ABSTRACT
Objective
To investigate cumulative corticosteroid (CC) burden in patients with chronic rhinosinusitis with nasal polyps (CRSwNP), with or without coexisting asthma (global airway disease, GAD), referred for biologic treatment, and to assess the prevalence of CC‐related comorbidities, including secondary adrenal insufficiency, osteopenia and/or osteoporosis.
Methods
Prospective cohort study of adults with chronic rhinosinusitis with nasal polyps and/or GAD referred to tertiary care for biologic treatment evaluation: Assessments included DXA scan, corticosteroid case history, Synacthen test, and analyses of cumulative CS exposure (systemic [SCS], inhaled [ICS], and nasal [NCS]) using prescription data.
Results
Of 90 referred patients, 87 (97%) had complete data set and were included in the final cohort. The prevalence of Type 2 diabetes was significantly higher among patients with CRSwNP only compared with GAD (26% vs. 4%, p = 0.019), whereas subclinical adrenal suppression was detected only in the GAD group (6%, 4/70). Rates of osteopenia or osteoporosis were comparable (47% vs. 43%). Higher CC exposure was associated with lower bone mineral density (BMD) at the lumbar spine, femoral neck, and total hip (all p < 0.02). Notably, these rates are considerably higher than those reported for the general Danish population aged ≥ 50 years, in which approximately 21.1% of women and 6.5% of men are estimated to have osteoporosis.
Conclusion
Patients with CRSwNP and GAD had a substantial CC burden from combined systemic, inhaled, and nasal steroid use. This was associated with subclinical adrenal suppression and reduced BMD, while Type 2 diabetes was more prevalent in patients only with CRSwNP.
Level of Evidence
4
Keywords: global airways, secondary adrenal insufficiency, systemic corticosteroids
1. Introduction
Chronic rhinosinusitis (CRS) is a persistent inflammatory disease of the nasal cavity and sinuses, classified into CRS with nasal polyps (CRSwNP) or without polyps (CRSsNP) [1, 2]. In western societies, CRSwNP is commonly driven by Type 2 inflammation (T2). Characterized by eosinophilic infiltration in nasal tissue and/or peripheral eosinophilia, often defined as ≥ 250 cells/μL, though thresholds vary across studies [3]. CRSwNP often coexists with asthma (“global airway disease” [GAD]) [2, 4]. Corticosteroids remain the cornerstone of treatment for both CRSwNP and asthma [5]. For most patients, daily use of nasal corticosteroids (NCS) and inhaled corticosteroids (ICS) is essential to achieving disease control.
Systemic corticosteroids (SCS) are reserved for exacerbations or severe, difficult‐to‐treat disease, despite the increasing availability of CS‐sparing treatments such as biologics and Functional Endoscopic Sinus Surgery (FESS) [2, 4, 6, 7, 8] Although guidelines recommend minimizing SCS in CRSwNP and GAD, its use remains widespread particularly among patients with concomitant T2 diseases [5]. Repeated SCS exposure has been linked to significant adverse outcomes such as secondary adrenal insufficiency (SAI), osteoporosis, and Type 2 diabetes, even at moderate doses [9, 10, 11]. Only 0.1%–2% of topical nasal steroids is absorbed systemically [12], while approximately 20% of ICS are absorbed [13]. However, ICS and topical corticosteroids used for dermatological conditions may negatively affect bone health [14, 15]. Studies showing dose‐dependent associations between corticosteroid exposure and reduced bone mineral density (BMD), and increased fracture risk [14, 15]. This suggest that risk of corticosteroid exposure‐related complications likely increases with simultaneous exposure from multiple administration routes [4]. However, the cumulative corticosteroid (CC) burden, including both systemic and local exposure, and the prevalence of associated comorbidities such as SAI and osteoporosis, remain poorly characterized in patients with CRSwNP and GAD. The objective of this study was to investigate the CC burden in patients with CRSwNP or GAD referred for biologic treatment, and to assess the prevalence of corticosteroid‐related comorbidities, including SAI, bone mineral loss, osteoporosis, and osteopenia.
2. Materials and Methods
2.1. Design
A prospective cross‐sectional study was conducted among consecutive patients referred to the Department of Otorhinolaryngology, Copenhagen University Hospital—Rigshospitalet, for evaluation of biologic therapy between April 2023 and June 2024. Patients were referred from ENT specialists, pulmonologists, or other ENT departments for specialist evaluation of eligibility for biologic therapy for CRSwNP and/or GAD and therefore represent a selected tertiary‐care population.
The study was approved by the Danish Scientific Ethical Committee (H‐22040751) and the Capital Region of Copenhagen's Data Privacy Center (P‐2022‐493). All participants provided written informed consent, and the study adhered to the Declaration of Helsinki. The trial was registered at ClinicalTrials.gov (NCT 05553951).
2.2. Inclusion and Exclusion Criteria
As part of routine clinical practice, all participants underwent a standardized clinical assessment. Adults diagnosed with CRSwNP or GAD who attended the outpatient clinic during the study period and completed the evaluation were included. Exclusion criteria were inability to complete questionnaires, language barriers, or non‐Danish residency without a Danish civil registration number (Figure 1).
FIGURE 1.
Flowchart over enrollment. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com]
2.3. Definitions and Patient‐Reported Outcomes
Demographic data were collected from Statistics Denmark and medical records through the electronic patient journals (Sundhedsplatformen [SP], Epic Systems Inc., USA).
All patients underwent a case history review concerning total corticosteroid exposure (local and systemic) within the last 10 years.
Following questionnaire data were collected from a national registry using RedCap prior to the first screening visit:
2.4. Clinical Examinations
All patients were referred to a DXA scan as part of routine clinical care to assess BMD (g/cm2) at the lumbar spine (L1–L4), total hip, and femoral neck on both sides due to long‐term corticosteroid exposure. Concerning clinical osteoporosis and osteopenia; Osteoporosis was defined as an ICD‐10 diagnosis of osteoporosis (DM80–82), that is, fragility fracture spine or hip and/or a DXA‐scanning T‐score of < −2.5; osteopenia is defined as DXA‐scanning T‐score < −1. Diagnostic codes are listed in Table S1 and osteopenia was defined as a DXA T‐score between −1.0 and –2.5, measured at the lumbar spine, total hip, or femoral neck, according to WHO criteria [20, 21].
To evaluate the adrenal gland function, a standard Synacthen test was performed after ≥ 12 h off ICS/NCS and ≥ 3 months off SCS. A venous catheter was inserted for baseline plasma cortisol sampling (t = 0), followed by intravenous injection of 0.25 mg ACTH and a 5 mL saline flush. After 30 min, a second sample was drawn (t = 30) after discarding the first 2.5 mL to avoid dilution. Samples were analyzed the same day. Patients violating steroid exclusion criteria were retested after 3 months; five patients required retesting, only retest results were included. Normal adrenal function was defined as cortisol > 400 nmol/L, and insufficiency as < 400 nmol/L [22]. SAI was defined by low baseline cortisol and an inadequate or delayed 30‐min response. Those diagnosed with adrenal insufficiency were referred for hydrocortisone replacement. An endocrinologist (PS) reviewed inconclusive Synachten and DXA results for final classification.
2.5. Epidemiological Definitions
Using the nationwide Danish registries, the following data were obtained from the National Patient Registry and/or the National Prescription Registry, encompassing all hospital diagnoses and redeemed prescriptions from 1995 and onwards [23]:
Corticosteroid‐exposure‐related diseases: Using all hospital diagnoses (ICD‐10 codes) 10 years prior to patients' inclusion dates and redeemed prescriptions from 1995 onwards, the occurrence of common corticosteroid‐exposure‐related diseases as defined by Skov et al. [24] was investigated. An overview of diagnosis and prescription codes can be found in Table S2.
- Corticosteroid burden: Using prescription records from 1995 until patients' inclusion dates, prednisolone‐equivalent exposures for inhaled, nasal, and systemic corticosteroids were estimated [25]
-
○For inhaled and nasal corticosteroids, equivalence was based on Majiers et al. [25, 26], where 1000 mcg of budesonide and fluticasone propionate were equivalent to 2 and 5 mg of prednisolone, respectively [25, 26]. For non‐budesonide/fluticasone propionate formulations, budesonide‐equivalent doses [9] were calculated prior to conversion, performed by K.E.J.H.
-
○For systemic corticosteroids, equivalence was based on Meikle et al. [25, 26]. An overview of equivalence can be found in Table S3. Prednisolone‐equivalent estimates for inhaled and intranasal corticosteroids represent a pragmatic measure of cumulative clinical exposure based on published conversion factors derived from human trial data [26]. These estimates do not constitute pharmacokinetic adjustment for formulation‐specific bioavailability, systemic absorption, or interindividual variability.
-
○
Burden prior to specialist management: Cumulative corticosteroid exposure (SCS, ICS, NCS) from 1995 to the first contact with an ENT or respiratory specialist.
2.6. Statistics
Descriptive statistics for demographic and clinical data were obtained from the national Global Airways registry. Continuous variables are presented as mean (SD) or median [25th, 75th percentile], and categorical variables as number (%). Group comparisons used t‐test, Wilcoxon–Mann–Whitney, and chi‐squared or Fisher's exact test (for cell counts < 5).
Bivariate linear regression examined unadjusted associations between cumulative corticosteroid exposure and BMD at different skeletal sites. Multivariable linear regression assessed adjusted associations with CC exposure. Age‐, sex‐, and education‐adjusted odds for SAI, osteoporosis/osteopenia, and osteoporosis were estimated using standard or Firth's logistic regression, the latter applied due to few SAI events. Results are reported as odds ratios (OR) with 95% confidence intervals (CI). Statistical significance was set at p ≤ 0.05. Analyses were conducted in R.
2.7. Power Calculation
In a previous study of severe asthma, 60% of patients who received daily prednisolone (> 5 mg) for 3 months developed adrenal insufficiency (33% complete and 27% partial) [28]. Patients with CRSwNP are typically treated with systemic corticosteroids, receiving on average three courses per year (range 0–9) [29]. For sample size estimation, this treatment pattern was translated into an assumed annual CC exposure, reflecting repeated short courses rather than continuous treatment. This assumption was used solely for sample size estimation and does not reflect observed exposure levels in the present cohort.
SCS is known to be higher in patients with combined CRSwNP and asthma compared to those with CRSwNP alone [30]. Based on these differences, we estimated that the risk of SAI in CRSwNP patients would be approximately half that observed in asthma (≈30%). As some patients had prior SCS, we further adjusted this estimate upward by 25%, resulting in an expected prevalence of ≥ 25% for systemic steroid‐related side effects (bone loss or SAI). In addition, many patients had high‐dose NCS exposure, which—like topical corticosteroid creams—may also contribute to SAI [14].
Based on these assumptions, an expected SAI prevalence of 25% was considered realistic. To detect a difference from the general population (assuming a 25% prevalence, α = 0.05, power = 80%, and a 10% dropout rate), a total sample size of 90 patients was required.
3. Results
We included 89 Danish adults with CRSwNP or GAD; 73% were men with a median age of 52 years [IQR 40–61]. Twenty‐one patients had CRSwNP, while 79% had both CRSwNP and asthma (GAD) (Table 1). Among patients with CRSwNP, 74% (n = 14) had at least one corticosteroid‐related comorbidity, compared to 69% (n = 48) in those with GAD. Type 2 diabetes was significantly more prevalent in CRSwNP (26%) compared to GAD (5.7%, p = 0.019) (Tables 1 and S4).
TABLE 1.
Baseline characteristics of 89 Danish patients with chronic rhinosinusitis with nasal polyps or global airway disease.
| All1 N = 89 | Global airway disease a n = 70 | CRSwNP a N = 19 | p b | |
|---|---|---|---|---|
| Sex | ||||
| Male | 65 (73%) | 51 (73%) | 14 (74%) | > 0.9 |
| Age (years) | 52 [40–61] | 52 [41–61] | 45 [40–59] | 0.5 |
| Education level | ||||
| Primary education | 26 (19%) | 22 (21%) | 4 (13%) | 0.7 |
| Vocational education | 35 (26%) | 25 (24%) | 10 (32%) | |
| Bacherlor's degree or higher | 68 (50%) | 52 (50%) | 16 (52%) | |
| Unknown and others | 7 (5.1%) | 6 (5.7%) | < 4 | |
| Comorbidities | ||||
| Any comorbidity % | 62 (70%) | 48 (69%) | 14 (74%) | 0.7 |
| Number of registered comorbidities | ||||
| 0 | 27 (30%) | 22 (31%) | 6 (26%) | > 0.9 |
| 1 | 24 (27%) | 19 (27%) | 5 (26%) | |
| 2 | 21 (24%) | 16 (23%) | 5 (26%) | |
| 3 | 14 (16%) | 11 (15%) | < 4 | |
| 4 | < 4 | < 4 | < 4 | |
| Individual comorbidities | ||||
| Adrenal insufficiency | < 4 | < 4 | 0 (0%) | < 0.9 |
| Diabetes mellitus, type 2 | 9 (10%) | 4 (5.7%) | 5 (26%) | 0.019 |
| Osteoporosis | 5 (5.6%) | 5 (7.1%) | 0 (0%) | 0.6 |
| Working status | ||||
| Employed | 95 (70%) | 75 (71%) | 20 (65%) | 0.5 |
| Transfer income | 15 (11%) | 12 (11%) | < 4 | |
| Retired | 10 (7.4%) | 6 (5.7%) | 4 (13%) | |
| Unknown and others | 16 (12%) | 12 (11%) | 3 (13%) | |
| Sinonasal burden | ||||
| SNOT‐22 | 62 [49–75] | 64 [47–75] | 60 [53–79] | 0.8 |
| SNOT‐22 ≥ 40 | 78 (88%) | 60 (86%) | 18 (95%) | |
| Severity of CRS (VAS scale) | 85 [75–95] | 52 [75–93] | 90 [78–99] | 0.4 |
| Unknown | 5 | 3 | 2 | |
| Number of FESS prior to inclusion | 2 [1–3] | 2 [1–3] | 2 [1–3] | 0.3 |
| Airway burden | ||||
| FEV1 | 3.53 [2.74–4.24] | 3.49 [2.56–4.22] | 3.54 [3.00–4.60] | 0.12 |
| FEV1 pct | 97 [81–108] | 95 [77–106] | 104 [91–112] | 0.11 |
| FEV1 pct < 80% | 68 (76%) | 52 (74%) | 16 (84%) | 0.5 |
| FeNO | 29 [16–50] | 28 [15–52] | 29 [25–45] | 0.4 |
| ACQ‐5 | 1.90 [0.95–2.85] | 1.80 [1.00–3.00] | N/A | |
| Unknown | 1 | 1 | N/A | |
| ACQ‐5 > 1.5 | 52 (59%) | 41 (59%) | N/A | |
| Unknown | 1 | 1 | N/A | |
| VAS asthma | 60 [49–74] | 60 [50–74] | N/A | |
Abbreviations: ACQ‐5, asthma control questionnaire; FeNO, Fractional exhaled Nitric Oxide; FESS, Functional Endoscopic Sinus Surgery; FEV1, forced expiratory volume in 1 s; VAS of asthma, patient‐reported asthma severity (VAS); VAS of CRSwNP, patient‐reported chronic rhinosinusitis severity (VAS).
Median (IQR); n (%).
Wilcoxon rank sum test; Fisher's exact test; Pearson's chi‐squared test.
3.1. Trends in Annual and Daily Cumulative Corticosteroid Exposure
When assessed longitudinally, within the study population, the proportion of participants receiving corticosteroid increased from 1995 to 2024, regardless of the route of administration. However, among corticosteroid users, the median annual exposure to NCS, ICS, SCS, and CC exposure remained relatively constant over time (Figures 2A,B).
FIGURE 2.
Longitudinal (A) prevalence of use of corticosteroids and (B) average daily/annual exposure stratified by route of administration in 89 patients with chronic rhinosinusitis with nasal polyps or global airway disease referred for biologic treatment. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com]
Prior to specialist follow‐up, CC was lower in patients with CRSwNP compared to those with GAD (median 1331 mg prednisolone‐equivalent [589–2,524] vs. 1,955 mg [IQR: 811–5,321]), although not reaching statistically significance (p = 0.058) (Tables 2 and S2). Daily NCS exposure was significantly lower in CRSwNP than in GAD (101.365 μg [52.059–282.250]) vs (189.027 μg [77.392–624.648]; p < 0.05).
TABLE 2.
Self‐reported corticosteroid exposure and total cumulative corticosteroid exposure, including nasal, inhaled, and systemic routes, before and during specialist management in 78 patients with chronic rhinosinusitis with nasal polyps or global airway disease referred for biologic treatment.
| Characteristic | All a N = 78 | Global airways disease a n = 64 | CRSwNP a n = 14 | p b |
|---|---|---|---|---|
| Self‐reported use of systemic SCS | ||||
| Self ‐reported SCS exposure | 552 [250–1,435] | 750 [252–2,338] | 501 [164–750] | 0.071 |
| Exposure to corticosteroids prior specialist assessment | ||||
| Follow‐up years | 18 [12–22] | 17 [12–22] | 21 [13–23] | 0.3 |
| mg Pred‐eq SCS a exposure prior to specialist | 429 [25–1,208] | 496 [117–921] | 171 [0–1,533] | 0.6 |
| Percent SCS exposure prior to specialist | 33.3 [11.2–82.6] | 31.1 [1.8–75] | 56.4 [0–89] | 0.8 |
| Missing value | 5 | 4 | 1 | |
| mcg Bud‐eq NCS exposure prior to specialist | 185.149 [6.918–538.150] | 189.027 [77.392–624.468] | 101.365 [52.059–282.250] | 0.042 |
| Percent NCS exposure prior to specialist assessment | 24.5 [8.3–488] | 22.1 [6.8–44.8] | 45 [18.2–66.7] | 0.043 |
| mcg Bud‐eq ICS exposure prior to specialist assessment | 242.060 [0–704.032] | 372.000 [83–1,353] | 0 [0–32.5] | < 0.001 |
| Percent ICS exposure prior to specialist assessment | 20.4 [2.7–45.3] | 21.7 [6.7–46.7] | 8.7 [0–23] | 0.2 |
| Missing value | 6 | 0 | 6 | |
| mg Pred‐eq cumulative exposure prior to specialist | 1,870 [768–4,188] | 1,955 [811–5,321] | 1,331 [589–2,524] | 0.058 |
| Percent cumulative exposure prior to specialist | 32.6 [12.8–56.4] | 31.6 [13.0–45.8] | 59.1 [12.3–82.7] | 0.14 |
| Missing value | 1 | 1 | 0 | |
| Exposure of corticosteroid during specialist management | ||||
| mcg Pre d‐eq SCS exposure | 1,250 [617–2,969] | 1,175 [617–3,031] | 1,596 [531–2,873] | 0.8 |
| mcg Bud‐eq NCS exposure | 1,013.432 [448.889–2,132.665] | 1,474.162 [652.242–2,769.581] | 334.790 [259.677–555.294] | < 0.001 |
| mcg Bud‐eq ICS exposure | 1,718 [552–3,747] | 1,994 [1,011–4,130] | 41 [0–237] | < 0.001 |
| mg Pred‐eq Cumulative exposure | 8,006 [3,975–15,385] | 9,611 [5,001–19,080] | 3,405 [1,865–5,126] | < 0.001 |
Note: Exposure is expressed as micrograms (μg) or milligrams (mg) in prednisolone‐equivalent (Pred‐eq) or budesonide‐equivalent (Bud‐eq) doses. Cumulative exposure represents the total corticosteroid burden (SCS + NCS + ICS). Bold formatting is used to indicate statistically significant values.
Abbreviations: SCS, systemic; ICS, inhaled corticosteroids; NCS, nasal.
Median [IQR].
Wilcoxon rank sum test.
During specialist follow‐up, CC exposure (SCS, ICS, and NCS) was significantly lower in patients with CRSwNP compared to those with GAD 3,405 [1,865–5,126] vs 9,611 mg [IQR 5,001–19,080] vs.; p < 0.01) (Tables 2 and S2). Daily NCS exposure was also significantly lower in CRSwNP than in GAD (334.790 μg [259.677–555.294] vs. 1,472.162 μg [652.242–2,769.581]; p < 0.01).
3.2. BMD and Osteoporosis
Median BMD values were generally comparable between patients with CRSwNP and those with GAD, except for lumbar spine BMD, which was significantly lower in GAD (1.16 [1.05–1.27]) compared to those with CRSwNP (1.25 [1.14–1.40]; p < 0.05) (Table 3 and S5).
TABLE 3.
Results of Synachten test (0 and 30 min, delta cortisol) and DXA‐derived bone mineral density (BMD, g/cm2) in 89 patients with chronic rhinosinusitis with nasal polyps or global airway disease referred for biologic treatment.
| All a N = 89 | Global airway dieases a n = 70 | CRSwNP only a n = 19 | p b | |
|---|---|---|---|---|
| Synachten testing | ||||
| Baseline/morning plasma cortisol (nmol/l) | 260 [211–326] | 261 [202–325] | 252 [231–359] | 0.6 |
| Plasma cortisol at 30 min (nmol/l) | 562 [521–609] | 548 [511–600] | 591 [553–643] | 0.043 |
| Cortisol delta < 400 nmol/l | 76 (86%) | 63 (91%) | 13 (68%) | 0.019 |
| DXA scan BMD | ||||
| Lumbar spine BMD (g/cm²) | 1.16 [1.07–1.28] | 1.16 [1.05–1.27] | 1.25 [1.14–1.40] | 0.043 |
| Missing value | < 5 | < 5 | < 5 | |
| Femoral neck BMD (g/cm²) | 0.96 [0.87–1.05] | 0.95 [0.87–1.04] | 1.02 [0.88–1.17] | 0.2 |
| Missing value | < 5 | < 5 | < 5 | |
| Total hip BMD (g/cm²) | 1.01 [0.91–1.13] | 1.01 [0.90–1.11] | 1.07 [0.94–1.20] | 0.3 |
| Missing value | < 5 | < 5 | < 5 | |
Note: Bold formatting is used to indicate statistically significant values.
Median, [IQR], n (%).
Wilcoxon rank sum test, Fisher's exact test.
However, a significant negative correlation was observed between total CC exposure and BMD (g/cm2) at all three measurement sites: lumbar spine (R = −0.35, p = 0.002), femoral neck (R = −0.36, p = 0.002), and total hip (R = −0.28, p = 0.017) (Figure 3A–C).
FIGURE 3.
(A–C) Linear regression analyses between log2‐transformed total cumulative corticosteroid exposure and bone mineral density (BMD) in 87 patients with chronic rhinosinusitis with nasal polyps or global airway disease. (A) Lumbar spine BMD. (B) Femoral neck BMD. (C) Total hip BMD. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com]
3.3. Secondary Adrenal Insufficiency
After exclusion of one patient due to an inconclusive Synacten test (technical difficulties), 30‐min serum cortisol levels were significantly higher in patients with CRSwNP compared to those with GAD (591 nmol/L [553–643] vs. 548 nmol/L [511–600], p < 0.044) (Table 3), indicating partial corticosteroid‐induced suppression. Linear regression showed a weak but significant negative correlation between CC exposure and 30 min cortisol (R 2 = 0.07, p = 0.023; Figure 4B).
FIGURE 4.
(A–D) Linear regression analyses showing associations between log2‐transformed cumulative corticosteroid exposure and serum cortisol levels in 89 patients with chronic rhinosinusitis with nasal polyps or global airway disease. (A) Baseline morning cortisol (0 min). (B) Cortisol after 30 min. (C) Δ cortisol (0–30 min). (D) Serum cortisol at 30 min vs. patient‐reported systemic corticosteroid exposure. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com]
3.4. Associations With Osteoporosis and Adrenal Insufficiency
No covariates were significantly associated with ICD‐10–defined osteoporosis. CC exposure was significantly associated with higher odds of SAI (OR: 1.01, 95% CI: 1.01–1.03; p < 0.001 for every 250 mg increase in cumulative CS exposure) (Table 4). For DXA scan‐defined osteoporosis or osteopenia (based on T‐scores), age showed a borderline association with this outcome (OR: 1.04, 95% CI: 1.00–1.08; p = 0.053), while sex, education, or CC exposure were not significant.
TABLE 4.
Odds ratios (OR, 95% CI) from multivariate logistic regression analyses for osteoporosis, osteoporosis/osteopenia, and secondary adrenal insufficiency in patients with chronic rhinosinusitis with nasal polyps or global airway disease referred for biologic therapy.
| Predictor variable | Osteoporosis OR (95% CI) | p | Osteoporosis/osteopenia OR (95% CI) | p | Secondary adrenal insufficiency OR (95% CI) | p |
|---|---|---|---|---|---|---|
| Age (per year) | 1.01 (0.94–1.15) | 0.70 | 1.04 (1.00–1.08) | 0.053 | 0.97 (0.89–1.04) | 0.40 |
| Female (vs male) | 0.00 (0.00–0.00) | > 0.90 | 1.44 (0.48–4.34) | 0.20 | 0.20 (0.00–1.83) | 0.20 |
| Higher education (vs. primary/vocational) | 1.89 (0.29–15.5) | 0.50 | 0.85 (0.32–2.25) | 0.70 | 1.82 (0.33–12.7) | 0.50 |
| Cumulative CS exposure (per 250 mg) | 1.00 (0.98–1.01) | > 0.90 | 1.00 (0.99–1.01) | 0.60 | 1.01 (1.01–1.03) | < 0.001 |
Note: Predictor variables include age, sex, education, and cumulative corticosteroid exposure (per 250 mg). Bold formatting is used to indicate statistically significant values.
Abbreviations: CI, confidence interval; CS, corticosteroids; OR, exp(β) from logistic regression.
4. Discussion
In this cross‐sectional study of 89 individuals with CRSwNP or GAD referred to tertiary care for evaluation of biologic therapy eligibility, we found considerable CC exposure prior to specialist referral. Prior to first specialist assessment, patients with CRSwNP had lower cumulative CC exposure (1.33 g) compared with those with GAD (1.96 g), corresponding approximately to four–five standard courses of prednisolone (37.5 mg for 10 days), respectively.
Moreover, a substantial proportion of patients exhibited over or subclinical corticosteroid exposure‐related complications, including low BMD and SAI, whereas Type 2 diabetes was more prevalent among those with lower exposure. These findings highlight the considerable corticosteroid exposure in this population and the presence of both clinical and subclinical corticosteroid‐related complications [5].
Higher CC exposure was significantly associated with lower BMD across skeletal sites and increased odds of SAI. However, the prevalence of osteopenia and osteoporosis, defined by ICD‐10 codes or T‐score criteria, was similar in CRSwNP vs GAD (32%, n = 6 vs. 40%, n = 28; p = 0.5), suggesting that both groups may already have exceeded a threshold for impaired bone health. Notably, the rates of osteopenia and osteoporosis in our cohort far exceeded those in the general Danish population aged ≥ 50 years, where approximately 21.1% of women and 6.5% of men are estimated to have osteoporosis [20, 21] where most of the current population was males, which agrees with the frequency between men and women suffering from CRSwNP [20, 21].
Patients with CRSwNP, despite lower corticosteroid exposure than those with GAD, had a higher prevalence of Type 2 diabetes. This finding should be interpreted with caution, as the present study was not designed to assess a causal relationship between CRSwNP and metabolic disease. Price et al. and Håkansson et al. have reported a high prevalence of metabolic comorbidities, including Type 2 diabetes, in both CRSwNP and GAD, reflecting an increased overall comorbidity burden rather than disease‐specific effects [5, 30].
Both prior to and during specialist management, patients with CRSwNP were exposed to substantially lower cumulative doses of corticosteroids than patients with GAD. This aligns with previous findings of greater corticosteroid use among patients with overlapping airway diseases [5, 30]. Price et al. and Håkansson et al. similarly observed that concurrent asthma and CRS are associated with higher CC doses, often prescribed outside specialist settings [5, 30]. Lin et al. found that fragmented care—across general practice, private ENT, and respiratory specialists—contributes to cumulative “stacked” exposure and an increased risk of complications [32]. Davis et al. found that annual systemic corticosteroid doses equivalent to three treatment courses per year in GAD, consistent with our findings, and such exposure exceed levels (> 500 mg lifetime) linked to corticosteroid‐related morbidity [24, 28].
Taken together, these findings illustrate the consequences of CC exposure in both upper and lower airway disease, including skeletal, adrenal, and metabolic effects. They underscore the need for early identification of high‐exposure patients, improved coordination and broader implementation of corticosteroid‐sparing treatments, including biologics that reduce systemic corticosteroid use and the need for FESS surgery. Although EPOS criteria for biologic therapy include systemic steroids use, we question policies requiring such treatment before biologics initiation. Despite the availability of targeted biologics, prolonged or repeated corticosteroid use remains common in patients with T2 diseases [5, 30], possibly due to patients moving between specialists [33, 34].
CC exposure was significantly associated with SAI, consistent with findings in asthma populations. Broersen et al. demonstrated marked interindividual variability in hypothalamic–pituitary–adrenal (HPA) axis suppression [10], while Nachawi et al. and Brennan et al. reported adrenal insufficiency even with low or intermittent corticosteroid regimens [35, 36]. In this study, GAD patients exhibited more pronounced adrenal suppression, likely reflecting greater cumulative exposure. Although overt adrenal insufficiency was uncommon, subclinical suppression—evidenced by blunted 30‐min cortisol responses—may contribute to fatigue, hypotension, and reduced stress tolerance [10].
High CC exposure was associated with lower BMD. This finding is clinically relevant as reduced bone mass increases fracture risk, even without manifest osteoporosis. Wong et al. [15] demonstrated a significant inverse relationship between cumulative ICS exposure and BMD at the lumbar spine and hip, indicating that inhaled therapy can contribute to bone loss [37]. Egeberg et al. found a dose–response association between cumulative potent topical (skin) corticosteroids exposure and increased risk of osteoporosis and fractures [14]. Jha et al. showed that both systemic and local corticosteroids (NCS and ICS) impair bone metabolism through reduced osteoblast activity and increased osteoclast function [38]. Taken together, the findings highlight that bone loss is a systemic consequence of CC exposure, with effects evident regardless of whether treatment is administered systemically, inhaled, or intranasally.
From a clinical perspective, our findings highlight the systemic consequences of CC exposure in patients with CRSwNP and GAD. It underlines the need for proactive identification of at‐risk patients through coordinated multidisciplinary care. Routine DXA screening should be considered for patients with prolonged disease, older age, or high CC exposure, even without skeletal symptoms. Steroid‐sparing treatments should be implemented to prevent long‐term adrenal and bone complications. Supplementation with calcium and vitamin D should also be ensured.
The treatable traits framework offers a promising precision‐medicine approach in chronic airway diseases [39, 40]. This paradigm shifts focus from diagnostic labels to modifiable, clinically relevant traits [39, 40]. Applied to patients with CRSwNP or GAD, it may enable systematic identification of CC burden, SAI, BMD loss, and poor treatment adherence. Clinicians only detect what they actively seek; early recognition of subclinical manifestations may prevent progression and reduce long‐term morbidity. Targeting these traits allows individualized management, improving outcomes and reducing CC exposure [39, 40].
These findings should, however, be interpreted considering the study's strengths and limitations. A key strength is the consecutive inclusion of a real‐world, phenotypically diverse cohort referred for biologic treatment, offering valuable insight into current practice patterns and corticosteroid‐related consequences. The integration of multiple data sources—including clinical, laboratory, and pharmacy records—strengthened internal validity. Nonetheless, the cross‐sectional design precludes causal inference. The absence of healthy controls reflects limited access to an unexposed comparison group within the clinical and registry‐based study framework and restricts external comparison of absolute risk estimates.
Registry‐based prescription data reflect redeemed prescriptions rather than confirmed medication intake and may therefore not fully reflect administered doses and thus lead to overestimation. In contrast, non‐prescription corticosteroid use is not recorded, which may lead to underestimation of true corticosteroid exposure.
Although age and sex were adjusted for in multivariable analyses, the limited sample size precluded stratified analysis or formal assessment of effect modification by age or sex, and residual confounding cannot be excluded. Moreover, the CC exposure was estimated using a prescriptions‐based conversion factor and did not fully account for differences in formulation potency, systemic bioavailability, or absorption across administration routes. This may have influenced the magnitude of observed associations with adrenal and bone outcomes. Finally, the small number of osteoporosis cases reduced statistical power to detect eventual associations.
5. Conclusion
Patients with CRSwNP and GAD referred for biological treatment experienced a substantial CC exposure due to overlapping use of systemic, inhaled, and nasal corticosteroids across care settings. This exposure was associated with lower BMD across all skeletal sites, SAI, and a significantly higher prevalence of Type 2 diabetes in patients with CRSwNP. These findings highlight the need for improved coordination between care providers, multidisciplinary management, systematic screening of treatable traits to prevent long‐term complications, and earlier introduction of corticosteroid‐sparing therapies when clinically indicated.
Funding
The authors have nothing to report.
Conflicts of Interest
Outside the submitted work and unrelated to this. C.H. has received unregistered research grants from GSK and Sanofi. K.E.J.H. has received personal fees from AstraZeneca, Chiesi, GSK, Sanofi, Novo Nordisk, and TEVA. P.S. has nothing to declare. K.A. has received personal fees from GSK, Sanofi, and AstraZeneca. J.T. is funded by GSK. C.S.U. has received personal fees for lectures, being on advisory boards, etc. from AstraZeneca, Berlin‐Chemie Menarini, Boehringer Ingelheim, Novartis, GSK, Sanofi, TEVA, Orion Pharma, TFF Pharmaceuticals, Pfizer, Chiesi, Covis Pharma, Takeda, Hikma Pharmaceuticals, Novo Nordisk, and Roche. B.A. has nothing to declare. V.B. has received personal fees from AstraZeneca, GSK, TEVA, Sanofi Genzyme, MSD, Chiesi, Boehringer Ingelheim, Novartis, ALK‐Abello, Mundipharma, BIRK NPC, and Pharmaxis.
Supporting information
Table S1: ICD‐10 codes used to define osteoporosis and fracture categories. ICD‐10 codes were used to identify osteoporosis with and without pathological fractures, as well as fracture sites relevant to the study outcomes. Codes were grouped into clinically meaningful categories for analysis.
Table S2: Corticosteroid exposure‐related diseases in 89 patients with chronic rhinosinusitis with nasal polyps or global airway.
Table S3: Systemic and locally corticosteroids equivalence in 89 patients with chronic rhinosinusitis with nasal polyps or global airway.
Table S4:: Prevalence of common corticosteroid exposure‐related diagnoses from national registries in 89 patients with chronic rhinosinusitis with nasal polyps or global airway.
Table S5: lary70500‐sup‐0001‐Tables.docx.: Prevalence of osteoporosis, osteopenia, and fracture diagnoses based on ICD‐10 codes and/or T‐scores. Osteoporosis was defined as either an ICD‐10 diagnosis of osteoporosis (M80–M82) or a T‐score ≤ −2.5 at any measured site. Osteopenia was defined as a T‐score between −1.0 and −2.5.
Acknowledgments
We would like to thank the Department of Otorhinolaryngology, Head and Neck Surgery & Audiology, RH, for giving the research group the opportunity to establish this important study in daily clinical practice.
Data Availability Statement
Research data are not shared.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: ICD‐10 codes used to define osteoporosis and fracture categories. ICD‐10 codes were used to identify osteoporosis with and without pathological fractures, as well as fracture sites relevant to the study outcomes. Codes were grouped into clinically meaningful categories for analysis.
Table S2: Corticosteroid exposure‐related diseases in 89 patients with chronic rhinosinusitis with nasal polyps or global airway.
Table S3: Systemic and locally corticosteroids equivalence in 89 patients with chronic rhinosinusitis with nasal polyps or global airway.
Table S4:: Prevalence of common corticosteroid exposure‐related diagnoses from national registries in 89 patients with chronic rhinosinusitis with nasal polyps or global airway.
Table S5: lary70500‐sup‐0001‐Tables.docx.: Prevalence of osteoporosis, osteopenia, and fracture diagnoses based on ICD‐10 codes and/or T‐scores. Osteoporosis was defined as either an ICD‐10 diagnosis of osteoporosis (M80–M82) or a T‐score ≤ −2.5 at any measured site. Osteopenia was defined as a T‐score between −1.0 and −2.5.
Data Availability Statement
Research data are not shared.