the process of joint lavage showed a null-effect.  Reporting on adverse events and drop-out rates was unsatisfactory, and they were unable to draw conclusions for these secondary outcomes.  The authors concluded that joint lavage does not result in a relevant benefit for patients with knee OA in terms of pain relief or improvement of function.

Ronn et al (2011) noted that OA of the knee is common, and the chances of suffering from OA increase with age.  Its treatment should be initially non-operative-and requires both pharmacological and non-pharmacological treatment modalities.  If conservative therapy fails, surgery should be considered.  Surgical treatments for knee OA include arthroscopy, cartilage repair, osteotomy, and knee arthroplasty.  Determining which of these procedures is most appropriate depends on several factors, including the location, stage of OA, co-morbidities on the one side and patients suffering on the other side.  Arthroscopic lavage and debridement is often carried out, but does not alter disease progression.  If OA is limited to one compartment, uni-compartmental knee arthroplasty or unloading osteotomy can be considered.  They are recommended in young and active patients in regard to the risks and limited durability of total knee replacement.  Total arthroplasty of the knee is a common and safe method in the elderly patients with advanced knee OA.

The effectiveness of arthroscopic partial meniscectomy for torn meniscus is unknown.  Arthroscopic partial meniscectomy is performed in patients with symptomatic osteoarthritis of the knee who also have primary signs and symptoms of a torn meniscus.  Guidelines from the AAOS stated: "We are unable to recommend for or against arthroscopic partial meniscectomy in patients with osteoarthritis of the knee with a torn meniscus".  The AAOS identified only a single study of arthroscopic partial meniscectomy that met criteria for inclusion in their analysis.  The study, by Herrlin et al (2007), compared arthroscopic partial meniscectomy followed by supervised exercise to supervised exercise alone and measured Knee injury and Osteoarthritis Outcome Score (KOOS) pain, symptoms, activities of daily life, sports/recreation, and quality of life subscales scores as outcomes.  The study was downgraded from moderate- to low-strength because 40 % of patients declined participation and the arthroscopic group had non-homogeneous preoperative KOOS scores.  The authors reported no significant treatment benefits of meniscectomy using any of the outcomes at 8 weeks and 6 months.  Since there was only one low-strength study, the AAOS recommendation was graded inconclusive.

Additional studies of arthroscopic partial meniscectomy have been published since the AAOS guideline that have found no benefit to arthroscopic partial meniscectomy for torn meniscus.  Sihvonen and colleagues (2013) conducted a multi-center, randomized, double-blind, sham-controlled trial in 146 patients 35 to 65 years of age who had knee symptoms consistent with a degenerative medial meniscus tear and no knee osteoarthritis.  Patients were randomly assigned to arthroscopic partial meniscectomy or sham surgery.  The primary outcomes were changes in the Lysholm and Western Ontario Meniscal Evaluation Tool (WOMET) scores (each ranging from 0 to 100, with lower scores indicating more severe symptoms) and in knee pain after exercise (rated on a scale from 0 to 10, with 0 denoting no pain) at 12 months after the procedure.  The investigators reported that, in the intention-to-treat analysis, there were no significant between-group differences in the change from baseline to 12 months in any primary outcome.  The mean changes (improvements) in the primary outcome measures were as follows: Lysholm score, 21.7 points in the partial-meniscectomy group as compared with 23.3 points in the sham-surgery group (between-group difference, -1.6 points; 95 % CI: -7.2 to 4.0); WOMET score, 24.6 and 27.1 points, respectively (between-group difference, -2.5 points; 95 % CI: -9.2 to 4.1); and score for knee pain after exercise, 3.1 and 3.3 points, respectively (between-group difference, -0.1; 95 % CI: -0.9 to 0.7).  The investigators reported that there were no significant differences between groups in the number of patients who required subsequent knee surgery (2 in the partial-meniscectomy group and 5 in the sham-surgery group) or serious adverse events (1 and 0, respectively). 

Katz et al (2013) conducted a multi-center, randomized, controlled trial involving symptomatic patients 45 years of age or older with a meniscal tear and evidence of mild-to-moderate osteoarthritis on imaging.  The investigators randomly assigned 351 patients to surgery and post-operative physical therapy or to a standardized physical-therapy regimen (with the option to cross-over to surgery at the discretion of the patient and surgeon).  The patients were evaluated at 6 and 12 months.  The primary outcome was the difference between the groups with respect to the change in the WOMAC physical-function score (ranging from 0 to 100, with higher scores indicating more severe symptoms) 6 months after randomization.  In the intention-to-treat analysis, the mean improvement in the WOMAC score after 6 months was 20.9 points (95 % CI: 17.9 to 23.9) in the surgical group and 18.5 (95 % CI: 15.6 to 21.5) in the physical-therapy group (mean difference, 2.4 points; 95 % CI: -1.8 to 6.5).  At 6 months, 51 active participants in the study who were assigned to physical therapy alone (30 %) had undergone surgery, and 9 patients assigned to surgery (6 %) had not undergone surgery.  The results at 12 months were similar to those at 6 months.  The frequency of adverse events did not differ significantly between the groups.

Patello-Femoral Replacement (Arthroplasty)

Lonner (2007) stated that patella-femoral arthroplasty (PFA) can be an effective intermediate treatment for the patient with isolated arthritis of the anterior compartment of the knee. In the absence of patellar mal-alignment, results were optimized when an implant with sound geometric features was used, the prosthesis was appropriately aligned, and the soft tissues were balanced. Although previous prosthesis designs resulted in a relatively high prevalence of failure because of PF mal-tracking, PF catching, and anterior knee pain (AKP), newer prosthesis designs showed promise in reducing the prevalence of PF dysfunction. Progressive tibio-femoral cartilage degeneration was another so-called failure mechanism; such progressive degeneration underscored the importance of restricting the procedure to patients who do not have tibio-femoral chondromalacia. Because long-term failure as a result of tibio-femoral degeneration may occur in approximately 25 % of patients, PFA may be considered an intermediate procedure for select patients with PF arthritis.

Ackroyd et al (2007) reported the mid-term results of a new PFA for established isolated PF arthritis. These researchers reviewed the experience of 109 consecutive PF resurfacing arthroplasties in 85 patients who were followed-up for at least 5 years. The 5-year survival rate, with revision as the end-point, was 95.8 % (95 % CI: 91.8 % to 99.8 %). There were no cases of loosening of the prosthesis. At 5 years the median Bristol pain score improved from 15 of 40 points (interquartile range [IQR] of 5 to 20) pre-operatively, to 35 (IQR of 20 to 40), the median Melbourne score from 10 of 30 points (IQR of 6 to 15) to 25 (IQR of 20 to 29), and the median Oxford score from 18 of 48 points (IQR of 13 to 24) to 39 (IQR of 24 to 45). Successful results, judged on a Bristol pain score of at least 20 at 5 years, occurred in 80 % (66) of knees. The main complication was radiological progression of arthritis, which occurred in 25 patients (28 %) and emphasized the importance of the careful selection of patients. The authors concluded that these results gave increased confidence in the use of PFA. However, this study only provided mid-term results (5 years); and radiological progression of arthritis occurred in 28 % of patients; long-term results are needed. 

Luring et al (2011) stated that isolated OA of the PF joint occurs in 9 % of patients over 40 years of age and women are more often affected. Options of treatment were varied and not sufficiently justified by the literature. These investigators performed a literature research with keywords in the field of femoro-patellar OA in the relevant databases. Studies were categorized into different treatment options and analyzed. There are almost no Level I studies comparing the different treatment options. In the literature there are indications that relief of pain can be achieved by conservative treatment, arthroscopic surgery, cartilage conserving surgery and isolated arthroplasty. The authors concluded that in view of the fact that there are almost no prospective RCTs, none of the options for treatment can be highly recommended. They stated that there is still no gold standard for the treatment of isolated patella-femoral OA.

Davies (2013) noted that unicompartmental PFAs are uncommon; however numbers are increasing and there are a variety of new prostheses available. The Femoro-Patella Vialla (FPV, Wright Medical, UK) device was the second most commonly used PF unicompartmental prosthesis in the 2012 British National Joint Register. There are however no published outcomes data for this device. In this study, a total of 52 consecutive cases were studied prospectively using Oxford Knee Score and American Knee Society (AKS) Scores pre-operatively and at follow-up to a minimum of 2 years. Overall, Oxford Knee Scores improved from 30 points pre-operatively (36.6 %) to 19 points (60 %) at 1-year. American Knee Society Knee scores improved from 51 points pre-operatively to 81 points at 1-year. Functional scores improved from 42 points pre-operatively to 70 points at 1-year. Moreover, 13 (25 %) patients had an excellent outcome with pain abolished and near normal knee function; 11 (21 %) patients gained very little improvement and scored their knees similar or worse to their pre-operative state. There were no infective or thrombo-embolic complications. Seven cases have been revised to a total knee replacement (TKR) for on-going pain in 6 cases and progression of arthritis in the tibio-femoral compartments in 1 case. The patellar button was found to be very poorly fixed in all cases that were revised. The authors concluded that early results with the FPV prosthesis showed that successful outcomes can be achieved; however the results were unpredictable and a significant minority of patients had on-going symptoms that they found unacceptable. They stated that the early revision rate was high in this series.

Al-Hadithy et al (2014) stated that isolated PF joint OA affects approximately 10 % of patients aged over 40 years and treatment remains controversial. The FPV PF joint replacement has been shown to restore functional kinematics of the knee close to normal. Despite its increasing popularity in recent years, there are no studies evaluating the mid-term results with an objective scoring assessment. These investigators reported the clinical and radiological outcomes of FPV PF joint replacement in patients with isolated PF arthritis. Between 2006 and 2012, these researchers performed 53 consecutive FPV PFAs in 41 patients with isolated PFl joint OA. The mean follow-up was 3 years. Mean Oxford Knee Scores improved from 19.7 to 37.7 at latest follow-up. The progression of tibio-femoral OA was seen 12 % of knees. Two knees required revision to TKR at 7 months post-operatively, which these investigators attributed to poor patient selection. There were no cases of mal-tracking patellae, and no lateral releases were performed. The authors concluded that these findings suggested the FPV PFl prosthesis provided good pain relief and survivorship with no significant mal-tracking patellae. This was a relatively small study (n = 41 patients) with mid-term results. These findings need to be validated by well-designed studies with larger sample size and long-term follow-u

Lustig (2014) noted that PFA remains controversial, primarily due to the high failure rates reported with early implants. Several case series have been published over the years, which described the results with various 1st- and 2nd-generation implants. These researchers summarized results published up to now and identified common themes for implants, surgical techniques, and indications. First-generation resurfacing implants had relatively high failure rates in the medium-term. Second-generation implants, with femoral cuts based on total knee arthroplasty (TKA) designs, have yielded more promising medium-term results. The surgical indications were quite specific and must be chosen carefully to minimize poor results. Short-term complications were generally related to patellar mal-tracking, while long-term complications were generally related to progression of OA in the tibio-femoral joint. Implant loosening and polyethylene wear were rare. The author concluded that recent improvements in implant design and surgical techniques have resulted in better short- and medium-term results; however, more work is needed to evaluate the long-term outcomes of modern implant designs.

King et al (2015) reported the incidence of patellar fracture after PFA and determined associated factors as well as outcomes of patients with and without this complication. A total of 77 knees in 59 patients with minimum 2-year follow-up were included. Seven (9.1 %) patients experienced a patellar fracture at a mean of 34 (range of 16 to 64) months post-operatively. All were treated non-operatively. Lower body mass index (BMI; p = 0.03), change in patellar thickness (p < 0.001), amount of bone resected (p = 0.001), and larger trochlear component size (p = 0.01) were associated with a greater incidence of fracture. Fewer fractures occurred when the post-operative patellar height exceeded the pre-operatively measured height. No statistically significant differences were found in outcome scores between groups at mean 4-year follow-up. It should be noted that a fair amount of fractures at mid-term; and it is unclear if the incidence would increase at long-term.

Patellar Denervation

van Jonbergen et al (2014) noted that they have previously shown that in the absence of patellar resurfacing the use of electrocautery around the margin of the patella improved the 1-year clinical outcome of TKR. In this prospective, randomized study, these researchers compared the mean 3.7 year (1.1 to 4.2) clinical outcomes of 300 TKRs performed with and without electrocautery of the patellar rim -- this was an update of a previous report. The overall prevalence of AKP was 32 % (95 % CI: 26 to 39), and 26 % (95 % CI: 18 to 35) in the intervention group compared with 38 % (95 % CI: 29 to 48) in the control group (chi-squared test; p = 0.06). The overall prevalence of AKP remained unchanged between the 1-year and 3.7-year follow-up (chi-squared test; p = 0.12). The mean total WOMAC and the AKS knee and function scores at 3.7 years' follow-up were similar in the intervention and control groups (repeated measures analysis of variance p = 0.43, p = 0.09 and p = 0.59, respectively). There were no complications. A total of 10 patients (intervention group, n = 3; control group, n = 7) required secondary patellar resurfacing after the 1st year. The authors concluded that the findings of this study suggested that the improved clinical outcome with electrocautery denervation compared with no electrocautery was not maintained at a mean of 3.7 years' follow-up.

Handel et al (2014) determined possible differences in the mid-term results of TKA in patients treated with and without denervation of the patella. This study included 80 TKR in 71 patients who were treated with TKR, either with (n = 40) or without (n = 40) simultaneous denervation of the patella out of a total population with 122 knee replacements in 100 patients. Comparability of both groups was achieved by applying matching criteria. All patients were reviewed by isokinetic tests, physical and radiological examination. The mean follow-up time was 2.2 years. The mean hospital for special surgery (HSS) score revealed no statistically significant differences between both groups (with denervation 77.9 ± 11.1 and without denervation 77.8 ± 11.0, p = 0.976). The isokinetic torque measurements with low angle velocity (60°/s) indicated slightly higher values during extension (60.2 ± 32.2 Nm versus 55.8 ± 25.2 Nm, p = 0.497) and flexion (52.4 ± 28.3 Nm versus 46.1 ± 22.3 Nm, p = 0.272) movements of the affected knee joint. However, the differences did not reach statistical significance. At high angle velocity (180°/s) no differences could be found between both groups. No cases of post-operative necrosis of the patella were observed. Anterior knee pain after denervation was reported in 6 cases (15 %) compared to 10 cases (25 %) in patients who were treated without denervation (p = 0.402). The authors concluded that no statistically significant differences could be found between patients with and without denervation of the patella for TKA.

Pulavarti et al (2014) randomized 126 consecutive patients undergoing primary TKA into 2 groups: Group 1-- patella denervation (n = 63) and Group 2 -- no patella denervation (n = 63). Assessment was performed pre-operatively and at 3, 12 and 24 months post-operatively. Average follow-up of patients was 26.5 months for denervation group and 26.3 months for no denervation group (p = 0.84). Pain scores for AKP were significantly better in the denervation group at 3 months but not at 12 and 24 months. Patient satisfaction was higher in the denervation group. Flexion range was higher in the denervation group at 3, 12 and 24 months review (p < 0.01). However, the authors noted that there were no statistically significant differences with other validated knee scores.

Cheng et al (2014) stated that the impact of patellar denervation with electrocautery in TKA on post-operative outcomes has been under debate. These researchers conducted a meta-analysis and systematic review to compare the benefits and risks of circum-patellar electrocautery with those of non-electrocautery in primary TKAs. Comparative studies and RCTs were identified by conducting an electronic search of articles dated up to September 2012 in PubMed, EMBASE, Scopus, and the Cochrane databases. A total of 6 studies that focus on a total of 849 knees were analyzed. A random-effects model was conducted using the inverse-variance method for continuous variables and the Mantel-Haenszel method for dichotomous variables. There was no significant difference in the incidence of AKP between the electrocautery and non-electrocautery groups. In term of patellar score and Knee Society Score (KSS), circum-patellar electrocautery improved clinical outcomes compared with non-electrocautery in TKAs. The statistical differences were in favor of the electrocautery group; but have minimal clinical significance. In addition, the overall complications indicated no statistical significance between the 2 groups. The authors concluded that the findings of this study showed no strong evidence either for or against electrocautery compared with non-electrocautery in TKAs.

In a meta-analysis, Li and colleagues (2014) examined if patellar denervation with electrocautery after TKA could reduce the post-operative AKP. A total of 5 RCTs with 572 patients and 657 knees were eligible for this meta-analysis. The results showed that patellar denervation with electrocautery was associated with less AKP, lower VAS, higher patellar scores and better Knee Function Score (KFS) compared with no patellar denervation. Complications did not differ significantly between the 2 groups. The authors concluded that the existing evidence indicated that patellar denervation with electrocautery may be a better approach, as it improved both AKP and knee function after TKA. Moreover, they stated that future multi-center RCTs with large sample sizes are needed to verify these findings.

Arirachakaran et al (2015) conducted a systematic review and network meta-analysis of RCTs with the aim of comparing relevant clinical outcomes between patellar denervation, resurfacing and non-resurfacing. A database search was performed using PubMed and Scopus search engines; RCTs or quasi-experimental designs comparing clinical outcomes between treatments by a search of articles dated from inception to October 23, 2012. Unstandardized mean difference (UMD) and random effects methods were applied for pooling continuous and dichotomous outcomes, respectively. A longitudinal mixed regression model was used for network meta-analysis to indirectly compare treatment effects; 18 of 315 studies identified were eligible. Compared with patellar non-resurfacing, patellar denervation had a UMD that displayed a significant improvement in symptoms with values in pain VAS and KSS of -0.6 [95 % CI: -1.13 to -0.25] and 2.55 (95 % CI: 0.43 to 4.68), respectively. The UMD in VAS, KSS, and KFS in patellar resurfacing showed no significant improvement in symptoms when compared to non-resurfacing. Patients who underwent surgery with patellar resurfacing had a lower re-operation rates with pooled relative risks (RRs) of 0.69 (95 % CI: 0.50 to 0.94) when compared to non-resurfacing. The network meta-analysis suggested a benefit of borderline significance for patellar denervation with a pooled RR of 0.63 (95 % CI: 0.38 to 1.03), showing that there is a lower chance of AKP when compared to non-resurfacing. Patellar resurfacing also displayed a significantly lower chance of re-operation with a pooled RR of 0.68 (95 % CI: 0.50 to 0.92) when compared to non-resurfacing. Multiple active treatment comparisons indicated that patellar denervation resulted in greater improvement in KFS than patellar resurfacing. The authors concluded that the findings of this review suggested that either patellar denervation or patellar resurfacing may be selected for the management of the PF component in TKR. They noted that patellar denervation may help improve post-operative knee function, but does not improve pain when compared to patellar resurfacing.

Kwon et al (2015) stated that there is controversy over the need for electrocauterization of the patella in non-resurfacing TKA. In a prospective RCT, these researchers examined if this procedure is beneficial. A total of 50 patients who underwent electrocautery were compared with 50 patients who did not undergo this procedure. These investigators determined cartilage status, pre-operative and post-operative AKS score, the WOMAC and the PF scores for a minimum of 5 years. The 2 groups did not differ significantly in demographics, intra-operative cartilage status, or pre-operative or post-operative outcomes. No complications were detected in either group. The authors concluded that they found no benefits of electrocautery of the patella in patellar non-resurfacing TKA up to 5 years.

Cryotherapy

The American Academy of Orthopaedic Surgeons (AAOS)’s evidence-based clinical practice guideline on “Surgical management of osteoarthritis of the knee” (2015) noted that cryotherapy is one of the interventions that were considered but not recommended.

Intra-Articular Corticosteroid Injection

In a randomized, blinded, placebo-controlled clinical trial, Henriksen et al (2015) evaluated the clinical benefits of an intra-articular corticosteroid injection given before exercise therapy in patients with OA of the knee. The participants had radiographic confirmation of clinical OA of the knee, clinical signs of localized inflammation in the knee, and knee pain during walking (score greater than 4 on a scale of 0 to 10).  Subjects were randomly allocated (1:1) to an intra-articular 1-ml injection of the knee with methylprednisolone acetate (Depo-Medrol), 40 mg/ml, dissolved in 4 ml of lidocaine hydrochloride (10 mg/ml) (corticosteroid group) or a 1-ml isotonic saline injection mixed with 4 ml of lidocaine hydrochloride (10 mg/ml) (placebo group).  Two weeks after the injections, all participants started a 12-week supervised exercise program.  The primary outcome was change in the Pain subscale of the KOOS questionnaire (range of 0 to 100; higher scores indicate greater improvement) at week 14.  Secondary outcomes included the remaining KOOS subscales and objective measures of physical function and inflammation.  Outcomes were measured at baseline, week 2 (exercise start), week 14 (exercise stop), and week 26 (follow-up).  A total of 100 patients were randomized to the corticosteroid group (n = 50) or the placebo group (n = 50); 45 and 44 patients, respectively, completed the trial.  The mean (SE) changes in the KOOS Pain subscale score at week 14 were 13.6 (1.8) and 14.8 (1.8) points in the corticosteroid and placebo groups, respectively, corresponding to a statistically insignificant mean difference of 1.2 points (95 % CI: -3.8 to 6.2; p = 0.64).  These researchers found no statistically significant group differences in any of the secondary outcomes at any time-point.  The authors concluded that no additional benefit resulted from adding an intra-articular injection of 40 mg of corticosteroid before exercise in patients with painful OA of the knee.  They stated that further research is needed to establish optimal and potentially synergistic combinations of conservative treatments.

Zilretta is an extended release form triamcinolone acetonide (Kenalog-40 injection) and is FDA-approved for the treatment of osteoarthritis pain of the knee. Zilretta is dosed as a single 32 mg intra-articular injection. The labeling states that the efficacy and safety of repeat administration have not been evaluated (Flexion, 2017). Zilretta is not interchangeable with other formulations of triamcinolone acetonide. The labeling states that Zilretta is not suitable for use in small joints, such as the hand. The labeling states that the efficacy and safety of Zilretta for management of osteoarthritis pain of shoulder and hip have not been evaluated.

The labeling states that, in the pivotal study for FDA approval, Zilretta demonstrated a statistically significant reduction in pain intensity at the primary endpoint versus placebo (Flexion, 2017). However, in a secondary exploratory analysis, statistical significance was not demonstrated between the Zilretta and the active control (immediate-release triamcinolone acetonide) treatment groups for the change from baseline at Week 12 in weekly mean Average Daily Pain intensity scores (see Conaghan, et al., below).

Conaghan et al (2018) stated intra-articular corticosteroids relieve osteoarthritis pain, but rapid systemic absorption limits efficacy. FX006 (Zilretta), a novel, microsphere-based, extended-release triamcinolone acetonide (TA) formulation, prolongs TA joint residence and reduces systemic exposure compared with standard TA crystalline suspension (TAcs). The authors assessed symptomatic benefits and safety of FX006 compared with saline-solution placebo and TAcs. In this Phase-3, multicenter, double-blinded, 24-week study, adults ≥40 years of age with knee osteoarthritis (Kellgren-Lawrence grade 2 or 3) and average-daily-pain (ADP)-intensity scores of ≥5 and ≤9 (0 to 10 numeric rating scale) were centrally randomized (1:1:1) to a single intra-articular injection of FX006 (32 mg), saline-solution placebo, or TAcs (40 mg). The primary end point was change from baseline to week 12 in weekly mean ADP-intensity scores for FX006 compared with saline-solution placebo. Secondary end points were area-under-effect (AUE) curves of the change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with saline-solution placebo, AUE curves of the change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with TAcs, change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with TAcs, and AUE curves of the change in weekly mean ADP-intensity scores from baseline to week 24 for FX006 compared with saline-solution placebo. Exploratory end points included week-12 changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Knee Injury and Osteoarthritis Outcome Score Quality of Life (KOOS-QOL) subscale scores for FX006 compared with saline-solution placebo and TAcs. Adverse events were elicited at each inpatient visit. The primary end point was met. Among 484 treated patients (n = 161 for FX006, n = 162 for saline-solution placebo, and n = 161 for TAcs), FX006 provided significant week-12 improvement in ADP intensity compared with that observed for saline-solution placebo (least-squares mean change from baseline: -3.12 versus -2.14; p < 0.0001) indicating ∼50% improvement. FX006 afforded improvements over saline-solution placebo for all secondary and exploratory end points (p < 0.05). Improvements in osteoarthritis pain were not significant for FX006 compared with TAcs using the ADP-based secondary measures. Exploratory analyses of WOMAC-A, B, and C and KOOS-QOL subscales favored FX006 (p ≤ 0.05). Adverse events were generally mild, occurring at similar frequencies across treatments. The authors concluded that FX006 provided significant, clinically meaningful pain reduction compared with saline-solution placebo at week 12 (primary end point).

In a phase IIb study, Conaghan, et al. (2018) compared the analgesic benefits of 2 FX006 (Zilretta) doses with saline placebo injection. Participants with knee OA (Kellgren/Lawrence grade 2–3) and average daily pain (ADP) intensity ≥5 to ≤9 (on a 0–10 Numerical Rating Scale) were randomized (1:1:1) to receive single IA injections of FX006 32 mg (n = 104) or 16 mg (n = 102) or saline placebo (n = 100). The primary end point was the least squares mean (LSM) change from baseline to week 12 in weekly mean ADP intensity scores for FX006 32 mg versus saline placebo. The investigators reported that the primary end point was not met (LSM change at week 12 −3.1 with FX006 32 mg versus −2.5 with saline placebo; LSM difference [95% confidence interval] −0.58 [−1.22, 0.07]) (P = 0.08). However, improvements in ADP intensity were significantly greater with FX006 32 mg than saline placebo at weeks 1–11 and week 13. Improvements in ADP intensity were significantly greater with FX006 16 mg versus saline placebo at weeks 1–9. A dose‐response effect in duration of maximal analgesic effect was evident (13 weeks with 32 mg versus 9 weeks with 16 mg), with FX006 32 mg providing increased therapeutic benefit relative to FX006 16 mg. All treatments were well tolerated. The investigators concluded that, although the primary end point was not met, their findings indicate a prolonged reduction in symptoms with FX006 with an evident dose response and a safety profile similar to saline placebo.

Bodick et al (2015) stated intra-articular corticosteroids are a mainstay in the treatment of knee osteoarthritis, and in clinical trials, they demonstrate a large initial analgesic effect that wanes over one to four weeks with the rapid efflux of drug from the joint. The present study was undertaken to determine if FX006, an extended-release formulation of triamcinolone acetonide, can provide pain relief that is superior to the current standard of care, immediate-release triamcinolone acetonide. In this Phase-2, double-blind, multicenter study, 228 patients with moderate to severe knee osteoarthritis pain were randomized to a single intra-articular injection of FX006 (containing 10, 40, or 60 mg of triamcinolone acetonide) or 40 mg of immediate-release triamcinolone acetonide. Data on the mean daily pain on the 11-point Numeric Rating Scale were collected over twelve weeks; the primary efficacy end point was the change from baseline to each of eight, ten, and twelve weeks in the weekly mean of the mean daily pain intensity scores analyzed with a longitudinal mixed-effects model. The 10-mg dose of FX006 produced pain relief that was improved relative to immediate-release triamcinolone acetonide at two through twelve weeks, although the difference in pain relief was not significant (p ≥ 0.05). The 40-mg dose of FX006 produced pain relief that was improved at two through twelve weeks and was significantly superior to immediate-release triamcinolone acetonide at five to ten weeks (p < 0.05 at each time point). At the 40-mg dose of FX006, prespecified secondary analyses, including responder analyses and all Western Ontario and McMaster Universities subscales, were significantly superior (p < 0.05) to immediate-release triamcinolone acetonide at eight weeks, and the time-weighted mean pain relief (assessed with mean daily pain intensity scores) was significantly superior to immediate-release triamcinolone acetonide over one to twelve weeks (p = 0.04). The 60-mg dose did not provide additional improvement relative to the 40-mg dose. Adverse events were generally mild and similar across all treatments. The authors concluded that intra-articular injection of FX006, an extended-release formulation of triamcinolone acetonide, provided a clinically relevant improvement in pain relief in patients with knee osteoarthritis relative to immediate-release triamcinolone acetonide, the current standard of care.

Russell, et al. (2018) compared blood glucose levels following intra-articular injection of triamcinolone acetonide extended-release (TA-ER) versus standard triamcinolone acetonide crystalline suspension (TAcs) in patients with knee osteoarthritis and comorbid type 2 diabetes. In this double-blind, randomized, parallel-group, phase 2 study (NCT02762370), 33 patients with knee osteoarthritis (American College of Rheumatology criteria) and type 2 diabetes mellitus (HbA1c 6.5-9.0% [48-75 mmol/mol]; 1-2 oral hypoglycemic agents) were treated with intra-articular TA-ER (32 mg n = 18) or TAcs 40 mg (n = 15). Continuous glucose monitoring-measured glucose (CGMG) was assessed from 1 week pre-injection through 2 weeks post-injection. Endpoints included change in average daily CGMG from baseline (days -3 to -1) to days 1-3 post-injection (CGMGdays1-3) (primary) and percent time average hourly CGMG levels remained in prespecified glycemic ranges. The change CGMGdays1-3 was significantly lower following TA-ER versus TAcs (14.7 vs 33.9 mg/dl, least-squares-mean-difference [95% CI]: -19.2 [-38.0, -0.4]; P = 0.0452). The clinical significance of this difference in this transient difference in average daily CGMG levels between TA-ER and TAcs is unknown. The percentage of time over days 1-3 that CGMG was in the target glycemic range (70-180 mg/dl) was numerically greater for TA-ER (63.3%) versus TAcs (49.7%), and that CGMG was >180 mg/dl was lower for TA-ER (34.5%) vs TAcs (49.9%) (statistical significance of these differences not tested). Non-glycemic adverse events were mild and comparable between groups

Percutaneous Calcium Phosphate Injections

Chatterjee et al (2015) noted that injury to sub-chondral bone is associated with knee pain and OA. A percutaneous calcium phosphate injection is a novel approach in which sub-chondral bone marrow edema lesions are percutaneously injected with calcium phosphate.  In theory, calcium phosphate provides structural support while it is gradually replaced by bone.  However, little clinical evidence supports the effectiveness of percutaneous calcium phosphate injections.  These researchers asked:
  1. Does percutaneous calcium phosphate injection improve validated patient-reported outcome measures?
  2. What proportion of patients experience failure of treatment (defined as a low score on the Tegner Lysholm Knee Scoring Scale)? And
  3. Is there a relationship between outcome and age, sex, BMI, and pre-operative grade of OA?  Between September 2012 and January 2014, these investigators treated 33 patients with percutaneous calcium phosphate injections; 25 satisfied this study inclusion criteria; of those, 3 were lost to follow-up and 22 (88 %; 13 men, 9 women) with a median age of 53.5 years (range of 38 to 70) were available for retrospective chart review and telephone evaluation at a minimum of 6 months (median of 12 months; range of 6 to 24).
The general indications for this procedure were the presence of sub-chondral bone marrow edema lesions observed on MR images involving weight-bearing regions of the knee associated with localized pain on weight-bearing and palpation and failure to respond to conservative therapy (greater than 3 months).  Patients with pain secondary to extensive non-degenerative meniscal tears with a flipped displaced component at the level of bone marrow edema lesions, or with mechanical axis deviation greater than 8° were excluded.  All patients had Grades III or IV chondral lesions (modified Outerbridge grading system for chondromalacia) overlying MRI-identified sub-chondral bone marrow edema lesions.  Percutaneous calcium phosphate injection was performed on the medial tibial condyle (15 patients), the medial femoral condyle (5 patients), and the lateral femoral condyle (2 patients).  Concomitant partial meniscectomy was performed in 18 patients.  Pre-operative and post-operative scores from the KOOS and the Tegner Lysholm Knee Scoring Scale were analyzed.  For patients available for follow-up, the outcome scores improved after treatment.  The KOOS improved from a mean of 39.5 ± 21.8 to 71.3 ± 23 (95 % CI: 18.6 to 45.2; p < 0.001) and the Tegner and Lysholm score from 48 ± 15.1 to 77.5 ± 20.6 (95 % CI: 18.8 to 40.2; p < 0.001).  However, 7 of the 22 patients had poor clinical outcomes as assessed by the Tegner Lysholm Knee Scoring Scale, whereas 3 had fair results, 5 had good results, and 7 had excellent results.  The post-operative Tegner Lysholm score was inversely related to the pre-operative Kellgren-Lawrence OA grade (R(2) = 0.292; F (1.20) = 9.645; p = 0.006).  These researchers found no relationship between outcome scores and age, sex, or BMI.  The authors concluded that in a study that would have been expected to present a best-case analysis (short-term follow-up, loss to follow-up of patients with potentially unsatisfactory results, and use of invasive co-treatments including arthroscopic debridement), the authors found that percutaneous calcium phosphate injection in patients with symptomatic bone marrow edema lesions of the knee and advanced OA yielded poor results in a concerning proportion of patients.  Based on these results, these investigators advised against the use of percutaneous calcium phosphate injections for patients with advanced osteoarthritic changes.

Arthroscopic Meniscal Surgery

In a comparative, prospective, cohort study, Thorlund and co-workers (2017) compared patient reported outcomes from before surgery to 52 weeks after surgery between individuals undergoing arthroscopic partial meniscectomy (APM) for traumatic meniscal tears and those for degenerative meniscal tears.  This study was performed in 4 public orthopedic departments in the Region of Southern Denmark; subject were recruited between February 1, 2013 and January 31, 2014, and at 1 of the original 4 hospitals from February 1, 2014 to January 31, 2015.  Subjects were selected from Knee Arthroscopy Cohort Southern Denmark, aged 18 to 55 years, and undergoing APM for a traumatic or degenerative meniscal tear (defined by a combination of age and symptom onset).  Both participant groups underwent APM for a meniscal tear, with operating surgeons recording relevant information on knee pathology.  Patient reported outcomes were recorded via online questionnaires.  Primary outcome was the average between-group difference in change on 4 of 5 subscales of the KOOS.  The 4 subscales covered pain, symptoms, sport and recreational function, and quality of life (KOOS4).  A 95 % CI excluding differences greater than 10 KOOS points between groups was interpreted as absence of a clinically meaningful difference.  Analyses adjusted for age, sex, and BMI.  A total of 397 eligible adults (42 % women) with a traumatic or degenerative meniscal tear (n = 141, mean age of 38.7 years (SD 10.9); n = 256, 46.6 years (6.4); respectively) were included in the main analysis.  At 52 weeks after APM, 55 (14 %) patients were lost to follow-up.  Statistically, participants with degenerative meniscal tears had a significantly larger improvement in KOOS4 scores than those with traumatic tears (adjusted between-group difference -5.1 (95 % CI: -8.9 to -1.3); p = 0.008).  In the analysis including KOOS4 score at all time-points, a significant time-by-group interaction was observed in both the unadjusted (p = 0.025) and adjusted analysis (p = 0.024), indicating better self-reported outcomes in participants with degenerative tears.  However, the difference between groups was at no time-point considered clinically meaningful.  The authors concluded that these results questioned the current tenet that patients with traumatic meniscal tears experience greater improvements in patient reported outcomes after APM than patients with degenerative tears.

Tornbjerg and colleagues (2017) stated that the relationship between meniscal tears and other joint pathologies with patient-reported symptoms is not clear.  These researchers investigated associations between structural knee pathologies identified at surgery with pre-operative knee pain and function in patients undergoing arthroscopic meniscal surgery.  This study included 443 patients from the Knee Arthroscopy Cohort Southern Denmark (KACS), a prospective cohort following patients 18 years or older undergoing arthroscopic meniscal surgery at 4 hospitals between February 1, 2013 and January 31, 2014.  Patient-reported outcomes, including the KOOS, were obtained by online questionnaires prior to surgery.  Knee pathology was assessed by the operating surgeons using a modified version of the International Society of Arthroscopy, Knee Surgery and Orthopedic Sports Medicine (ISAKOS) classification of meniscal tears questionnaire, supplemented with information extracted from surgery reports.  Following hypothesis-driven pre-selection of candidate variables, backward elimination regressions were performed to investigate associations between patient-reported outcomes and structural knee pathologies.  Regression models only explained a small proportion of the variability in self-reported pain and function (adjusted R2 = 0.10 to 0.12) and this association was mainly driven by age, gender and BMI.  The authors concluded that specific meniscal pathology and other structural joint pathologies found at meniscal surgery were not associated with pre-operative self-reported pain and function in patients with meniscal tears questioning inferences made about a direct relationship between these.  They stated that these findings questioned the role of arthroscopic surgery to address structural pathology as a means to improve patient-reported outcomes in patients having surgery for a meniscal tear.

Monk and associates (2017) stated that arthroscopic surgery of the knee is one of the most frequently performed orthopedic procedures; 1/3 of these procedures are performed for meniscal injuries.  It is essential that this commonly performed surgery be supported by robust evidence.  In a systematic review, these investigators compared the effectiveness of arthroscopic surgery for meniscal injuries in all populations.  These researchers carried out an online search for RCTs and systematic reviews (SRs) that compared therapeutic options for meniscal injury.  The following databases (inception to April 2015) were included in the search: CENTRAL; Medline; Embase; NHS Evidence; National Guideline Clearing House, Database of Abstracts of Reviews of Effects, Health Technology Assessment; ISRCTN; Clinicaltrials.gov; WHO trials platform.  Only studies whose participants were selected on the basis of meniscal injury were included; no restrictions were placed on patient demographics.  Two independent reviewers applied AMSTAR (A Measurement Tool to Assess Systematic Reviews) criteria for SRs and the Cochrane Collaboration risk-of-bias tool for RCTs.  A total of 9 RCTs and 8 SRs were included in the review.  No difference was found between arthroscopic meniscal debridement compared with non-operative management as a 1st-line treatment strategy for patients with knee pain and a degenerative meniscal tear (MD: Knee injury and Osteoarthritis Outcome Score, 1.6 [95 % CI: -2.2 to 5.2], pain VAS, -0.06 [95 % CI: -0.28 to 0.15]).  Some evidence was found to indicate that patients with resistant mechanical symptoms who initially fail non-operative management may benefit from meniscal debridement.  No studies compared meniscal repair with meniscectomy or non-operative management.  Initial evidence suggested that meniscal transplant might be favorable in certain patient groups.  The authors concluded that further evidence is needed to determine which patient groups have good outcomes from each intervention.  Given the current widespread use of arthroscopic meniscal surgeries, more research is needed to support evidence-based practice in meniscal surgery in order to reduce the numbers of ineffective interventions and support potentially beneficial surgery.

In a multi-center, participant-blinded and outcome assessor-blinded RCT, Sihvonen and colleagues (2018) examined if APM is superior to placebo surgery in the treatment of patients with degenerative tear of the medial meniscus.  This trial included a total of 146 adults, aged 35 to 65 years, with knee symptoms consistent with degenerative medial meniscus tear and no knee osteoarthritis; they were randomized to APM or placebo surgery.  The primary outcome was the between-group difference in the change from baseline in the WOMET and Lysholm knee scores and knee pain after exercise at 24 months after surgery.  Secondary outcomes included the frequency of un-blinding of the treatment-group allocation, participants' satisfaction, impression of change, return to normal activities, the incidence of serious adverse events (SAEs) and the presence of meniscal symptoms in clinical examination.  Two subgroup analyses, assessing the outcome on those with mechanical symptoms and those with unstable meniscus tears, were also carried out.  In the intention-to-treat analysis, there were no significant between-group differences in the mean changes from baseline to 24 months in WOMET score: 27.3 in the APM group as compared with 31.6 in the placebo-surgery group (between-group difference, -4.3; 95 % CI: -11.3 to 2.6); Lysholm knee score: 23.1 and 26.3, respectively (-3.2; 95 5 CI: -8.9 to 2.4) or knee pain after exercise, 3.5 and 3.9, respectively (-0.4; 95 % CI: -1.3 to 0.5).  There were no statistically significant differences between the 2 groups in any of the secondary outcomes or within the analyzed subgroups.  The authors concluded that in this 2-year follow-up of patients without knee osteoarthritis but with symptoms of a degenerative medial meniscus tear, the outcomes after APM were no better than those after placebo surgery.  No evidence could be found to support the prevailing ideas that patients with presence of mechanical symptoms or certain meniscus tear characteristics or those who have failed initial conservative treatment are more likely to benefit from APM.  Moreover, they stated that given the mounting evidence, anyone still advocating APMs should promptly launch methodologically rigorous, practical, real-world trial(s) embedded in the flow of practice to prove that APM truly works in the asserted subgroups of patients.

Commenting on the afore-mentioned study by Sihvonen et al (2018), Coblyn (2018) stated that “Researchers reported in 2014 that, in a randomized trial of 146 patients (age range, 35-65) with knee pain and non-traumatic meniscal tears without osteoarthritis, those who underwent arthroscopic partial meniscectomies showed no benefit after 1 year compared with those who underwent sham procedures.  Both groups showed marked improvement in knee pain-related scores, and no significant differences were observed between groups in secondary outcomes (NEJM JW Gen Med Feb 15 2014 and N Engl J Med 2013; 369:2515). Now, the same investigators report a 2-year follow-up.  After 2 years of follow-up, no differences between groups were noted in any of the standardized knee pain scores.  In addition, all secondary outcome scores were similar, including in subgroups of patients with mechanical symptoms and certain meniscus tear characteristics.  This paper extends the conclusion reported earlier: No significant difference in outcomes was found between meniscectomy and a sham procedure among patients with knee pain and meniscal tears without osteoarthritis.  Time and physical therapy should remain the initial treatments for patients like these”.

Balneotherapy for the Treatment of Osteoarthritis of the Knee

In a meta-analysis, Matsumoto and colleagues (2017) examined the effect of balneotherapy on relieving pain and stiffness and improving physical function, compared to controls, among patients with knee OA.  These investigators searched electronic databases for eligible studies published from 2004 to December 31, 2016, with language restrictions of English or Japanese.  They screened publications in Medline, Embase, Cochrane library, and the Japan Medical Abstracts Society Database using two approaches, MeSH terms and free words.  Studies that examined the effect of balneotherapy for treating knee OA of a greater than or equal to 2-week duration were included; WOMAC scores were used as the outcome measure.  A total of 102 publications were assessed according to the exclusion criteria of the study; 8 clinical trial studies, which comprised a total of 359 cases and 375 controls, were included in this meta-analysis.  The meta-analysis analyzed improvement in WOMAC score at the final follow-up visit, which varied from 2 to 12 months post-intervention.  This meta-analysis indicated that balneotherapy was clinically effective in relieving pain and stiffness, and improving function, as assessed by WOMAC score, compared to controls.  However, there was high heterogeneity (88 to 93 %).  The authors concluded that it is possible that balneotherapy may reduce pain and stiffness, and improve function, in individuals with knee OA, although the quality of current publications contributed to the heterogeneity observed in this meta-analysis.

Furthermore, UpToDate reviews on “Management of knee osteoarthritis” (Deveza and Bennell, 2018a) and “Management of moderate to severe knee osteoarthritis” (Deveza and Bennell, 2018b) do not mention balneotherapy as a therapeutic option.

Bone Marrow Aspirate Concentrate

Shapiro and colleagues (2017) hypothesized that bone marrow aspirate concentrate (BMAC) is feasible, safe, and effective for the treatment of pain due to mild-to-moderate degenerative joint disease of the knee.  In this prospective, single-blind, placebo-controlled trial, a total of 25 patients with bilateral knee pain from bilateral OA were randomized to receive BMAC into 1 knee and saline placebo into the other.  A total of 52 ml of bone marrow was aspirated from the iliac crests and concentrated in an automated centrifuge.  The resulting BMAC was combined with platelet-poor plasma for an injection into the arthritic knee and was compared with a saline injection into the contralateral knee, thereby utilizing each patient as his or her own control.  Safety outcomes, pain relief, and function as measured by Osteoarthritis Research Society International (OARSI) measures and the VAS score were tracked initially at 1 week, 3 months, and 6 months after the procedure.  There were no serious adverse events from the BMAC procedure; OARSI Intermittent and Constant Osteoarthritis Pain and VAS pain scores in both knees decreased significantly from baseline at 1 week, 3 months, and 6 months (p ≤ 0.019 for all).  Pain relief, although dramatic, did not differ significantly between treated knees (p > 0.09 for all).  The authors concluded that early results showed that BMAC is safe to use and is a reliable and viable cellular product.  Study patients experienced a similar relief of pain in both BMAC- and saline-treated arthritic knees.  They stated that further study is needed to determine the mechanisms of action, duration of efficacy, optimal frequency of treatments, and regenerative potential.

Combination of High Tibial Osteotomy and Autologous Bone Marrow Derived Cell Implantation

Cavallo and colleagues (2018) stated that high tibial osteotomy (HTO) is a recommended treatment for medial compartment knee OA.  Newer cartilage regenerative procedures may add benefits to the results of HTO.  In this prospective study, these researchers examined the safety and also results of HTO associated with autologous bone marrow derived cells (BMDC) implantation in relatively young and middle aged active individuals with early OA of the knee.  A total of 24 patients (mean age of 47.9 years) with varus knee and symptomatic medial compartment OA were treated with medial opening-wedge HTO in conjunction with implantation of BMDC into the chondral lesions.  The clinical outcomes were assessed by IKDC, KOOS, VAS, and Tegner scores.  The radiographic studies were performed pre-operatively and at follow-ups.  No major complications were seen during the operations and post-operative follow-ups.  All clinical scores were significantly improved for the IKDC score (from 32.7 ± 15 to 64 ± 21) (p < 0.005), KOOS score (from 30 ± 11 to 68 ± 19) (p < 0.005), VAS (from 7.5 to 3) and Tegner score (from 1.2 to 2.1) (p < 0.004).  The authors concluded that HTO in conjunction with BMDC implantation is a safe and feasible treatment and is associated with good results in short-term follow-up for early medial compartment OA in varus knees. Level of evidence: IV.

The authors stated that drawbacks of this preliminary study were the lack of control group, short-term follow-up (2 to 3 years), absence of second look arthroscopy and histological assessment of the regenerated cartilage.  They stated that further RCTs are needed to confirm the clinical advantage of this procedure in early osteoarthritic patients.

Extracorporeal Shock Wave Therapy

Kang and colleagues (2018) noted that bone marrow edema (BME) represents a reversible but highly painful finding in MRI of patients with knee OA.  In a retrospective study, these researchers evaluated the efficacy of extracorporeal shock wave therapy (ESWT) on painful BME in OA of the knee.  This study focused on people who had early-to-mid stage OA with knee pain and MRI findings of BME.  Patients who underwent ESWT or prescribed alendronate treatment in the authors’ department were analyzed.  Knee pain and function were measured using the VAS for pain and the WOMAC, respectively.  The degree of BME was measured with MRI scans.  A total of 126 patients who received ESWT treatment (Group A, n = 82) or alendronate treatment (Group B, n = 44) were included.  All patients were followed-up clinically and radiographically for a minimum of 12 months.  The mean follow-up was 23.5 months (range of 12 to 38 months).  The VAS and WOMAC score decreased more significantly after treatment in Group A than that in Group B (p < 0.01) within 3 months.  In 6-month MRI follow-ups, there was higher incidence of distinct reduction and complete regression of BME of the affected knee in Group A than that in Group B (p < 0.01).  The authors concluded that ESWT is an effective, reliable, and non-invasive treatment in patients with painful BME in OA of the knee followed by a rapid normalization of the MRI appearance.  It has the potential to shorten the natural course of this disease.  Moreover, they stated that multi-center RCTs with long-term outcomes are needed to validate this conclusion.

The authors stated that this study had several drawback.  The mechanisms and indications of ESWT have not been very clear.  The indications are mainly based on the supported literatures and previous clinical observation.  This study was limited by virtue of the retrospective analysis.  There was no randomized and blinded control group with conservative treatment in this study.  Intravenous prostacyclin could achieve a reduction in BME, with a considerable improvement of painful symptoms, by improving tissue blood supply in a variety of situations through multiple mechanisms, such as vasodilatation and inhibition of platelet aggregation.  It is that pain relief and rapid regression of BME due to the action of prostacyclin in reducing capillary permeability and dilating vessels.  Based on this, all patients in both groups were treated with combined alprostadil in this study.  The functional improvement in the knee was assessed subjectively using the VAS and functional scores, but no objective measures were utilized.  The follow-up time was relatively short (23.5 months).  This study was only a pilot clinical study.

Intra-Articular Injections of Autologous Conditioned Serum

Zarringam and colleagues (2018) stated that Orthokin is an intra-articular autologous conditioned serum (ACS).  Its use might have a beneficial biological effect on pain and function of OA in the knee.  However, earlier studies lack any consensus on its clinical application and disease-modifying effect.  In a prospective, cohort study, these investigators examined the long-term effect of Orthokin injection treatment on prevention of surgical treatment for end-stage knee OA.  Patients of the previously published Orthokin cohort were contacted to examine if any intra-articular surgical intervention or osteotomy of the studied knee had taken place during the past decade.  A log-rank test was performed to evaluate the differences in the survival distribution for the 2 types of intervention: Orthokin versus placebo.  The survival distributions for the 2 interventions were not statistically significantly different, χ2(1) = 2.069, p = 0.150.  After 7.5 ± 3.9 years, 46.3 % of the placebo and 40.3 % of the Orthokin group had been treated surgically.  The authors concluded that the use of Orthokin in knee OA patients did not result in a delay regarding surgical treatment.  The intra-articular use of Orthokin did not appear to prevent or delay surgical intervention at 10 years after treatment for end-stage knee OA.

Percutaneous Autologous Fat Injections

In a case-series study, Adriani and colleagues (2017) evaluated the safety and efficacy of autologous aspirated and purified fat tissue injected percutaneously into the knee joint for the treatment of symptomatic OA.  These researchers reviewed 30 patients, who received an autologous percutaneous fat injection for the treatment of knee OA from January 2012 to March 2015.  Mean patients' age was 63.3 ± 5.3 years (range of 50 to 80 years); BMI was 25.1 ± 1.7.  Clinical evaluation was based on pain VAS and WOMAC score for functional and subjective assessment.  These investigators also noted the adverse reactions and the consumption of NSAIDs in the post-treatment period.  All patients reported improvements with respect to pain: average VAS was 7.7 ± 1.2 at baseline, 5.2 ± 0.2 at 1-month follow-up, and 4.3 ± 1 at 3-month follow-up.  A slight deterioration (5.0 ± 1.1) was evidenced at 1 year.  Total WOMAC score was 89.9 ± 1.7 at baseline, 66.3 ± 1 at 1 month, 68.6 ± 1.7 at 3 months, and 73.2 ± 1.8 at 12 months of follow-up.  The authors concluded that these preliminary findings suggested that percutaneous autologous fat injections are a valid therapeutic option for knee OA.  Level of Evidence = IV.  This was a small case-series study (n =30) with short-term follow-up (1 year).  These preliminary findings need to be validated by well-designed studies with long-term follow-up.

Stem Cell Therapy

In a cases-control study, Koh and Choi (2012) examined if isolated mesenchymal stem cells (MSCs) derived from the infra-patellar fat pad could effectively improve clinical results when percutaneously injected into arthritic knees.  A total of 25 stem cell injections combined with arthroscopic debridement were administered to patients with knee OA.  A mean of 1.89 × 10(6) stem cells were prepared with approximately 3.0 ml of platelet-rich plasma (PRP) and injected in the selected knees of patients in the study group.  The mean Lysholm, Tegner activity scale, and VAS scores of patients in the study group improved significantly by the last follow-up visit.  No major adverse events related to the injections were observed during the treatment and follow-up periods.  The results were compared between the study and control groups, in which the patients had undergone arthroscopic debridement and PRP injection without stem cells.  Although the pre-operative mean Lysholm, Tegner activity scale, and VAS scores of the study group were significantly poorer than those of the control group, the clinical results at the last follow-up visit were similar and not significantly different between the 2 groups.  The authors concluded that the short-term results of this study are encouraging and show that infra-patellar fat pad-derived MSC therapy with intra-articular injections is safe, and provides assistance in reducing pain and improving function in patients with knee OA.  These preliminary findings need to be validated by well-designed studies.

Mei and associates (2017) stated that MSC-based cell therapy is a promising avenue for OA treatment.  These researchers evaluated the efficacy of intra-articular injections of culture-expanded allogenic adipose tissue-derived stem cells (ADSCs) for the treatment of anterior cruciate ligament transection (ACLT)-induced rat OA model.  The paracrine effects of major histocompatibility complex (MHC)-unmatched ADSCs on chondrocytes were investigated in-vitro.  Rats were divided into an OA group that underwent ACLT surgery and a sham-operated group that did not undergo ACLT surgery.  Four weeks after surgery mild OA was induced in the OA group.  Subsequently, the OA rats were randomly divided into ADSC and control groups.  A single dose of 1 × 106 ADSCs suspended in 60 μL phosphate-buffered saline (PBS) was intra-articularly injected into the rats of the ADSC group.  The control group received only 60 μL PBS.  Progression of OA was evaluated macroscopically and histologically at 8 and 12 weeks after surgery.  ADSC treatment did not cause any adverse local or systemic reactions.  The degeneration of articular cartilage was significantly weaker in the ADSC group compared to that in the control group at both 8 and 12 weeks.  Chondrocytes were co-cultured with MHC-unmatched ADSCs in trans-wells to assess the paracrine effects of ADSCs on chondrocytes.  Co-culture with ADSCs counteracted the IL-1β-induced mRNA up-regulation of the extracellular matrix-degrading enzymes MMP-3 and MMP-13 and the pro-inflammatory cytokines TNF-α and IL-6 in chondrocytes.  Importantly, ADSCs increased the expression of the anti-inflammatory cytokine IL-10 in chondrocytes.  The authors concluded that the findings of this study indicated that the intra-articular injection of culture-expanded allogenic ADSCs attenuated cartilage degeneration in an experimental rat OA model without inducing any adverse reactions; MHC-unmatched ADSCs protected chondrocytes from inflammatory factor-induced damage.  The paracrine effects of ADSCs on OA chondrocytes are at least part of the mechanism by which ADSCs exert their therapeutic activity.  Moreover, they stated that further studies are needed to validate this hypothesis.

Fan and colleagues (2018) examined the effect and mechanism of pre-cartilaginous stem cells (PSCs) engraftment-inducing tissue repair in a knee OA rat model.  Knee OA model was constructed in Sprague Dawley (SD) rats by partial removal of the medial meniscus of the right knee; PSCs were engrafted by injecting PSCs into the right knee cavity.  At 4 and 8 weeks after model construction, the serum levels of inter-leukine (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 were assessed using enzyme-linked immunosorbent assay (ELISA).  Hematoxylin-eosin (HE) staining was performed to assess the histopathology of synovial membrane and cartilage.  Western blot analysis was used to assess Notch1, Bcl-2 and Bax levels in the articular cartilage.  At 4 and 8 weeks, OA rats demonstrated significantly higher IL-1β, TNF-α, and IL-6 levels than normal rats (p < 0.05), whereas PSCs treatment prominently attenuated IL-1β up-regulation (p < 0.05).  In OA rats, the number of chondrocytes dramatically decreased over time in OA rats, with disruption of chondrocytes organization and cell layers.  PSCs alleviated the deterioration of cartilage, as evidenced by the relatively smooth articular surface, distinct tidemark and clear cell layers.  The model and treatment groups demonstrated substantially higher Notch1 expression.  The Bcl-2/Bax value in the OA rats was lower than the control group, while PSCs treatment led to increase in Bcl-2/Bax value.  The authors concluded that PSCs treatment down-regulated the expression of inflammatory cytokines, alleviating OA in the knee of rats.  Notch1 signaling pathway plays an important role in this ameliorating effect of PSCs treatment.  These findings need to be validated in well-designed studies with human subjects.

In a case-series study, Goncars and associates (2018) evaluated the main symptoms of knee OA and tissue structure changes after a single-dose bone marrow-derived mononuclear cell (BM MNC) intra-articular injection.  Patients with knee OA Kellgren Lawrence (K-L) grade II and III received 1 injection of BM MNC.  The clinical results were analyzed with the KOOS and KSS before, 3, 6, and 12 months after injection.  Radiological evaluation was performed with a calibrated X-ray and MRI before and 6 to 7 months post-injection.  A total of 34 knees were treated with BM MNC injections.  Mean (± SD) age of patient group was 53.96 ± 14.15 years; there were 16 men, 16 women, KL grade II, 16; KL grade III, 18.  The average injected count of BM MNCs was 45.56 ± 34.94 × 106 cells.  At the end-point of 12 months, 65 % of patients still had minimal perceptible clinical improvement of the KOOS total score.  The mean improvement of KOOS total score was +15.3 and of the KSS knee score was +21.45 and the function subscale +27.08 (p < 0.05) points.  The Whole Organ Magnetic Resonance Imaging Score (WORMS) improved from 44.31 to 42.93 points (p < 0.05).  No adverse effects after the BM-MNC injection were observed.  The authors concluded that single-dose BM MNC partially reduced clinical signs of the knee OA stage II/III and in some cases, decreased degenerative changes in the joint building tissue over 12-month period.  This was a small case-series study (n = 34 knees) with short-term follow-ups (12 months).  These preliminary findings need to be validated by well-designed studies with long-term follow-up.

Appendix

Zilretta is administered as a 32 mg single intra-articular injection in the knee. Zilretta is not interchangeable with other formulations of injectable triamcinolone acetonide.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

Arthroscopic debridement:

CPT codes covered if selection criteria are met:

29874 Arthroscopy, knee, surgical; for removal of loose body or foreign body (eg, osteochondritis dissecans fragmentation, chondral fragmentation)

HCPCS codes covered if selection criteria are met:

G0289 Arthroscopy, knee, surgical, for removal of loose body, foreign body, debridement/shaving of articular cartilage (chondroplasty) at the time of other surgical knee arthroscopy in a different compartment of the same knee

ICD-10 codes covered if selection criteria are met:

M17.0 - M17.9 Osteoarthritis of knee
M23.000 - M23.369 Derangement of meniscus due to old tear or injury
M25.561 - M25.569 Pain in knee
M25.661 - M25.669 Stiffness of knee, not elsewhere classified
Q68.6 Discoid meniscus

Arthroscopic partial meniscectomy:

CPT codes covered if selection criteria are met:

29880 Arthroscopy, knee, surgical; with meniscectomy (medial AND lateral, including any meniscal shaving) including debridement/shaving of articular cartilage (chondroplasty), same or separate compartment(s), when performed
29881     with meniscectomy (medial OR lateral, including any meniscal shaving) including debridement/shaving of articular cartilage (chondroplasty), same or separate compartment(s), when performed

CPT codes not covered for indications listed in the CPB (not all-inclusive):

Balneotherapy - no specific code:

0101T Extracorporeal shock wave involving musculoskeletal system, not otherwise specified, high energy
15876 - 15879 Suction assisted lipectomy [for percutaneous autologous fat injections]
20610 - 20611 Arthrocentesis, aspiration and/or injection; major joint or bursa (eg, shoulder, hip, knee joint, subacromial bursa) [bone marrow aspirate concentrate] [intra-articular injections of autologous conditioned serum]
27437 Arthroplasty, patella; without prosthesis [not covered for patellofemoral replacement (arthroplasty)]
27438     with prosthesis [not covered for patellofemoral replacement (arthroplasty)]
27457 Osteotomy, proximal tibia, including fibular excision or osteotomy (includes correction of genu varus [bowleg] or genu valgus [knock-knee]); after epiphyseal closure [Combination of high tibial osteotomy and autologous bone marrow derived cell implantation]
29870 Arthroscopy, knee, diagnostic, with or without synovial biopsy (separate procedure)
29871     for infection, lavage and drainage [not covered for arthroscopic lavage]
29875     synovectomy, limited (eg, plica or shelf resection) (separate procedure) [not covered for patellar denervation]
29877     debridement/shaving of articular cartilage (chondroplasty) [not covered for arthroscopic debridement for persons with osteoarthritis presenting with knee pain only or with severe osteoarthritis (Outerbridge classification III or IV*)]
30286 Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; autologous [ Stem cell therapy]
38232 Bone marrow harvesting for transplantation; autologous [Combination of high tibial osteotomy and autologous bone marrow derived cell implantation] [bone marrow aspirate concentrate]
38241 Hematopoietic progenitor cell (HPC); autologous transplantation [Combination of high tibial osteotomy and autologous bone marrow derived cell implantation] [Stem cell therapy]
96372 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular [for percutaneous autologous fat injections]

HCPCS codes not covered for indications listed in the CPB:

Q9993 Injection, triamcinolone acetonide, preservative-free, extended-release, microsphere formulation, 1 mg

Other HCPCS codes related to the CPB:

C1776 Joint device (implantable)

ICD-10 codes covered if selection criteria are met:

S83.200A - S83.289S Tear of meniscus, current injury

ICD-10 codes not covered for indications listed in the CPB:

M23.200 - M23.269 Derangement of meniscus due to old tear or injury
M25.561 - M25.569 Pain in knee
M25.661 - M25.669 Stiffness of knee, not elsewhere classified

The above policy is based on the following references:

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  2. Baumgaertner MR, Cannon WD Jr, Vittori JM, et al. Arthroscopic debridement of the arthritic knee. Clin Orthop. 1990;(253):197-202.
  3. Ogilvie-Harris DJ, Fitsialos DP. Arthroscopic management of the degenerative knee. Arthroscopy. 1991;7(2):151-157.
  4. Gibson JN, White MD, Chapman VM, Strachan RK. Arthroscopic lavage and debridement for osteoarthritis of the knee. J Bone Joint Surg Br. 1992;74(4):534-537.
  5. Yang SS, Nisonson B. Arthroscopic surgery of the knee in the geriatric patient. Clin Orthop. 1995;(316):50-58.
  6. Moseley JB Jr, Wray NP, Kuykendall D, et al. Arthroscopic treatment of osteoarthritis of the knee: A prospective, randomized, placebo-controlled trial. Results of a pilot study. Am J Sports Med. 1996;24(1):28-34.
  7. Ravaud P, Moulinier L, Giraudeau B, et al. Effects of joint lavage and steroid injection in patients with osteoarthritis of the knee: Results of a multicenter, randomized, controlled trial. Arthritis Rheum. 1999;42(3):475-482.
  8. Kalunian KC, Moreland LW, Klashman DJ, et al. Visually-guided irrigation in patients with early knee osteoarthritis: A multicenter randomized, controlled trial. Osteoarthritis Cartilage. 2000;8(6):412-418.
  9. American College of Rheumatology, Subcommittee on Osteoarthritis Guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum. 2000;43(9):1905-1915.
  10. Outerbridge RE. The etiology of chondromalacia patellae. 1961. Clin Orthop. 2001;(389):5-8.
  11. Fond J, Rodin D, Ahmad S, Nirschl RP. Arthroscopic debridement for the treatment of osteoarthritis of the knee: 2- and 5-year results. Arthroscopy. 2002;18(8):829-834.
  12. Bradley JD, Heilman DK, Katz BP, et al. Tidal irrigation as treatment for knee osteoarthritis: A sham-controlled, randomized, double-blinded evaluation. Arthritis Rheum. 2002;46(1):100-108.
  13. Moseley JB, O'Malley K, Petersen NJ, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med. 2002;347(2):81-88.
  14. Wray NP, Moseley JB, O'Malley K. Authors reply to comments on 'Arthroscopic surgery for osteoarthritis of the knee'. N Engl J Med. 2002;347(21):1718-1719.
  15. Bailey RE. Arthroscopic surgery ineffective for osteoarthritis of the knee. J Fam Pract. 2002;51(10):813.
  16. Bernstein J, Quach T. A perspective on the study of Moseley et al: Questioning the value of arthroscopic knee surgery for osteoarthritis. Cleve Clin J Med. 2003;70(5):401, 405-406, 408-410.
  17. Gillespie WJ. Arthroscopic surgery was not effective for relieving pain or improving function in osteoarthritis of the knee. ACP J Club. 2003;138(2):49.
  18. Jackson RW, Dieterichs C. The results of arthroscopic lavage and debridement of osteoarthritic knees based on the severity of degeneration: A 4- to 6-year symptomatic follow-up. Arthroscopy. 2003;19(1):13-20.
  19. Dervin GF, Stiell IG, Rody K, Grabowski J. Effect of arthroscopic debridement for osteoarthritis of the knee on health-related quality of life. J Bone Joint Surg Am. 2003;85-A(1):10-19.
  20. Centers for Medicare & Medicaid Services (CMS). Arthroscopy for the osteoarthritic knee (#CAG-00167N). National Coverage Analysis (NCA). Baltimore, MD: CMS; July 3, 2003. Available at: http://www.cms.hhs.gov/ncdr/memo.asp?id=7. Accessed July 28, 2003.
  21. Allgood P. Arthroscopic lavage for knee osteoarthritis. In: Bazian, Ltd. Ed. STEER: Succinct and Timely Evaluated Evidence Reviews. Southampton, UK: Wessex Institute for Health Research & Development, University of Southampton; 2003; 3(3). Available at: http://www.signpoststeer.org/. Accessed August 28, 2003.
  22. Forster MC, Straw R. A prospective randomised trial comparing intra-articular Hyalgan injection and arthroscopic washout for knee osteoarthritis. Knee. 2003;10(3):291-293.
  23. Center for Medicare and Medicaid Services (CMS). National Coverage Determination (NCD) for arthroscopic lavage and arthroscopic debridement for the osteoarthritic knee. Medicare Coverage Database. CMS Pub. No. 100-3, Sec. 150.9. Baltimore, MD: CMS; effective June 11, 2004. Available at: http://www.cms.hhs.gov/medlearn/matters/mmarticles/2004/MM3281.pdf. Accessed June 21, 2004.
  24. Calvert GT, Wright RW. The use of arthroscopy in the athlete with knee osteoarthritis. Clin Sports Med. 2005;24(1):133-152.
  25. Pagnano MW, Clarke HD, Jacofsky DJ, et al. Surgical treatment of the middle-aged patient with arthritic knees. Instr Course Lect. 2005;54:251-259.
  26. Laupattarakasem W, Laopaiboon M, Sumananont C. Arthroscopic debridement for knee osteoarthritis (Protocol for Cochrane Review). Cochrane Database Syst Rev. 2005;(1):CD005118.
  27. Ontario Ministry of Health and Long-Term Care, Medical Advisory Secretariat (MAS). Arthroscopic lavage and debridement for osteoarthritis of the knee. Health Technology Literature Review. Toronto, ON: Ontario Ministry of Health and Long-Term Care; September 2005. Available at: http://www.health.gov.on.ca/english/providers/program/mas/tech/reviews/pdf/rev_lavdeb_090105.pdf. Accessed October 12, 2006.
  28. Stuart MJ, Lubowitz JH. What, if any, are the indications for arthroscopic debridement of the osteoarthritic knee? Arthroscopy. 2006;22(3):238-239.
  29. Aaron RK, Skolnick AH, Reinert SE, Ciombor DM. Arthroscopic debridement for osteoarthritis of the knee. J Bone Joint Surg Am. 2006;88(5):936-943.
  30. Siparsky P, Ryzewicz M, Peterson B, Bartz R. Arthroscopic treatment of osteoarthritis of the knee: Are there any evidence-based indications? Clin Orthop Relat Res. 2007;455:107-112.
  31. Samson DJ, Grant MD, Ratko TA, et al. Treatment of primary and secondary osteoarthritis of the knee. Evid Rep Technol Assess (Full Rep). 2007;(157):1-157.
  32. Kirkley A, Birmingham TB, Litchfield RB, et al. A randomized trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med. 2008;359(11):1097-1107.
  33. Englund M, Guermazi A, Gale D, et al. Incidental meniscal findings on knee MRI in middle-aged and elderly persons. N Engl J Med. 2008;359(11):1108-1115.
  34. Marx RG. Arthroscopic surgery for osteoarthritis of the knee? N Engl J Med. 2008;359(11):1169-1170.
  35. Laupattarakasem W, Laopaiboon M, Laupattarakasem P, Sumananont C. Arthroscopic debridement for knee osteoarthritis. Cochrane Database Syst Rev. 2008;(1):CD005118.
  36. American Academy of Orthopaedic Surgeons (AAOS). Clinical practice guideline on the treatment of osteoarthritis of the knee (non-arthroplasty). Rosemont, IL: American Academy of Orthopaedic Surgeons (AAOS); 2008. Available at: http://www.aaos.org/Research/guidelines/OAKguideline.pdf. Accessed January 7, 2009.
  37. Agency for Healthcare Research and Quality (AHRQ). Three treatments for osteoarthritis of the knee: Evidence shows lack of benefit. Clinician’s Guide. Effective Health Care. AHRQ Pub. No. 09-EHC001-3. Rockville, MD: AHRQ; April, 2009. Available at: http://effectivehealthcare.ahrq.gov/repFiles/20090408_OsteoKneeClinician.pdf. Accessed August 31, 2009.
  38. Samson DJ, Grant MD, Ratko TA, et al. Treatment of primary and secondary osteoarthritis of the knee. Evidence Report/Technology Assessment No. 157. Prepared for the Agency for Healthcare Research (AHRQ) by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center (Contract No. 290-02-0026). AHRQ Publication No. 07-E012. Rockville, MD: AHRQ; September 2007. 
  39. Lützner J, Kasten P, Günther KP, Kirschner S. Surgical options for patients with osteoarthritis of the knee. Nat Rev Rheumatol. 2009;5(6):309-316.
  40. Campbell MK, Skea ZC, Sutherland AG, et al.; KORAL study group. Effectiveness and cost-effectiveness of arthroscopic lavage in the treatment of osteoarthritis of  the knee: A mixed methods study of the feasibility of conducting a surgical placebo-controlled trial (the KORAL study). Health Technol Assess. 2010;14(5):1-180.
  41. Reichenbach S, Rutjes AW, Nüesch E, et al. Joint lavage for osteoarthritis of the knee. Cochrane Database Syst Rev. 2010;(5):CD007320.
  42. Howell SM. The role of arthroscopy in treating osteoarthritis of the knee in the older patient. Orthopedics. 2010;33(9):652.
  43. Feeley BT, Gallo RA, Sherman S, Williams RJ. Management of osteoarthritis of the knee in the active patient. J Am Acad Orthop Surg. 2010;18(7):406-416.
  44. Ronn K, Reischl N, Gautier E, Jacobi M. Current surgical treatment of knee osteoarthritis. Arthritis. 2011;2011:454873.
  45. Koh YG, Choi YJ. Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis. Knee. 2012;19(6):902-907.
  46. Herrlin S, Hallander M, Wange P, et al. Arthroscopic or conservative treatment of degenerative medial meniscal tears: A prospective randomised trial. Knee Surg Sports Traumatol Arthrosc. 2007;15(4):393-401.
  47. American Academy of Orthopaedic Surgeons (AAOS). Treatment of osteoarthritis of the knee. Evidence-Based Guidelines, 2nd ed. Adopted by the American Academy of Orthopaedic Surgeons Board of Directors, May 18, 2013. Rosemont, IL: AAOS; 2013.
  48. Katz JN, Brophy RH, Chaisson CE, et al. Surgery versus physical therapy for a meniscal tear and osteoarthritis. N Engl J Med. 2013;368(18):1675-1684.
  49. Sihvonen R, Paavola M, Malmivaara A, et al.;  Finnish Degenerative Meniscal Lesion Study (FIDELITY) Group. Arthroscopic partial meniscectomy versus sham surgery for a degenerative meniscal tear. N Engl J Med. 2013;369(26):2515-2524.

Patellofemoral Replacement (Arthroplasty)

  1. Lonner JH. Patellofemoral arthroplasty. J Am Acad Orthop Surg. 2007;15(8):495-506.
  2. Ackroyd CE, Newman JH, Evans R, et al. The Avon patellofemoral arthroplasty: Five-year survivorship and functional results. J Bone Joint Surg Br. 2007;89(3):310-315.
  3. Luring C, Tingart M, Drescher W, et al. Therapy of isolated arthritis in the patellofemoral joint: Are there evidence-based options? Orthopade. 2011;40(10):902-906.
  4. Davies AP. High early revision rate with the FPV patello-femoral unicompartmental arthroplasty. Knee. 2013;20(6):482-484.
  5. Al-Hadithy N, Patel R, Navadgi B, et al. Mid-term results of the FPV patellofemoral joint replacement. Knee. 2014;21(1):138-141.
  6. Lustig S. Patellofemoral arthroplasty. Orthop Traumatol Surg Res. 2014;100(1 Suppl):S35-S43.
  7. King AH, Engasser WM, Sousa PL, et al. Patellar fracture following patellofemoral arthroplasty. J Arthroplasty. 2015;30(7):1203-1236.

Patellar Denervation

  1. van Jonbergen HP, Scholtes VA, Poolman RW. A randomised, controlled trial of circumpatellar electrocautery in total knee replacement without patellar resurfacing: A concise follow-up at a mean of 3.7 years. Bone Joint J. 2014;96-B(4):473-478.
  2. Handel M, Riedt S, Lechler P, et al. Denervation of the patella: Influence on mid-term results after total knee arthroplasty. Orthopade. 2014;43(2):143-147.
  3. Pulavarti RS, Raut VV, McLauchlan GJ. Patella denervation in primary total knee arthroplasty - a randomized controlled trial with 2 years of follow-up. J Arthroplasty. 2014;29(5):977-981.
  4. Cheng T, Zhu C, Guo Y, et al. Patellar denervation with electrocautery in total knee arthroplasty without patellar resurfacing: A meta-analysis. Knee Surg Sports Traumatol Arthrosc. 2014;22(11):2648-2654.
  5. Li T, Zhou L, Zhuang Q, et al. Patellar denervation in total knee arthroplasty without patellar resurfacing and postoperative anterior knee pain: A meta-analysis of randomized controlled trials. J Arthroplasty. 2014;29(12):2309-2313.
  6. Arirachakaran A, Sangkaew C, Kongtharvonskul J. Patellofemoral resurfacing and patellar denervation in primary total knee arthroplasty. Knee Surg Sports Traumatol Arthrosc. 2015;23(6):1770-1781.
  7. Kwon SK, Nguku L, Han CD, et al. Is electrocautery of patella useful in patella non-resurfacing total knee arthroplasty?: A prospective randomized controlled study. J Arthroplasty. 2015;30(12):2125-2127.

Miscellaneous Interventions

  1. American Academy of Orthopaedic Surgeons (AAOS). Surgical management of osteoarthritis of the knee: evidence-based clinical practice guideline. Rosemont (IL): American Academy of Orthopaedic Surgeons (AAOS); December 4, 2015. Available at: http://www.guideline.gov/content.aspx?id=49934&search=intra-articular+injection+AND+osteoarthritis+of+the+knee+. Accessed June 17, 2016.
  2. Henriksen M, Christensen R, Klokker L, et al. Evaluation of the benefit of corticosteroid injection before exercise therapy in patients with osteoarthritis of the knee: A randomized clinical trial. JAMA Intern Med. 2015;175(6):923-930.
  3. Chatterjee D, McGee A, Strauss E, et al. Subchondral calcium phosphate is ineffective for bone marrow edema lesions in adults with advanced osteoarthritis. Clin Orthop Relat Res. 2015;473(7):2334-2342.
  4. Sihvonen R, Englund M, Turkiewicz A, Jarvinen TL, for the Finnish Degenerative Meniscal Lesion Study Group. Mechanical symptoms and arthroscopic partial meniscectomy in patients with degenerative meniscus tear: A secondary analysis of a randomized trial. Ann Intern Med. 2016;164(7):449-455.
  5. Thorlund JB, Englund M, Christensen R, et al. Patient reported outcomes in patients undergoing arthroscopic partial meniscectomy for traumatic or degenerative meniscal tears: Comparative prospective cohort study. BMJ. 2017;356:j356.
  6. Tornbjerg SM, Nissen N, Englund M, et al. Structural pathology is not related to patient-reported pain and function in patients undergoing meniscal surgery. Br J Sports Med. 2017;51(6):525-530.
  7. Monk P, Garfjeld Roberts P, Palmer AJ, et al. The urgent need for evidence in arthroscopic meniscal surgery. Am J Sports Med. 2017;45(4):965-973.
  8. Matsumoto H, Hagino H, Hayashi K, et al. The effect of balneotherapy on pain relief, stiffness, and physical function in patients with osteoarthritis of the knee: A meta-analysis. Clin Rheumatol. 2017;36(8):1839-1847.
  9. Shapiro SA, Kazmerchak SE, Heckman MG, et al. A prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis. Am J Sports Med. 2017;45(1):82-90.
  10. Adriani E, Moio M, Di Paola B, et al. Percutaneous fat transfer to treat knee osteoarthritis symptoms: Preliminary results. Joints. 2017;5(2):89-92.
  11. Mei L, Shen B, Ling P, et al. Culture-expanded allogenic adipose tissue-derived stem cells attenuate cartilage degeneration in an experimental rat osteoarthritis model. PLoS One. 2017;12(4):e0176107.
  12. Sihvonen R, Paavola M, Malmivaara A, et al; FIDELITY (Finnish Degenerative Meniscal Lesion Study) Investigators. Arthroscopic partial meniscectomy versus placebo surgery for a degenerative meniscus tear: A 2-year follow-up of the randomised controlled trial. Ann Rheum Dis. 2018;77(2):188-195.
  13. Coblyn JS. More evidence that meniscal tears might not require surgery. NEJM Journal Watch. March 1, 2018. Available at: https://www.jwatch.org/na46172/2018/03/01/more-evidence-meniscal-tears-might-not-require-surgery.
  14. Deveza LA, Bennell K. Management of knee osteoarthritis. UpToDate Inc., Waltham, MA. Last reviewed May 2018a.
  15. Deveza LA, Bennell K. Management of moderate to severe knee osteoarthritis. UpToDate Inc., Waltham, MA. Last reviewed May 2018b.
  16. Cavallo M, Sayyed-Hosseinian SH, Parma A, et al. Combination of high Tibial osteotomy and autologous bone Marrow derived cell implantation in early osteoarthritis of knee: A preliminary study. Arch Bone Jt Surg. 2018;6(2):112-118.
  17. Kang S, Gao F, Han J, et al. Extracorporeal shock wave treatment can normalize painful bone marrow edema in knee osteoarthritis: A comparative historical cohort study. Medicine (Baltimore). 2018;97(5):e9796.
  18. Zarringam D, Bekkers JEJ, Saris DBF. Long-term effect of injection treatment for osteoarthritis in the knee by Orthokin autologous conditioned serum. Cartilage. 2018;9(2):140-145.
  19. Fan MP, Si M, Li BJ, et al. Cell therapy of a knee osteoarthritis rat model using precartilaginous stem cells. Eur Rev Med Pharmacol Sci. 2018;22(7):2119-2125.
  20. Goncars V, Kalnberzs K, Jakobsons E, et al. Treatment of knee osteoarthritis with bone marrow-derived mononuclear cell injection: 12-month follow-up. Cartilage. 2018 Jan 1 [Epub ahead of print].
  21. Flexion Therapeutics, Inc., Zilretta (triamcinolone acetonide extended-release injectable suspension), for intra-articular use. Prescribing Information. Burlington, MA:Flexion Therapeutics, Inc.; October 2017.
  22. Bodick N, Lufkin J, Willwerth C, et al. An intra-articular, extended-release formulation of triamcinolone acetonide prolongs and amplifies analgesic effect in patients with osteoarthritis of the knee: A randomized clinical trial. J Bone Joint Surg Am.2015;97(11):877-88.
  23. Conaghan PG, Cohen SB, Berenbaum F, et al. Brief report: A phase IIb trial of a novel extended-release microsphere formulation of triamcinolone acetonide for intraarticular injection in knee osteoarthritis. Arthritis Rheumatol. 2018;70(2):204-211.
  24. Conaghan PG, Hunter DJ, Cohen SB, et al; FX006-2014-008 Participating Investigators. Effects of a single intra-articular injection of a microsphere formulation of triamcinolone acetonide on knee osteoarthritis pain: A double-blinded, randomized, placebo-controlled, multinational study. J Bone Joint Surg Am. 2018;100(8):666-677.
  25. Russell SJ, Sala R, Conaghan PG, et al. Triamcinolone acetonide extended-release in patients with osteoarthritis and type 2 diabetes: A randomized, phase 2 study. Rheumatology (Oxford). 2018 Sep 6. [Epub ahead of print]