corticosteroid injections and cartilage toxicity

introduction

As a sports medicine or orthopedic provider, patients often ask about side effects to medications and procedures.  A very frequent question pattern will likely arise and providers should be comfortable answering with an evidence based approach. One of the most common questions that arise with corticosteroid injections are whether or not the corticosteroid injection can wear your knee or cartilage down or if there is a limit to the amount of injections one can get.

Osteoarthritis (OA) is one of the most common chronic and debilitating diseases worldwide, with the knee and the hip being the joints most commonly affected. Intra-articular corticosteroid injections have been used since 1950 to treat arthritis symptoms.  Intra-articular injections are especially individuals who cannot tolerate the side-effects of long-term pharmaceutical therapy with acetaminophen and nonsteroidal anti-inflammatory drugs.

An analysis of the Medicare sample database found that more than one-third of patients with newly diagnosed knee OA were treated with at least one intra-articular corticosteroid injection [1]. Although its exact mechanism of action remains unknown, intra-articular corticosteroid injection (CSI or IACs) is thought to provide pain relief in patients with knee and hip OA by decreasing joint inflammation.

Although its exact mechanism of action remains somewhat unknown, CSIs are thought to provide pain relief in patients with knee and hip OA by decreasing joint inflammation. Short-term complications, including septic arthritis, injection site pain or joint flare, skin pigmentation, and atrophy, and systemic effects are very rare [3].

While meta-analyses have reported IACs may be beneficial in relieving pain, at least for a short period of time (up to 6 weeks after IACs) [3-4], recommendations of its use in management of knee OA varies. For example, the Osteoarthritis Research Society International (OARSI), the American College of Rheumatology (ACR), and the National Institute for Health and Care Excellence (NICE) recommended or conditionally recommended IACs for patients with knee OA [5-7].  However, the American Academy of Orthopaedic Surgeons (AAOS) did not reach a conclusion on its use for the management of knee OA [8].

A 2015 Cochrane Review update described the results of a meta-analysis of 27 clinical trials investigating the efficacy of intra-articular corticosteroid injection to treat knee OA. The meta-analysis concluded that the clinical benefits of intra-articular corticosteroid injection at 1–6 weeks remain unclear due to the low quality of evidence and found no remaining beneficial effect 6 months after injection. Because of limited high-quality clinical data, even the American Academy of Orthopedic Surgeons does not support an evidence-based recommendation that intra-articular corticosteroid injection is an appropriate treatment option for knee and hip OA [3].

While previous in vivo studies have reported a detrimental effect of IACs on cartilage [9-11], there is a paucity of data of the effect of CSIs on joint structure changes among patients with knee OA. The in vivo studies were done on mostly horse and rabbits.  One recent study did show a possible chondroprotective effect of triamcinolone in a dose-dependent manner with very high doses acting as chondrotoxic and chondroprotective in lower doses [16].   Results from two randomized controlled trials assessing the effect of repeated IACs on risk of knee structure change are conflicting [12-13]. 

One trial conducted in the early 2000’s reported that repeated IACs were not associated with change in joint space width (JSW) compared with intra-articular saline [12].  In a randomized, double-blind trial, 68 patients with OA of the knee received injections of triamcinolone acetonide 40 mg (34 patients) or saline (34 patients) into the study knee every 3 months for up to 2 years. The primary outcome variable was radiologic progression of joint space narrowing of the injected knee after 2 years.  This study concluded there were no deleterious effects of the long-term administration of IA steroids on the anatomical structure of the knee.

Another trial conducted recently showed that repeated IACs resulted in greater loss of cartilage volume, albeit the amount of cartilage loss was small and may not be clinically meaningful, compared with intra-articular saline [13].   There were 140 patients (75 women) with a mean age of 58 years.  Intra-articular triamcinolone resulted in significantly greater cartilage volume loss than did saline for a mean change in index compartment cartilage thickness of −0.21 mm vs −0.10 mm.  This was shown on MRI analysis after injections done every 3 months for a 2 year span.  The saline group had 3 treatment-related adverse events compared with 5 in the triamcinolone group and had a small increase in hemoglobin A1c levels [13]. 

2017 pain and function scores

Figure 1.  Pain and function scores from the 2017 McAlindon study.  Adopted from [13].

A 2019 randomized trial by Paik was done with extended release triamcinolone with knees with 323 patients concluded that “a repeat administration of triamcinolone acetonide ER may be similarly efficacious to an initial injection without having deleterious effects on cartilage or other aspects of joint structure [16].”  However, another cohort study of knee ROA, we found that IACs may be associated with an increased risk of knee rapid progression, and the risk appeared larger with continuous IACs use [17]  This study had 148 in the cohort that initiated additional injections due to pain, function or stiffness and 536 in the comparison cohort. 

A special radiology report by Kompel et al. did encourage further studies into understanding further complications, some of which have been mentioned in previous posts.  The report recommends that radiographs should always be obtained prior to performing intra-articular corticosteroid injection in patients with knee and hip OA. Radiographs may show subtle findings of preexisting subchondral insufficiency fracture and osteonecrosis. Review of radiographs and clinical history may also provide important prognostic information and lead to identification of risk factors associated with an unfavorable clinical response to intra-articular corticosteroid injection, including obesity, greater baseline pain and disability, and more severe radiographic OA.

Kompel radiology report and considerations

Figure 2.  Conclusions and considerations from Kompel et al. radiology report .  Adopted from [18].

The report highlighted possible side effects of IACs such as accelerated OA progression, subchondral insufficiency fracture, osteonecrosis, and rapid joint destruction with bone loss.  It includes a detailed overview of each individual adverse joint event. The report concludes that the providers should strive to better understand potential adverse joint events after intra-articular corticosteroid injection to avoid possible complications.

Of note, another recent retrospective evaluation of 682 hips that underwent an IAC with 40 mg of Triamcinolone for primary osteoarthritis of the hip was performed by Streck et. al. [20].  The rate of rapidly progressive osteoarthritis was 0.6%. One case was diagnosed with septic arthritis and treated with staged total hip arthroplasty (THA) and there were no signs of infection at a 5 years follow-up. Four hundred eighty three hips (76%) underwent THA, including 199 hips with THA less than 3 months following IAC and 181 hips with > 1 ICSI prior to THA.  The authors suggested that if IAC is performed under sterile conditions, the risk for septic arthritis or periprosthetic joint infection following THA, even in patients with multiple ICSI or ICSI within 3 months prior to surgery, is minimal [20].

In addition, recent trials compared recurrent IACs with hyaluronic acid (HA), platelet-rich plasma (PRP), saline or orgotein (follow-up 3–24 months). Greater improvements in pain, function and quality of life at 3–24 months were noted for the comparators than with IACs, with comparators demonstrating an equal or superior effect, or the intervention effect attenuated during follow-up. Recurrent IACs demonstrated no benefits in pain or function over placebo at 12–24 months. No serious adverse events were recorded [19].

Summary

In conclusion, intra-articular corticosteroid (IACs) injections are frequently performed with the hope of relieving joint pain. There is still debate on the continued questions involving IACs and chondrotoxicity despite these being a staple in management of osteoarthritis and being done for more than fifty years.  Large retrospective analyses and prospective studies evaluating accelerated osteoarthritis (OA) or joint destruction after IACs injections are lacking. Providers should keep these things in mind when discussing the benefits and risks of IACs.

References

  1. Koenig KM, Ong KL, Lau EC, et al. The Use of Hyaluronic Acid and Corticosteroid Injections Among Medicare Patients With Knee Osteoarthritis. J Arthroplasty 2016;31(2):351–355
  2.  Maricar N, Parkes MJ, Callaghan MJ, et al. Structural predictors of response to intra-articular steroid injection in symptomatic knee osteoarthritis. Arthritis Res Ther 2017;19(1):88.
  3. Jüni P, Hari R, Rutjes AW, et al. Intra-articular corticosteroid for knee osteoarthritis. Cochrane Database Syst Rev 2015
  4. Bannuru, Raveendhara R., et al. “Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis.” Annals of internal medicine 162.1 (2015): 46-54.
  5. Hochberg, Marc C., et al. “American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee.” Arthritis care & research 64.4 (2012): 465-474.
  6. McAlindon, Timothy E., et al. “OARSI guidelines for the non-surgical management of knee osteoarthritis.” Osteoarthritis and cartilage 22.3 (2014): 363-388.
  7. UK, National Clinical Guideline Centre. “Osteoarthritis: care and management in adults.” (2014).
  8. Jevsevar, David S. “Treatment of osteoarthritis of the knee: evidence-based guideline.” JAAOS-Journal of the American Academy of Orthopaedic Surgeons 21.9 (2013): 571-576.
  9. Behrens, F. R. E. D., N. O. R. A. Shepard, and N. E. L. S. O. N. Mitchell. “Alterations of rabbit articular cartilage by intra-articular injections of glucocorticoids.” JBJS 57.1 (1975): 70-76.
  10. MANKIN, HENRY J., and KARL A. CONGER. “The acute effects of intra-articular hydrocortisone on articular cartilage in rabbits.” JBJS 48.7 (1966): 1383-1388.
  11. Murray, Rachel C., et al. “The effects of intra-articular methylprednisolone and exercise on the mechanical properties of articular cartilage in the horse.” Osteoarthritis and cartilage 6.2 (1998): 106-114.
  12. Raynauld, Jean‐Pierre, et al. “Safety and efficacy of long‐term intraarticular steroid injections in osteoarthritis of the knee: A randomized, double‐blind, placebo‐controlled trial.” Arthritis & Rheumatism 48.2 (2003): 370-377.
  13. McAlindon, Timothy E., et al. “Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial.” Jama 317.19 (2017): 1967-1975.
  14. Bliddal, Henning, and Marius Henriksen. “Time to put steroid injections behind us?.” Nature Reviews Rheumatology 13.9 (2017): 519-520.
  15. Duryea, Jeffrey, et al. “Comparison of radiographic joint space width with magnetic resonance imaging cartilage morphometry: analysis of longitudinal data from the Osteoarthritis Initiative.” Arthritis care & research 62.7 (2010): 932-937.
  16. Paik, Julia, Sean T. Duggan, and Susan J. Keam. “Triamcinolone acetonide extended-release: a review in osteoarthritis pain of the knee.” Drugs 79 (2019): 455-462.
  17. Zeng, C., et al. “Intra-articular corticosteroids and the risk of knee osteoarthritis progression: results from the Osteoarthritis Initiative.” Osteoarthritis and cartilage 27.6 (2019): 855-862.
  18. Kompel, Andrew J., et al. “Intra-articular corticosteroid injections in the hip and knee: perhaps not as safe as we thought?.” Radiology 293.3 (2019): 656-663.
  19. Donovan, Richard L., et al. “Effects of recurrent intra-articular corticosteroid injections for osteoarthritis at three months and beyond: a systematic review and meta-analysis in comparison to other injectables.” Osteoarthritis and Cartilage (2022).

Streck, L.E., Braun, S., Spilo, K. et al. How safe are intra-articular corticosteroid injections to the hip?. BMC Musculoskelet Disord 24, 665 (2023).