Steroids for Asthma Now Associated with Brain Atrophy

Published on Aug 31, 2022

High-dose corticosteroids are the most commonly used substance in medicine. There are literally hundreds of clinical diagnoses from asthma to joint pain to chronic skin rashes that will cause you to leave a doctor’s office with a steroid shot or prescription. Despite this common use, we’ve known for many decades that these drugs are trouble. Now a new study suggests that even the low-dose inhaled steroids used by patients with asthma may be causing their brains to atrophy. As I always say, you just can’t make this stuff up.

Corticosteroids 101

Corticosteroids are powerful anti-inflammatories that are similar to substances found in the body, but your body uses about one-millionth the dose of the common commercially available drugs. Hence the milligram doses of corticosteroids commonly used by physicians are massive compared to what your body is used to seeing, which is where the problems with these medications begin. These medications when injected go by names like Depo-Medrol, betamethasone, dexamethasone, triamcinolone, methylprednisolone, Celestone, and Kenalog.

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Corticosteroid Side Effects

This is a very long list, so I’ll just touch on a few.

Destroying Cartilage

We’ve known for decades that injecting corticosteroid into joints destroy cartilage. In fact, the first paper on this topic was published in 1951! (1) That was followed by others in the 60s and then a parade of animal studies showing that corticosteroid shots hurt cartilage cells in joints, (2,3). If there was any doubt left that these drugs hurt joints, recently a randomized controlled trial in real patients with knee arthritis showed that patients who got corticosteroid shots for knee arthritis not only showed no improvement over saline injections, but they had an accelerated loss of cartilage (4).

Increased Risk of Infection or Joint Replacement

We’ve also known for a long time that patients who get corticosteroid shots for various types of joint pain or arthritis are at higher risk for infection if they get a joint replacement at some point down the road (5). This is a thing not only for knees but also for hips as well (6). We also know that getting a corticosteroid injection to help knee arthritis pain can increase the likelihood of needing a knee replacement versus not getting this kind of injection (7,11). Hence, corticosteroid injection side effects include increasing the risk of a joint replacement complication or an elevated likelihood of needing one in the first place.

Tendon Damage

Corticosteroid shot side effects include problems with tendon healing. For example, patients who had corticosteroid injections had fewer new blood vessels that could aid in tendon healing (8). In another study, tendon cells in patients getting corticosteroid injections were injured by the medication (9). In a more recent large review, corticosteroid shot side effects in patients undergoing rotator cuff repair included higher retear rates (surgical failure) as well as the need for revision surgery (10).

Systemic Side Effects

Can corticosteroids hurt the whole body? Yes. For example, one study demonstrated that corticosteroids used in epidural injections for back pain worsened osteoporosis in women (12). The same type of injection also wreaks havoc on the cortisol endocrine system which helps to keep you healthy (13). Finally, getting your knee joint injected also messes with your blood sugar, causing it to increase (14).

The New Research on Common Corticosteroids Used to Treat Asthma and Brain Damage

Inhaled corticosteroids are a mainstay of asthma treatment. These inhalers go by the names Fluticasone (Flovent HFA, Arnuity Ellipta), Budesonide (Pulmicort Flexhaler), Mometasone (Asmanex Twisthaler), Beclomethasone (Qvar RediHaler), and Ciclesonide (Alvesco). It has been thought that since these medications have corticosteroids in the microgram dose range (1,000 times less than the normal milligram dose range) that they are generally safe. However, is that true?

My first exposure to problems with inhaled corticosteroids came from a young otherwise healthy patient who was using them for esophageal inflammation. He had developed osteonecrosis (his hip bone was dying and crumbling) and this medication was his only risk factor. At first, I thought the medication and his problems couldn’t be related, but when I looked up the research, much to my surprise, inhaled corticosteroids were associated with impaired bone metabolism, osteonecrosis, and osteoporosis (15). That was an eye-opener.

The new research on inhaled corticosteroids and brain damage comes out of the UK Biobank and reviewed patients who used these and other steroid medications between 2006 and 2010 (16). The researchers looked at brain MRIs that had been performed on people aged 40-69 years old and found 557 inhaled corticosteroid users and 24,106 controls who didn’t use these medications. The researchers also included patients who were taking oral or injected steroids (systemic users).

The data showed that both inhaled and systemic use were associated with reduced white matter integrity compared with controls, with larger effect sizes in systemic users. Systemic use was also associated with larger caudate (higher brain functions) while inhaled users had smaller amygdala (emotional integration and motivation) than controls. On questionnaires about their mental health, systemic users performed worse on the symbol digit substitution task and reported more depressive symptoms, disinterest, tenseness/restlessness, and tiredness/lethargy compared with controls. Inhaled users only reported more tiredness/lethargy.

So what would the loss of white matter in the brain cause? These are things usually associated with the elderly, who lose white matter as they age. These symptoms are:

Trouble learning or remembering new things
A hard time with problem solving
Slowed thinking
Depression
Problems walking
Balance issues and more falls

If Replicated, These Findings Will Alter the Face of Modern Medicine

First, inhaled corticosteroids are still about a 1+ billion dollar USD market and that’s with many of these medications coming off patent (17). So don’t expect these drugs to disappear overnight if these effects continue to be seen in other studies. However, this study and others like it hopefully will cause a significant change in medicine from anti-inflammatory sledgehammer drugs that damage normal repair mechanisms to medications that can stimulate healing or modulate inflammation by working with, rather than against, the body’s repair mechanisms.

This is what we have been doing in interventional orthobiologics ever since several of us founded the field to deliver substances like PRP or BMC to various parts of the musculoskeletal system using precise imaging guidance. Now those same substances need to be more widely used in other areas of medicine like asthma. In addition, we’re about to see many new cell drugs and other growth factors and cytokines get FDA approval over the next 5-10 years. This revolution towards substances that work by enhancing repair rather than damaging it should fix this corticosteroid problem.

How fast this revolution occurs depends on an army of patients who refuse to be treated with drugs that we know will cause harm, but are used because they’re covered by a patient’s insurance plan. So this all depends on patients and physicians getting educated on the dangers of corticosteroid use.

The upshot? I’ve been preaching for 20 years that corticosteroids are bad news. We haven’t had a milligram dose steroid in our office for more than a decade and a half. Now it’s time for other physicians to ban the use of these substances on their patients.

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References:

(1) STEINBROCKER O, EHRLICH ME, SILVER M, SICHER W, BERKOWITZ S, CARP S, FEISTEIN H. The clinical application of cortisone and ACTH in arthritis and related conditions: methods and problems. II: Side effects complications, contraindications, precautions and conclusions. Ariz Med. 1951 Sep;8(9):29-35.

(2) Wang BL, Sun W, Shi ZC, et al. Decreased proliferation of mesenchymal stem cells in corticosteroid-induced osteonecrosis of femoral head. Orthopedics. 2008;31(5):444. doi:10.3928/01477447-20080501-33

(3) Bonnevialle N, Bayle X, Projetti F, Wargny M, Gomez-Brouchet A, Mansat P. Variations of the micro-vascularization of the greater tuberosity in patients with rotator cuff tears. Int Orthop. 2015;39(2):371‐376. doi:10.1007/s00264-014-2628-z

(4) McAlindon TE, LaValley MP, Harvey WF, 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.2017;317(19):1967–1975. doi: 10.1001/jama.2017.5283

(5) Richardson SS, Schairer WW, Sculco TP, Sculco PK. Comparison of Infection Risk with Corticosteroid or Hyaluronic Acid Injection Prior to Total Knee Arthroplasty. J Bone Joint Surg Am. 2019 Jan 16;101(2):112-118. doi: 10.2106/JBJS.18.00454.

(6) Ravi B, Escott BG, Wasserstein D, Croxford R, Hollands S, Paterson JM, Kreder HJ, Hawker GA. Intraarticular hip injection and early revision surgery following total hip arthroplasty: a retrospective cohort study. Arthritis Rheumatol. 2015 Jan;67(1):162-8. doi: 10.1002/art.38886.

(7) Wijn SRW, Rovers MM, van Tienen TG, Hannink G. Intra-articular corticosteroid injections increase the risk of requiring knee arthroplasty. Bone Joint J. 2020 May;102-B(5):586-592. doi: 10.1302/0301-620X.

(8) Bonnevialle N, Bayle X, Projetti F, Wargny M, Gomez-Brouchet A, Mansat P. Variations of the micro-vascularization of the greater tuberosity in patients with rotator cuff tears. Int Orthop. 2015;39(2):371‐376. doi:10.1007/s00264-014-2628-z

(9) Dean BJ, Franklin SL, Murphy RJ, Javaid MK, Carr AJ. Glucocorticoids induce specific ion-channel-mediated toxicity in human rotator cuff tendon: a mechanism underpinning the ultimately deleterious effect of steroid injection in tendinopathy?. Br J Sports Med. 2014;48(22):1620‐1626. doi:10.1136/bjsports-2013-093178

(10) Cimino AM, Veazey GC, McMurtrie JT, et al. The Effect of Corticosteroid Injections on Clinical Outcomes and Failure Rates after Rotator Cuff Repair: A Systematic Review [published online ahead of print, 2020 May 7]. Arthroscopy. 2020;S0749-8063(20)30379-0. doi:10.1016/j.arthro.2020.04.044

(11) Cimino AM, Veazey GC, McMurtrie JT, et al. The Effect of Corticosteroid Injections on Clinical Outcomes and Failure Rates after Rotator Cuff Repair: A Systematic Review [published online ahead of print, 2020 May 7]. Arthroscopy. 2020;S0749-8063(20)30379-0. doi:10.1016/j.arthro.2020.04.044

(12) Kang SS, Hwang BM, Son H, Cheong IY, Lee SJ, Chung TY. Changes in bone mineral density in postmenopausal women treated with epidural steroid injections for lower back pain. Pain Physician. 2012 May-Jun;15(3):229-36.

(13) Chon JY, Moon HS. Salivary cortisol concentration changes after epidural steroid injection. Pain Physician. 2012 Nov-Dec;15(6):461-6.

(14) Habib GS. Systemic effects of intra-articular corticosteroids. Clin Rheumatol. 2009;28(7):749‐756. doi:10.1007/s10067-009-1135-x

(15) Chee C, Sellahewa L, Pappachan JM. Inhaled corticosteroids and bone health. Open Respir Med J. 2014 Jan 31;8:85-92. doi: 10.2174/1874306401408010085. PMID: 25674178; PMCID: PMC4319192.

(16) van der Meulen M, Amaya JM, Dekkers OM, et alAssociation between use of systemic and inhaled glucocorticoids and changes in brain volume and white matter microstructure: a cross-sectional study using data from the UK BiobankBMJ Open 2022;12:e062446. doi: 10.1136/bmjopen-2022-062446

(17) Data Bridge Market Research. Global Inhaled Corticosteroids Market – Industry Trends and Forecast to 2029. https://www.databridgemarketresearch.com/reports/global-inhaled-corticosteroids-market Accessed 8/31/22