Incidence of Corticosteroid and Hyaluronic Acid Injections and Risk of Hospitalization: A Population-Based Cohort Study (2010–2023)

Incidence of Corticosteroid and Hyaluronic Acid Injections and Risk of Hospitalization: A Population-Based Cohort Study (2010–2023) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Incidence of Corticosteroid and Hyaluronic Acid Injections and Risk of Hospitalization: A Population-Based Cohort Study (2010–2023) Gal Litman, Lee Yaari, Mohamed Kittani, Mustafa Yassin, Barak Haviv This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7728618/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Intra-articular corticosteroid and hyaluronic acid injections are widely used for managing musculoskeletal disorders. Large-scale population-based data assessing the real-world safety of these injections remain limited. The current study evaluates long-term trends of these injections in the general population along with the incidence of acute subsequent hospitalizations. Methods: This was a retrospective, population-based cohort study using data from Clalit Health Services (CHS), Israel's largest health maintenance organization, between January 1, 2010 and December 31, 2023. Adult patients (≥18 years) who received at least one corticosteroid or hyaluronic acid injection were included. Data included demographics, injection characteristics, and clinical comorbidities. The primary outcome was hospitalizations within 30 days of injection due to infection or acute vascular event. Multivariable logistic regression was used to identify predictors of hospitalization. Results: The cohort included 404,797 patients with a mean age of 55±16 years; 55% were female. Injection rates increased from 10.5 to 20.9 per 1,000 individuals between 2010 and 2023. Despite a steady increase in overall injection numbers, hospitalization rates remained low and stable. The Charlson Comorbidity Index (CCI) was the only independent predictor of hospitalization in adjusted models (OR: 11.56; 95% CI: 1.09–122.25; p = 0.04). Conclusion: Despite increased utilization, hospitalization rates following injections remained low. Comorbidity burden, as measured by the Charlson Comorbidity Index, was the strongest predictor of adverse outcomes. These findings support the continued use of corticosteroid injections with careful patient selection and monitoring. Corticosteroids Hyaluronic Acid Epidemiology Hospitalizations Figures Figure 1 Figure 2 Figure 3 Introduction Intra-articular corticosteroid injections are a cornerstone in the management of musculoskeletal and inflammatory conditions, such as osteoarthritis, bursitis, and tendinopathies. They are valued for their potent anti-inflammatory and analgesic properties, which provide rapid symptom relief [1]. Hyaluronic acid injections are also commonly used, particularly for knee osteoarthritis, to restore synovial fluid viscosity and offer longer-term pain relief [2]. Despite their widespread use, concerns have been raised regarding the safety of these interventions, especially in patients with underlying comorbidities. Corticosteroids may induce transient immunosuppression, fluid retention, and hyperglycemia, which can predispose vulnerable individuals to infections and cardiovascular events [3, 4]. Diabetic patients are particularly susceptible to steroid-induced hyperglycemia, which may lead to complications such as diabetic ketoacidosis and acute infections [5]. While some studies have shown low complication rates for joint injections in outpatient settings [6, 7], others have highlighted increased risks in patients with diabetes and multimorbidity [6, 8, 9]. A recent meta-analysis affirmed that while repetitive corticosteroid injections are generally safe, patient-specific factors like comorbidity burden should guide clinical decisions [10]. However, large-scale population-based data assessing the real-world safety of these injections remain limited. This study was designed to address this gap by evaluating injection utilization trends and hospitalization risk, in a large diverse patient population over a 14-year period. Methods Study cohort This was a retrospective, population-based cohort study that used an anonymized electronic database from Clalit Health Services (CHS) in Israel. CHS is Israel's largest health maintenance organization. The study period was from January 1, 2010, to December 31, 2023. All CHS-insured individuals aged 18 years and older were included. The study was approved by the institutional (Rabin Medical Center) ethical committee (0216-24-RMC). All intra-articular and peri-articular injections administered in both outpatient and inpatient settings were identified. For each injection event, the administration date, specific agent, dosage, and injection site were extracted. The cumulative injection counts per patient and the timing of repeat injections were also recorded. Patients with incomplete demographic or clinical data were excluded. The following patient data were extracted: age, sex, region of residence, and comorbid conditions. Comorbidities were summarized using the Charlson Comorbidity Index (CCI), calculated based on diagnostic codes from medical records before the first injection [11]. Diabetes mellitus was analyzed both as a component of the CCI and as an independent variable. The primary outcome was all-cause hospitalization within 30 days of any corticosteroid injection with a principal or secondary discharge diagnosis of either a systemic or musculoskeletal infection or an acute vascular event. ICD-10 diagnosis codes were used to define the outcomes. Data analysis Descriptive statistics were used to characterize the study population and injection patterns over time. The incidence rates of injections and post-injection hospitalizations per 1,000 insured individuals or injections were calculated. Multivariable binary logistic regression was performed to evaluate associations between independent variables and the primary outcome. The independent variables included demographic data, BMI, CCI, diabetes status, number of injections, injection site, and type of agent. Odds ratios (ORs) with 95% confidence intervals (CIs) were reported. A p-value of <0.05 was considered statistically significant. All analyses were performed using SPSS software. Results A total of 404,797 adult patients who received at least one injection were included. The mean age was 55±16 years, with 55% of patients being female. The mean BMI was 28±5 kg/m², and the median CCI was 2 (IQR: 0-23). In total, 22% of the cohort had diabetes mellitus. The most common steroid injections were Betamethasone suspension (66.4%) and Methylprednisolone (29.1%). Hyaluronic acid injections made up a minor proportion of total injections (3.8% Sodium Hyaluronate; 0.7% Hylan G-F 20). Trends in Injection Utilization Over the 14-year study period, the total number of steroid injections rose significantly, from 28,601 in 2010 to 67,523 in 2023, representing a 136% increase (Figure 1). This corresponded to a rise in injection frequency from 10.5 to 20.9 per 1,000 patients. The number of single steroid injections per year fluctuated, showing no consistent upward or downward trend (Figure 2). Diabetic patients consistently accounted for 22% to 25% of single injection recipients annually. The frequency of hyaluronic acid injections remained a minor proportion of total injections, peaking at 465 in 2013 before decreasing to 230 by 2023 (Figure 3). Incidence of Hospitalizations Hospitalizations following a single injection remained rare in both diabetic and non-diabetic groups (Figure 4). Among diabetic patients, the hospitalization incidence ranged from 0.0037 per 1,000 in 2010 to 0.0043 per 1,000 in 2023. Non-diabetic patients showed slightly higher hospitalization rates, ranging from 0.0048 to 0.0143 per 1,000 during the study period. Predictors of Hospitalization Binary logistic regression was performed to identify factors associated with hospitalization within 30 days following injection. The model was statistically significant compared with the null (χ²(39) = 270.436, p < 0.001) but explained only a small proportion of the variance (Cox & Snell R² = 0.009, Nagelkerke R² = 0.058). Model fit was acceptable according to the Hosmer–Lemeshow test (χ²(8) = 5.875, p = 0.661). In the multivariable binary logistic regression model, the Charlson Comorbidity Index (CCI) score was the only independent predictor of hospitalization. A CCI score greater than 4 was significantly associated with hospitalization within the first month after a steroid injection (OR: 11.56, 95% CI: 1.09–122.25, p = 0.04). Other variables, including demographic factors, BMI, diabetes status alone, number of injections, injection site, and type of agent, were not significantly associated with hospitalization in the adjusted model (p > 0.05 for all). Discussion This population-based cohort study spanning 14 years provides comprehensive evidence on the utilization and short-term safety of corticosteroid and hyaluronic acid injections in musculoskeletal care. Despite a 136% increase in injection frequency between 2010 and 2023, hospitalization rates within 30 days post-injection remained low, a finding consistent with multiple large epidemiological studies demonstrating a generally favorable safety profile in real-world clinical settings [8, 9, 12-14]. Recent retrospective cohort studies and meta-analyses based on large health databases confirm these trends. For corticosteroid injections, a 2021 cohort study involving over 22,000 patients found an association between corticosteroid injections and a small but statistically significant increased risk of acute coronary syndromes within the week following injection, though the absolute risk remained low [9]. Another recent study analyzing doses of corticosteroid injections in older adults suggested that even cumulative exposure did not prominently increase fracture risk, indicating that adverse outcomes are rare and tend to be influenced by comorbidity burden rather than single injection events [8]. Meta-analyses comparing the safety and efficacy of steroid injections for common musculoskeletal conditions—including osteoarthritis and tendinopathies—demonstrate that these interventions are well tolerated and rarely result in serious adverse effects [7]. The incidence of acute infections, vascular events, and other serious complications reported in these large datasets aligns closely with the low hospitalization rates observed in the present study. Comprehensive reviews highlight that local side effects can occur, such as post-injection flare, skin hypopigmentation, and atrophy, but are self-limiting and infrequently require hospitalization. Systemic complications are more likely with repeated exposure and higher comorbidity scores, reinforcing the finding that the Charlson Comorbidity Index (CCI) is a robust predictor of adverse outcomes [11]. For hyaluronic acid (HA) injections, numerous population-based studies and systematic reviews report a similarly low incidence of serious adverse events [12, 15]. Registry data show adverse event rates as low as 0.008 overall, with the most common complications being mild and localized, such as injection site pain or swelling. A recent nationwide health insurance database analysis demonstrated that the risk of acute septic arthritis following HA injection is extremely low—usually less than 0.072%—and that single-agent HA injections are generally safer than repeated or combination regimens [12]. Larger observational cohorts confirm that repetitive hyaluronic acid injections do not increase infection rates significantly and may even delay the need for joint replacement surgery, particularly in knee osteoarthritis patients. Combining corticosteroids with hyaluronic acid has shown promise in improving symptomatic relief without increasing adverse event rates [16]. The European Alliance of Associations for Rheumatology (EULAR) established evidence-based recommendations to guide health professionals using intra-articular therapies in adult patients in order to improve safety and quality of care [17]. Taken together, these large-scale studies affirm the key finding of our report: hospitalization and serious adverse events following intra-articular corticosteroid or hyaluronic acid injections remain rare, are strongly associated with comorbidity burden, and are not independently linked to diabetes status, injection site, agent type, or patient demographics. This underscores the critical role of individualized risk stratification using validated tools such as the Charlson Comorbidity Index for optimizing patient safety [18]. Limitations of this, as in many epidemiological studies, include reliance on administrative coding, lack of granular detail on procedural technique, and underreporting of mild adverse events. Despite these, the consistency across diverse populations and healthcare systems strengthens confidence in these conclusions. Prospective studies focused on patient-reported outcomes and long-term follow-up are warranted to further clarify rare risks and optimize guidance for clinicians. In conclusion, corticosteroid and hyaluronic acid injections remain safe and effective interventions for musculoskeletal conditions. Hospitalization risk is primarily driven by comorbidity burden, as measured by the Charlson Comorbidity Index. These findings support continued use of intra-articular injections, with emphasis on individualized patient assessment and targeted monitoring strategies. References Benzon HT, Elmofty D, Shankar H, Rana M, Chadwick AL, Shah S, Souza D, Nagpal AS, Abdi S, Rafla C, Abd-Elsayed A, Doshi TL, Eckmann MS, Hoang TD, Hunt C, Pino CA, Rivera J, Schneider BJ, Stout A, Stengel A, Mina M, FitzGerald JD, Hirsch JA, Wasan AD, Manchikanti L, Provenzano DA, Narouze S, Cohen SP, Maus TP, Nelson AM, Shanthanna H. Use of corticosteroids for adult chronic pain interventions: sympathetic and peripheral nerve blocks, trigger point injections - guidelines from the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, the American Society of Interventional Pain Physician1s, and the International Pain and Spine Intervention Society. Reg Anesth Pain Med. 2025 Mar 12:rapm-2024-105593. Qiao X, Yan L, Feng Y, Li X, Zhang K, Lv Z, Xu C, Zhao S, Liu F, Yang X, Tian Z. Efficacy and safety of corticosteroids, hyaluronic acid, and PRP and combination therapy for knee osteoarthritis: a systematic review and network meta-analysis. BMC Musculoskelet Disord. 2023 Nov 30;24(1):5926. Habib GS. Systemic effects of intra-articular corticosteroids. Clin Rheumatol. 2009 Jul;28(7):749-56. Choudhry MN, Malik RA, Charalambous CP. Blood Glucose Levels Following Intra-Articular Steroid Injections in Patients with Diabetes: A Systematic Review. JBJS Rev. 2016 Mar 22;4(3):e5 Bonaventura A, Montecucco F. Steroid-induced hyperglycemia: An underdiagnosed problem or clinical inertia? A narrative review. Diabetes Res Clin Pract. 2018 May;139:203-220. Cheng J, Abdi S. Complications of Joint, Tendon, and Muscle Injections. Tech Reg Anesth Pain Manag. 2007 Jul;11(3):141-147. Gaujoux-Viala C, Dougados M, Gossec L. Efficacy and safety of steroid injections for shoulder and elbow tendonitis: a meta-analysis of randomised controlled trials. Ann Rheum Dis. 2009 Dec;68(12):1843-9. Sytsma TT, Thomas S, Fischer KM, Greenlund LS. Corticosteroid Injections and Risk of Fracture. JAMA Netw Open. 2024 May 1;7(5):e2414316. Thomas K, Schonmann Y. Orthopaedic corticosteroid injections and risk of acute coronary syndrome: a cohort study. Br J Gen Pract. 2021 Jan 28;71(703):e128-e133. Ayub S, Kaur J, Hui M, Espahbodi S, Hall M, Doherty M, Zhang W. Efficacy and safety of multiple intra-articular corticosteroid injections for osteoarthritis-a systematic review and meta-analysis of randomized controlled trials and observational studies. Rheumatology (Oxford). 2021 Apr 6;60(4):1629-1639. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-83. Honvo G, Reginster JY, Rannou F, Rygaert X, Geerinck A, Rabenda V, McAlindon T, Charles A, Fuggle N, Cooper C, Curtis E, Arden N, Avouac B, Bruyère O. Safety of Intra-articular Hyaluronic Acid Injections in Osteoarthritis: Outcomes of a Systematic Review and Meta-Analys3is. Drugs Aging. 2019 Apr;36(Suppl 1):101-127. Park JG, Sim J, Han SB. Association between intra-articular hyaluronic acid injections in delaying total knee arthroplasty and safety evaluation in primary knee osteoarthritis: analysis based on Health Insurance Review and Assessment Service (HIRA) claim da4tabase in Republic of Korea. BMC Musculoskelet Disord. 2024 Sep 4;25(1):706. Van Boxem K, Rijsdijk M, Hans G, de Jong J, Kallewaard JW, Vissers K, van Kleef M, Rathmell JP, Van Zundert J. Safe Use of Epidural Corticosteroid Injections: Recommendations of the WIP Benelux Work Group. Pain Pract. 2019 Jan;19(1):961-92. Gupta A, Channaveera C, Anand V, Sethi S. An Investigator-Initiated, Prospective, Single-Center, Open-Label Clinical Study to Evaluate Safety and Performance of Intra-Articular Hyaluronic Acid (IA-HA) (Biovisc Ortho) in Patients with Osteoarthritis (OA) of the 2Knee. Clin Pharmacol. 2021 May 11;13:73-82. Smith C, Patel R, Vannabouathong C, Sales B, Rabinovich A, McCormack R, Belzile EL, Bhandari M. Combined intra-articular injection of corticosteroid and hyaluronic acid reduces pain compared to hyaluronic acid alon6e in the treatment of knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2019 7Jun;27(6):1974-1983. Uson J, Rodriguez-García SC, Castellanos-Moreira R, O'Neill TW, Doherty M, Boesen M, Pandit H, Möller Parera I, Vardanyan V, Terslev L, Kampen WU, D'Agostino MA, Berenbaum F, Nikiphorou E, Pitsillidou IA, de la Torre-Aboki J, Carmona L, Naredo E. EULAR recommendations for intra-articular therapies. Ann Rheum Dis. 2021 Oct;80(10):1299-18305. Kamel SI, Rosas HG, Gorbachova T. Local and Systemic Side Effects of Corticosteroid Injections for Musculoskeletal Indications. AJR Am J Roentgenol. 2024 Mar;222(3):e2330458. Additional Declarations No competing interests reported. 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02:19:57","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6568,"visible":true,"origin":"","legend":"","description":"","filename":"e1e98161109f4c858d6b17b94e1ea1c9.json","url":"https://assets-eu.researchsquare.com/files/rs-7728618/v1/1007fdf84ce1201b528386a2.json"},{"id":93732108,"identity":"817fbf52-1225-412e-bef1-f415fcbf046e","added_by":"auto","created_at":"2025-10-17 02:27:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":146162,"visible":true,"origin":"","legend":"\u003cp\u003eTotal Steroid Injections per Year.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7728618/v1/26f6ffaaf445f6c2753d123c.png"},{"id":93730276,"identity":"bb764543-8c3d-4234-be5d-4f9f20680c93","added_by":"auto","created_at":"2025-10-17 02:19:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":184456,"visible":true,"origin":"","legend":"\u003cp\u003eSingle Injections in diabetic and non-diabetic patients.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7728618/v1/37e687086302ec86b45e4572.png"},{"id":93730279,"identity":"959319b7-d60f-4363-957a-70cb64c98d43","added_by":"auto","created_at":"2025-10-17 02:19:57","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":182285,"visible":true,"origin":"","legend":"\u003cp\u003eThe incidence of hyaluronic acid injections per 1,000 patients between 2010 and 2023.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7728618/v1/761fd3067f2071dea2a5f71c.png"},{"id":96245800,"identity":"95d3ff98-1f39-41c0-b7b5-0a94715cc3fb","added_by":"auto","created_at":"2025-11-19 07:22:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":848127,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7728618/v1/c419b80b-33d8-4b0a-b7c2-14b68d8f2bb9.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Incidence of Corticosteroid and Hyaluronic Acid Injections and Risk of Hospitalization: A Population-Based Cohort Study (2010–2023)","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIntra-articular corticosteroid injections are a cornerstone in the management of musculoskeletal and inflammatory conditions, such as osteoarthritis, bursitis, and tendinopathies. They are valued for their potent anti-inflammatory and analgesic properties, which provide rapid symptom relief [1]. Hyaluronic acid injections are also commonly used, particularly for knee osteoarthritis, to restore synovial fluid viscosity and offer longer-term pain relief [2].\u003c/p\u003e\n\u003cp\u003eDespite their widespread use, concerns have been raised regarding the safety of these interventions, especially in patients with underlying comorbidities. Corticosteroids may induce transient immunosuppression, fluid retention, and hyperglycemia, which can predispose vulnerable individuals to infections and cardiovascular events [3, 4]. Diabetic patients are particularly susceptible to steroid-induced hyperglycemia, which may lead to complications such as diabetic ketoacidosis and acute infections [5].\u003c/p\u003e\n\u003cp\u003eWhile some studies have shown low complication rates for joint injections in outpatient settings [6, 7], others have highlighted increased risks in patients with diabetes and multimorbidity [6, 8, 9]. A recent meta-analysis affirmed that while repetitive corticosteroid injections are generally safe, patient-specific factors like comorbidity burden should guide clinical decisions [10]. However, large-scale population-based data assessing the real-world safety of these injections remain limited.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study was designed to address this gap by evaluating injection utilization trends and hospitalization risk, in a large diverse patient population over a 14-year period.\u0026nbsp;\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy cohort\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis was a retrospective, population-based cohort study that used an anonymized electronic database from Clalit Health Services (CHS) in Israel. CHS is Israel's largest health maintenance organization. The study period was from January 1, 2010, to December 31, 2023. All CHS-insured individuals aged 18 years and older were included. The study was approved by the institutional (Rabin Medical Center) ethical committee (0216-24-RMC).\u003c/p\u003e\n\u003cp\u003eAll intra-articular and peri-articular injections administered in both outpatient and inpatient settings were identified. For each injection event, the administration date, specific agent, dosage, and injection site were extracted. The cumulative injection counts per patient and the timing of repeat injections were also recorded. Patients with incomplete demographic or clinical data were excluded.\u003c/p\u003e\n\u003cp\u003eThe following patient data were extracted: age, sex, region of residence, and comorbid conditions. Comorbidities were summarized using the Charlson Comorbidity Index (CCI), calculated based on diagnostic codes from medical records before the first injection [11]. Diabetes mellitus was analyzed both as a component of the CCI and as an independent variable.\u003c/p\u003e\n\u003cp\u003eThe primary outcome was all-cause hospitalization within 30 days of any corticosteroid injection with a principal or secondary discharge diagnosis of either a systemic or musculoskeletal infection or an acute vascular event. ICD-10 diagnosis codes were used to define the outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDescriptive statistics were used to characterize the study population and injection patterns over time. The incidence rates of injections and post-injection hospitalizations per 1,000 insured individuals or injections were calculated. Multivariable binary logistic regression was performed to evaluate associations between independent variables and the primary outcome. The independent variables included demographic data, BMI, CCI, diabetes status, number of injections, injection site, and type of agent. Odds ratios (ORs) with 95% confidence intervals (CIs) were reported. A p-value of \u0026lt;0.05 was considered statistically significant. All analyses were performed using SPSS software.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 404,797 adult patients who received at least one injection were included. The mean age was 55\u0026plusmn;16 years, with 55% of patients being female. The mean BMI was 28\u0026plusmn;5 kg/m\u0026sup2;, and the median CCI was 2 (IQR: 0-23). In total, 22% of the cohort had diabetes mellitus. The most common steroid injections were Betamethasone suspension (66.4%) and Methylprednisolone (29.1%). Hyaluronic acid injections made up a minor proportion of total injections (3.8% Sodium Hyaluronate; 0.7% Hylan G-F 20).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrends in Injection Utilization\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOver the 14-year study period, the total number of steroid injections rose significantly, from 28,601 in 2010 to 67,523 in 2023, representing a 136% increase (Figure 1). This corresponded to a rise in injection frequency from 10.5 to 20.9 per 1,000 patients.\u003c/p\u003e\n\u003cp\u003eThe number of single steroid injections per year fluctuated, showing no consistent upward or downward trend (Figure 2). Diabetic patients consistently accounted for 22% to 25% of single injection recipients annually.\u003c/p\u003e\n\u003cp\u003eThe frequency of hyaluronic acid injections remained a minor proportion of total injections, peaking at 465 in 2013 before decreasing to 230 by 2023 (Figure 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIncidence of Hospitalizations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHospitalizations following a single injection remained rare in both diabetic and non-diabetic groups (Figure 4). Among diabetic patients, the hospitalization incidence ranged from 0.0037 per 1,000 in 2010 to 0.0043 per 1,000 in 2023. Non-diabetic patients showed slightly higher hospitalization rates, ranging from 0.0048 to 0.0143 per 1,000 during the study period.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePredictors of Hospitalization\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBinary logistic regression was performed to identify factors associated with hospitalization within 30 days following injection. The model was statistically significant compared with the null (\u0026chi;\u0026sup2;(39) = 270.436, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001) but explained only a small proportion of the variance (Cox \u0026amp; Snell R\u0026sup2; = 0.009, Nagelkerke R\u0026sup2; = 0.058). Model fit was acceptable according to the Hosmer\u0026ndash;Lemeshow test (\u0026chi;\u0026sup2;(8) = 5.875, \u003cem\u003ep\u003c/em\u003e = 0.661). In the multivariable binary logistic regression model, the Charlson Comorbidity Index (CCI) score was the only independent predictor of hospitalization. A CCI score greater than 4 was significantly associated with hospitalization within the first month after a steroid injection (OR: 11.56, 95% CI: 1.09\u0026ndash;122.25, p = 0.04). Other variables, including demographic factors, BMI, diabetes status alone, number of injections, injection site, and type of agent, were not significantly associated with hospitalization in the adjusted model (p \u0026gt; 0.05 for all).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis population-based cohort study spanning 14 years provides comprehensive evidence on the utilization and short-term safety of corticosteroid and hyaluronic acid injections in musculoskeletal care. Despite a 136% increase in injection frequency between 2010 and 2023, hospitalization rates within 30 days post-injection remained low, a finding consistent with multiple large epidemiological studies demonstrating a generally favorable safety profile in real-world clinical settings [8, 9, 12-14].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRecent retrospective cohort studies and meta-analyses based on large health databases confirm these trends. For corticosteroid injections, a 2021 cohort study involving over 22,000 patients found an association between corticosteroid injections and a small but statistically significant increased risk of acute coronary syndromes within the week following injection, though the absolute risk remained low [9]. Another recent study analyzing doses of corticosteroid injections in older adults suggested that even cumulative exposure did not prominently increase fracture risk, indicating that adverse outcomes are rare and tend to be influenced by comorbidity burden rather than single injection events [8].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMeta-analyses comparing the safety and efficacy of steroid injections for common musculoskeletal conditions—including osteoarthritis and tendinopathies—demonstrate that these interventions are well tolerated and rarely result in serious adverse effects [7]. The incidence of acute infections, vascular events, and other serious complications reported in these large datasets aligns closely with the low hospitalization rates observed in the present study. Comprehensive reviews highlight that local side effects can occur, such as post-injection flare, skin hypopigmentation, and atrophy, but are self-limiting and infrequently require hospitalization. Systemic complications are more likely with repeated exposure and higher comorbidity scores, reinforcing the finding that the Charlson Comorbidity Index (CCI) is a robust predictor of adverse outcomes [11].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor hyaluronic acid (HA) injections, numerous population-based studies and systematic reviews report a similarly low incidence of serious adverse events [12, 15]. Registry data show adverse event rates as low as 0.008 overall, with the most common complications being mild and localized, such as injection site pain or swelling. A recent nationwide health insurance database analysis demonstrated that the risk of acute septic arthritis following HA injection is extremely low—usually less than 0.072%—and that single-agent HA injections are generally safer than repeated or combination regimens [12]. Larger observational cohorts confirm that repetitive hyaluronic acid injections do not increase infection rates significantly and may even delay the need for joint replacement surgery, particularly in knee osteoarthritis patients. Combining corticosteroids with hyaluronic acid has shown promise in improving symptomatic relief without increasing adverse event rates [16]. The European Alliance of Associations for Rheumatology (EULAR) established evidence-based recommendations to guide health professionals using intra-articular therapies in adult patients in order to improve safety and quality of care [17].\u003c/p\u003e\n\u003cp\u003eTaken together, these large-scale studies affirm the key finding of our report: hospitalization and serious adverse events following intra-articular corticosteroid or hyaluronic acid injections remain rare, are strongly associated with comorbidity burden, and are not independently linked to diabetes status, injection site, agent type, or patient demographics. This underscores the critical role of individualized risk stratification using validated tools such as the Charlson Comorbidity Index for optimizing patient safety [18].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLimitations of this, as in many epidemiological studies, include reliance on administrative coding, lack of granular detail on procedural technique, and underreporting of mild adverse events. Despite these, the consistency across diverse populations and healthcare systems strengthens confidence in these conclusions. Prospective studies focused on patient-reported outcomes and long-term follow-up are warranted to further clarify rare risks and optimize guidance for clinicians.\u003c/p\u003e\n\u003cp\u003eIn conclusion, corticosteroid and hyaluronic acid injections remain safe and effective interventions for musculoskeletal conditions. Hospitalization risk is primarily driven by comorbidity burden, as measured by the Charlson Comorbidity Index. These findings support continued use of intra-articular injections, with emphasis on individualized patient assessment and targeted monitoring strategies.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eBenzon HT, Elmofty D, Shankar H, Rana M, Chadwick AL, Shah S, Souza D, Nagpal AS, Abdi S, Rafla C, Abd-Elsayed A, Doshi TL, Eckmann MS, Hoang TD, Hunt C, Pino CA, Rivera J, Schneider BJ, Stout A, Stengel A, Mina M, FitzGerald JD, Hirsch JA, Wasan AD, Manchikanti L, Provenzano DA, Narouze S, Cohen SP, Maus TP, Nelson AM, Shanthanna H. Use of corticosteroids for adult chronic pain interventions: sympathetic and peripheral nerve blocks, trigger point injections - guidelines from the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, the American Society of Interventional Pain Physician1s, and the International Pain and Spine Intervention Society. Reg Anesth Pain Med. 2025 Mar 12:rapm-2024-105593.\u003c/li\u003e\n \u003cli\u003eQiao X, Yan L, Feng Y, Li X, Zhang K, Lv Z, Xu C, Zhao S, Liu F, Yang X, Tian Z. Efficacy and safety of corticosteroids, hyaluronic acid, and PRP and combination therapy for knee osteoarthritis: a systematic review and network meta-analysis. BMC Musculoskelet Disord. 2023 Nov 30;24(1):5926.\u003c/li\u003e\n \u003cli\u003eHabib GS. Systemic effects of intra-articular corticosteroids. Clin Rheumatol. 2009 Jul;28(7):749-56.\u003c/li\u003e\n \u003cli\u003eChoudhry MN, Malik RA, Charalambous CP. Blood Glucose Levels Following Intra-Articular Steroid Injections in Patients with Diabetes: A Systematic Review. JBJS Rev. 2016 Mar 22;4(3):e5\u003c/li\u003e\n \u003cli\u003eBonaventura A, Montecucco F. Steroid-induced hyperglycemia: An underdiagnosed problem or clinical inertia? A narrative review. Diabetes Res Clin Pract. 2018 May;139:203-220.\u003c/li\u003e\n \u003cli\u003eCheng J, Abdi S. Complications of Joint, Tendon, and Muscle Injections. Tech Reg Anesth Pain Manag. 2007 Jul;11(3):141-147.\u003c/li\u003e\n \u003cli\u003eGaujoux-Viala C, Dougados M, Gossec L. Efficacy and safety of steroid injections for shoulder and elbow tendonitis: a meta-analysis of randomised controlled trials. Ann Rheum Dis. 2009 Dec;68(12):1843-9.\u003c/li\u003e\n \u003cli\u003eSytsma TT, Thomas S, Fischer KM, Greenlund LS. Corticosteroid Injections and Risk of Fracture. JAMA Netw Open. 2024 May 1;7(5):e2414316.\u003c/li\u003e\n \u003cli\u003eThomas K, Schonmann Y. Orthopaedic corticosteroid injections and risk of acute coronary syndrome: a cohort study. Br J Gen Pract. 2021 Jan 28;71(703):e128-e133.\u003c/li\u003e\n \u003cli\u003eAyub S, Kaur J, Hui M, Espahbodi S, Hall M, Doherty M, Zhang W. Efficacy and safety of multiple intra-articular corticosteroid injections for osteoarthritis-a systematic review and meta-analysis of randomized controlled trials and observational studies. Rheumatology (Oxford). 2021 Apr 6;60(4):1629-1639.\u003c/li\u003e\n \u003cli\u003eCharlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-83.\u003c/li\u003e\n \u003cli\u003eHonvo G, Reginster JY, Rannou F, Rygaert X, Geerinck A, Rabenda V, McAlindon T, Charles A, Fuggle N, Cooper C, Curtis E, Arden N, Avouac B, Bruyère O. Safety of Intra-articular Hyaluronic Acid Injections in Osteoarthritis: Outcomes of a Systematic Review and Meta-Analys3is. Drugs Aging. 2019 Apr;36(Suppl 1):101-127.\u003c/li\u003e\n \u003cli\u003ePark JG, Sim J, Han SB. Association between intra-articular hyaluronic acid injections in delaying total knee arthroplasty and safety evaluation in primary knee osteoarthritis: analysis based on Health Insurance Review and Assessment Service (HIRA) claim da4tabase in Republic of Korea. BMC Musculoskelet Disord. 2024 Sep 4;25(1):706.\u003c/li\u003e\n \u003cli\u003eVan Boxem K, Rijsdijk M, Hans G, de Jong J, Kallewaard JW, Vissers K, van Kleef M, Rathmell JP, Van Zundert J. Safe Use of Epidural Corticosteroid Injections: Recommendations of the WIP Benelux Work Group. Pain Pract. 2019 Jan;19(1):961-92.\u003c/li\u003e\n \u003cli\u003eGupta A, Channaveera C, Anand V, Sethi S. An Investigator-Initiated, Prospective, Single-Center, Open-Label Clinical Study to Evaluate Safety and Performance of Intra-Articular Hyaluronic Acid (IA-HA) (Biovisc Ortho) in Patients with Osteoarthritis (OA) of the 2Knee. Clin Pharmacol. 2021 May 11;13:73-82.\u003c/li\u003e\n \u003cli\u003eSmith C, Patel R, Vannabouathong C, Sales B, Rabinovich A, McCormack R, Belzile EL, Bhandari M. Combined intra-articular injection of corticosteroid and hyaluronic acid reduces pain compared to hyaluronic acid alon6e in the treatment of knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2019 7Jun;27(6):1974-1983.\u003c/li\u003e\n \u003cli\u003eUson J, Rodriguez-García SC, Castellanos-Moreira R, O'Neill TW, Doherty M, Boesen M, Pandit H, Möller Parera I, Vardanyan V, Terslev L, Kampen WU, D'Agostino MA, Berenbaum F, Nikiphorou E, Pitsillidou IA, de la Torre-Aboki J, Carmona L, Naredo E. EULAR recommendations for intra-articular therapies. Ann Rheum Dis. 2021 Oct;80(10):1299-18305.\u003c/li\u003e\n \u003cli\u003eKamel SI, Rosas HG, Gorbachova T. Local and Systemic Side Effects of Corticosteroid Injections for Musculoskeletal Indications. AJR Am J Roentgenol. 2024 Mar;222(3):e2330458.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Corticosteroids, Hyaluronic Acid, Epidemiology, Hospitalizations","lastPublishedDoi":"10.21203/rs.3.rs-7728618/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7728618/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Intra-articular corticosteroid and hyaluronic acid injections are widely used for managing musculoskeletal disorders. Large-scale population-based data assessing the real-world safety of these injections remain limited. The current study evaluates long-term trends of these injections in the general population along with the incidence of acute subsequent hospitalizations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e This was a retrospective, population-based cohort study using data from Clalit Health Services (CHS), Israel's largest health maintenance organization, between January 1, 2010 and December 31, 2023. Adult patients (≥18 years) who received at least one corticosteroid or hyaluronic acid injection were included. Data included demographics, injection characteristics, and clinical comorbidities. The primary outcome was hospitalizations within 30 days of injection due to infection or acute vascular event. Multivariable logistic regression was used to identify predictors of hospitalization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e The cohort included 404,797 patients with a mean age of 55±16 years; 55% were female. Injection rates increased from 10.5 to 20.9 per 1,000 individuals between 2010 and 2023. Despite a steady increase in overall injection numbers, hospitalization rates remained low and stable. The Charlson Comorbidity Index (CCI) was the only independent predictor of hospitalization in adjusted models (OR: 11.56; 95% CI: 1.09–122.25; p = 0.04).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e Despite increased utilization, hospitalization rates following injections remained low. Comorbidity burden, as measured by the Charlson Comorbidity Index, was the strongest predictor of adverse outcomes. These findings support the continued use of corticosteroid injections with careful patient selection and monitoring.\u003c/p\u003e","manuscriptTitle":"Incidence of Corticosteroid and Hyaluronic Acid Injections and Risk of Hospitalization: A Population-Based Cohort Study (2010–2023)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-17 02:19:53","doi":"10.21203/rs.3.rs-7728618/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8a2c36ac-2826-478d-8b39-fcc208af1821","owner":[],"postedDate":"October 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-15T06:38:41+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-17 02:19:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7728618","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7728618","identity":"rs-7728618","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}