Systemic and local side-effects of corticosteroid injections including joint destruction

A patient will often come into our office with conflicting ideas about cortisone injections. The patient will tell us that his/her other doctors told them that cortisone injections are safe, effective, and will help their pain, if used sparingly. But, intuitively, the patient had doubts and concerns.

But as this patient continued to wait for a surgery, decisions had to be made as to how much pain management would be needed to “hold them over,” until the surgical date.

Corticosteroids are powerful anti-inflammatory substances. They are not used to relieve pain, but rather, to reduce inflammation, which in turn can lessen a patient’s level of discomfort. Numerous studies over the years have shown that prolonged use of cortisone will eventually cause degenerative joint disease in the joints they are injected into.

Understanding the possible complications of corticosteroid injections

Here are some of the most recent papers reminding doctors about the possible side effects of corticosteroids:

A January 2021 (1) study issued this statement:

“The current evidence would suggest that the use of corticosteroids provides moderate short-term benefit for reducing pain and improving functioning. These benefits generally last several weeks without long-term effectiveness. In addition to its limited short-term effectiveness, there are multiple potential adverse effects including toxicity to articular cartilage and numerous systemic side effects such as increases in blood glucose levels, a reduction in immune function, and an increased risk of infections.”

A December 2020 paper in the medical journal Radiology (2) says this:

• Current management of osteoarthritis is primarily focused on symptom control.
• Intra-articular corticosteroid injections are often used for pain management of hip and knee osteoarthritis in patients who have not responded to oral or topical analgesics.
• “Recent case series suggested that negative structural outcomes including accelerated osteoarthritis progression, subchondral insufficiency fracture (stress fractures in the bone beneath cartilage), complications of pre-existing osteonecrosis, and rapid joint destruction (including bone loss) may be observed in patients who received Intra-articular corticosteroid injections .
• The true cause and natural history of these complications are unclear and require further study. To determine the cause and natural history, large prospective studies evaluating the risk of osteoarthritis or joint destruction after Intra-articular corticosteroid injections are needed.

The research surrounding the corticosteroid side-effects in people with osteoarthritis have been published for decades. But what about the one-time use or judicious use of cortisione injections spread over a long period of time?

Let’s go back to 2010. Researchers wrote in BMC musculoskeletal disorders,(3) “In this literature review it was difficult to accurately quantify the incidence of adverse effects after extra-articular (around the joint) corticosteroid injection. Although one fatal adverse event after an extra-articular corticosteroid injection was reported, extra-articular corticosteroid injections are regularly administered worldwide. In (this study) the incidence of major adverse events  was up to 5.8%, ranging from depigmentation and atrophy of the skin to cellulitis; generally speaking these adverse effects could perhaps be classified as ‘relatively mild’. Based on these data the administration of extra-articular corticosteroid injections seems to be a ‘relatively safe’ intervention.”

The side-effects were mostly limited to the skin area. But what if the cortisone seeped into the bloodstream? Would it create whole body side-effects? What would those side-effects be?

Here are excerpts from Holland-Frei Cancer Medicine. 6th edition. Physiologic and Pharmacologic Effects of Corticosteroids Lorraine I. McKay, PhD and John A. Cidlowski, PhD.

• Corticosteroids are key regulators of whole-body homeostasis (balance) that provide an organism with the capacity to resist environmental changes and invasion of foreign substances. (These are changes and invasion that cause inflammation).
• The effects of corticosteroids are widespread, including profound alterations in carbohydrate, protein, and lipid metabolism, and the modulation of electrolyte and water balance.
• Corticosteroids affect all of the major systems of the body, including the cardiovascular, musculoskeletal, nervous, and immune systems.
• Because so many systems are sensitive to corticosteroid levels, (the body exerts) tight regulatory control on the system.
• The direct effects of corticosteroids are sometimes difficult to separate from their complex relationship with other hormones, in part due to the permissive action of low levels of corticosteroid on the effectiveness of other hormones, (it does not take much corticosteroid to do lot of hormonal and systematic changes in the body).
• The effects of corticosteroids can be classified into two general categories: glucocorticoid (intermediary metabolism, inflammation, immunity, wound healing, myocardial, and muscle integrity) and mineralocorticoid (salt, water, and mineral metabolism).

In this article we will look at the glucocorticoid effects.

• Prolonged exposure to glucocorticoids leads to a diabetic-like state due to the increase in plasma glucose, while low glucocorticoid concentrations lead to hypoglycemia, decreased glycogen stores, and hypersensitivity to insulin.
• The complex mechanisms for the side-effects of glucocorticoids are still unclear, but chronic administration can result in the atrophy of lymphatic tissue and muscle, osteoporosis, and thinning of the skin.
• Glucocorticoids impact lipid metabolism. They act on redistribution of body fat in hypercorticism (also referred to as Cushing syndrome). Large doses of glucocorticoids lead to redistribution of fat to the upper trunk and face, with a concomitant loss of fat in the extremities.
• Glucocorticoid effects on the kidney. The major renal complications of glucocorticoid therapy are nephrocalcinosis (increased calcium in the kidney), nephrolithiasis (kidney stones), and increased stone formation as a result of increased urinary calcium and uric acid.
• High doses of glucocorticoids may cause peptic ulceration or aggravate preexisting ulcers.
• Glucocorticoids influence many factors that modulate blood pressure.
• there is evidence that glucocorticoids make atherosclerosis and thromboembolic complications more severe.
• High glucocorticoid levels cause muscle wasting.
• Chronic glucocorticoid administration results in induction of osteoporosis, a serious limiting factor in the clinical use of steroids.
• Glucocorticoids slow wound healing by blocking the normal inflammatory reaction of breaking down and disorganizing collagen.

These are only a few of the things corticosteroids can do in a hyper level state. But can an injection of cortisone in the knee create any of these side effects?

In 1956 Dr. Martti Oka published a study in the Annals of the Rheumatic Diseases in which he examined the belief that this new treatment (cortisone injections had only been extensively used for 5 years at this time), was strictly a local treatment (stayed in the joint) and had no systemic effects.

Dr. Oka did not find this to be true however he wrote:

• “The results of these experiments show that intra-articularly injected hydrocortisone acetate is absorbed into the circulation to a considerable degree.” In fact the levels were so high that that systemic hormonal effects can be expected if large and frequent doses are used. It should be noted that these effects, Dr. Ok wrote, were transient in nature and lasted only 24 hours.

It was research like Dr. Oka’s that started to pave the way for more judicial uses of cortisone over the many decades since. It is also what lead many to believe that smaller doses of cortisone would not cause systemic problems for more than a very brief period of time.

Gradually, longer term effects were noted. Forty-two years after Dr. Oka’s paper, in the same Annals of the Rheumatic Diseases, (4) doctors in the Netherlands recording these findings in 1998:

• A systemic anti-inflammatory effect of glucocorticoid released from the joint found its way into the circulating blood.

How did it get there? In part by altering white blood cells or altered leucocyte trafficking. This is an alteration of the immune’s response to a hostile invader and/or suppression of release of pro-inflammatory cytokines, these are inflammation makers).

• So by shutting off inflammation, the glucocorticoid snuck into the bloodstream and continued its anti-inflammatory effect throughout the body.

For how long and to what effect did this glucocorticoid impact the body?

• blood methylprednisolone concentration were measured for 96 hours after intra-articular injection of methylprednisolone acetate.
• Significant suppression of the hypothalamic-pituitary-adrenal axis persisted throughout this time.
• After intra-articular injection of methylprednisolone, blood concentrations of glucocorticoid are sufficient to suppress monocyte TNF alpha release (systemic inflammation factors that are part of the healing cycle), for at least four days.

In 2014, Dr. George Habib (5) who has authored many studies trying to find out if, how, and when a cortisone injection into the knee has side-effects throughout the body, found that injection of the glucosteroid methylprednisolone acetate disrupted the hypothalamic-pituitary-adrenal axis in 25% of subject patients receiving the injection for knee osteoarthritis. These were patients who first failed to respond to nonsteroidal anti-inflammatory medications and physical therapy. The disruption was transient, lasting 2 – 4 weeks after the injection.

A disruption of the hypothalamic-pituitary-adrenal axis causes secondary adrenal insufficiency, or Addison disease like symptoms including dehydration, dizziness, fainting, fatigue, lightheadedness, loss of appetite, low blood pressure, low blood sugar, and excessive sweating.

These are symptoms created by free roaming corticosteroids in the blood. From shutting down healing inflammation in the effected joint to other areas of the body and a disruption of the hypothalamic-pituitary-adrenal axis, corticosteroids, as Dr. Oka pointed out in 1956, are not a localized event.

Research October 15, 2019. Steroid injections may lead to joint collapse or hasten the need for total hip or knee replacement.

Here is a study published in the journal Radiology from the Department of Radiology, Boston University School of Medicine (6) “Adverse joint events after intra-articular corticosteroid injection, including accelerated osteoarthritis progression, subchondral insufficiency fracture, complications of osteonecrosis, and rapid joint destruction with bone loss, are becoming more recognized by physicians, including radiologists, who may consider adding these risks to the patient consent.”

“What we wanted to do with our paper is to tell physicians and patients to be careful, because these injections are likely not as safe as we thought.”

In the accompanying press release issued by the Radiological Society of North America, the publishers of the journal Radiology, lead researcher of the study Ali Guermazi, M.D., Ph.D., professor of radiology and medicine at Boston University School of Medicine, found that corticosteroid injections may be associated with complications that potentially accelerate the destruction of the joint and may hasten the need for total hip and knee replacements.

“We’ve been telling patients that even if these injections don’t relieve your pain, they’re not going to hurt you,” Dr. Guermazi said. “But now we suspect that this is not necessarily the case.”

In a review of existing literature on complications after treatment with corticosteroid injections, Dr. Guermazi and colleagues identified four main adverse findings: accelerated osteoarthritis progression with loss of the joint space, subchondral insufficiency fractures (stress fractures that occur beneath the cartilage), complications from osteonecrosis (death of bone tissue), and rapid joint destruction including bone loss.

The researchers recommend careful scrutiny of patients with mild or no osteoarthritis on X-rays who are referred for injections to treat joint pain, especially when the pain is disproportionate to the imaging findings. Prior research has shown that these patients are at risk of developing rapid progressive joint space loss or destructive osteoarthritis after injections. Physicians may also want to reconsider a planned injection when the patient has acute change in pain not explained by X-rays as some underlying condition affecting joint health may be ongoing, the researchers said. Most importantly, younger patients and patients earlier in the course of the disease need to be told of the potential consequences of a corticosteroid injection before they receive it.

“Physicians do not commonly tell patients about the possibility of joint collapse or subchondral insufficiency fractures that may lead to earlier total hip or knee replacement,” Dr. Guermazi said. “This information should be part of the consent when you inject patients with intra-articular corticosteroids.”

With corticosteroid injections so widely used, the potential implications of the study are enormous, according to Dr. Guermazi.

“Intra-articular joint injection of steroids is a very common treatment for osteoarthritis-related pain, but potential aggravation of pre-existing conditions or actual side effects in a subset of patients need to be explored further to better understand the risks associated with it,” Dr. Guermazi said. “What we wanted to do with our paper is to tell physicians and patients to be careful, because these injections are likely not as safe as we thought.”

In a study in the Journal of the American Medical Association (JAMA) doctors found that among patients with knee osteoarthritis, an injection of a corticosteroid every three months over two years resulted in significantly greater cartilage volume loss and no significant difference in knee pain compared to patients who received a placebo injection.

Timothy E. McAlindon, D.M., M.P.H., of Tufts Medical Center, Boston, and colleagues randomly assigned 140 patients with symptomatic knee osteoarthritis with features of synovitis to injections in the joint with the corticosteroid triamcinolone (70 patients) or saline (70 patients) every 12 weeks for two years. The researchers found that injections with triamcinolone resulted in significantly greater cartilage volume loss than did saline and no significant difference on measures of pain. The saline group had three treatment-related adverse events compared with five in the triamcinolone group.(7)

In another study (8) scientists released their findings on the damaging effects of cortisone on cartilage and the inability of hyaluronic acid to repair this damage when used in combination. The idea of combining cortisone and hyaluronic acid is that the intra-articular injection of corticosteroids can treat the inflammatory pain of arthritis and the hyaluronic acid can treat the deleterious effect of these steroids on chondrocyte cells (it disintegrates cartilage).

Hyaluronic acid injections has been suggested as a means to counteract negative side effects through replenishment of synovial fluid that can decrease pain in affected joints. However, combination treatments of steroid and hyaluronic acid have not been completely understood or standardized and are still a matter of concern.(6) It may be better to avoid this treatment because results are lacking is what the study suggested.

Corticosteroids, like cortisone, are powerful anti-inflammatory substances. They are not used to relieve pain, but rather reduce inflammation, which in turn can lessen a patient’s level of discomfort.

Examples of conditions for which local cortisone injections are used include inflammation of a bursa (bursitis), a tendon (tendonitis), and a joint (arthritis). Knee arthritis, hip bursitis, painful foot conditions such as plantar fasciitis, rotator cuff tendinitis and many other conditions may be treated with cortisone injections.

In a study from Italy, researchers noted that local glucocorticoids have shown positive results in some tendinopathies but not in others. moreover, worsening of symptoms, reduction of native healing stem cells in joints , and even spontaneous tendon ruptures has been reported. Several experimental studies suggest that the direct action of glucocorticoids on tendons is detrimental.(9)

The prescribed use of cortisone is dropping

The American Academy of Orthopaedic Surgeons issues frequent guideline updates on the use of corticosteroids. The September 2019 guideline issued this statement:(10)

“Intra-articular corticosteroid injections have been used for decades in the management of symptomatic osteoarthritis of the knee and remain a common practice. The pain relief from a steroid injection is thought to work by reducing inflammation within the arthritic knee. Substantial variability remains among providers with regard to the technique used to perform the procedure, including the site of the injection, the medications injected, and the level of sterility. The success of steroid injections in relieving arthritic knee pain most often occurs in the short term. However, the efficacy of intra-articular corticosteroid injections varies within the published literature. The latest American Academy of Orthopaedic Surgeons clinical practice guideline does not support conclusive recommendations about the use of intra-articular corticosteroid injections for symptomatic knee osteoarthritis. Providers should be aware of the adverse effects and potential complications of these injections when using them in clinical practice.”

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References:

1 Stone S, Malanga GA, Capella T. Corticosteroids: Review of the History, the Effectiveness, and Adverse Effects in the Treatment of Joint Pain. Pain Physician. 2021 Jan;24(S1):S233-S246. PMID: 33492920.
2 Guermazi A, Neogi T, Katz JN, Kwoh CK, Conaghan PG, Felson DT, Roemer FW. Intra-articular Corticosteroid Injections for the Treatment of Hip and Knee Osteoarthritis-related Pain: Considerations and Controversies with a Focus on Imaging—Radiology Scientific Expert Panel. Radiology. 2020 Oct 20:200771.
3 Brinks, A., Koes, B. W., Volkers, A. C., Verhaar, J. A., & Bierma-Zeinstra, S. M. (2010). Adverse effects of extra-articular corticosteroid injections: a systematic review. BMC Musculoskeletal Disorders, 11, 206. http://doi.org/10.1186/1471-2474-11-206
4 Steer JH, Ma DT, Dusci L, Garas G, Pedersen KE, Joyce DA. Altered leucocyte trafficking and suppressed tumour necrosis factor α release from peripheral blood monocytes after intra-articular glucocorticoid treatment. Annals of the rheumatic diseases. 1998 Dec 1;57(12):732-7.
5 Habib G, Jabbour A, Artul S, Hakim G. Intra-articular methylprednisolone acetate injection at the knee joint and the hypothalamic–pituitary–adrenal axis: a randomized controlled study. Clinical rheumatology. 2014 Jan 1;33(1):99-103.
6Andrew J. Kompel, Frank W. Roemer, Akira M. Murakami, Luis E. Diaz, Michel D. Crema, Ali Guermazi Intra-articular Corticosteroid Injections in the Hip and Knee: Perhaps Not as Safe as We Thought? Published Online:Oct 15 2019 https://doi.org/10.1148/radiol.2019190341
7 From the JAMA news department, May 16, 2017
8. Siengdee P, Radeerom T, Kuanoon S, Euppayo T, Pradit W, Chomdej S, Ongchai S, Nganvongpanit K. Effects of corticosteroids and their combinations with hyaluronanon on the biochemical properties of porcine cartilage explants. BMC Vet Res. 2015 Dec 4;11(1):298. doi: 10.1186/s12917-015-0611-6.
9 Abate M, Salini V, Schiavone C, Andia I. Clinical benefits and drawbacks of local corticosteroids injections in tendinopathies. Expert Opin Drug Saf. 2017 Mar;16(3):341-349. doi: 10.1080/14740338.2017.1276561. Epub 2016 Dec 28.