Impact of cumulative exposure to high-dose oral glucocorticoids on fracture risk in Denmark: a population-based case-control study
Archives of Osteoporosis
Impact of cumulative exposure to high-dose oral glucocorticoids on fracture risk in Denmark: a population-based case-control study
M. Amine Amiche 0 1 2 4 5 6
Shahab Abtahi 0 1 2 4 5 6
Johanna H. M. Driessen 0 1 2 4 5 6
Peter Vestergaard 0 1 2 4 5 6
Frank de Vries 0 1 2 4 5 6
Suzanne M. Cadarette 0 1 2 4 5 6
Andrea M. Burden 0 1 2 4 5 6
Andrea M. Burden 0 1 2 4 5 6
0 Care and Public Health Research Institute (CAPHRI) , Maastricht , The Netherlands
1 Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre
2 Leslie Dan Faculty of Pharmacy, University of Toronto , Toronto, ON , Canada
3 , Maastricht , The Netherlands
4 Department of Endocrinology, Aalborg University Hospital , Aalborg , Denmark
5 Department of Clinical Medicine, Aalborg University , Aalborg , Denmark
6 NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University , Maastricht , The Netherlands
Summary We examined the effect of cumulative exposure to high doses of oral glucocorticoids on fracture risk. Compared to short-course users (daily dose ≥ 15 mg + cumulative < 1 g), heavy users (daily dose ≥ 15 mg + cumulative dose ≥ 1 g) had the highest risk of fracture. These patients should be monitored for fracture management strategies. Purpose The effect of cumulative exposure to high daily doses of oral glucocorticoids on fracture risk remains debated. We therefore aimed to examine the hip fracture risk associated with short courses and heavy use of high-dosed oral glucocorticoids. Methods We conducted a population-based case-control study using the Danish National Health Service data, 1996-2011. Cases were those aged ≥ 18 years who sustained a hip (primary outcome) fracture (n = 81,342). Vertebral and forearm fractures were considered in secondary analyses. Controls (matched 1:1) were those without a fracture. Average daily dose (DD) and total cumulative dose (CD) were calculated among current oral glucocorticoid users. Among patients with a high daily dose (DD ≥ 15 mg), we identified short-course users as those with a CD < 1 g and heavy users as those with a CD ≥ 1 g. We estimated adjusted odds ratio (adj.OR) of fracture with current glucocorticoid use compared to never-use, using conditional logistic regression. Results A high DD (≥ 15 mg) and high CD (≥ 1 g) were independently associated with an increased hip fracture risk (adj.OR 2.5; 95% CI 2.2-2.9; adj.OR 1.6; 95% CI 1.5-1.8, respectively). However, the risk was substantially increased among heavy users (DD ≥ 15 mg and CD ≥ 1 g: adj.OR 2.9; 95% CI 2.5-3.4) as compared to short-course users (DD ≥ 15 mg and CD < 1 g: adj.OR 1.4; 95% CI 1.1-1.9). Associations were stronger for vertebral fractures, yet little association was identified for forearm fractures. Conclusion Among patients receiving a high DD (≥ 15 mg), heavy users (≥ 1 g CD) showed the most substantial increase in hip fracture risk. Among those receiving high DD, a threshold of 1 g CD may identify heavy users that are candidates for focused fracture management services.
Oral glucocorticoids; Osteoporosis; Hip fracture; Case-control
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5
Division of Pharmacoepidemiology and Clinical Pharmacology,
Utrecht Institute of Pharmaceutical Sciences, Utrecht University,
Utrecht, The Netherlands
Abbreviations
CD Cumulative dose
CI Confidence interval
DD Daily dose
OR Odds ratio
Background
Oral glucocorticoids are widely prescribed drugs with
established clinical benefits for patients with chronic
inflammatory and autoimmune diseases, such as chronic respiratory
disease, inflammatory arthritis, and dermatologic disease
[
1–3
]. It is estimated that the prevalence of oral glucocorticoid
use among adults ranges between 1.5 and 3% worldwide [
4
].
Unfortunately, oral glucocorticoid use is limited by significant
side effects that usually appear after an extended period of
exposure [
5–7
]. Glucocorticoid-induced musculoskeletal
disorders, such as osteoporosis, are a major problem and a
welldocumented side effect [
8–13
]. Indeed, it is estimated that oral
glucocorticoids are associated with a 30 to 120% increased
risk of hip fracture and 2- to 3-fold increase in vertebral
fracture risk compared with non-use [
14–16
]. For inflammatory
conditions, short courses of high doses with tapering regimens
are often required for symptom management. While it is
wellknown that oral glucocorticoid-induced bone loss and fracture
risk is dose-dependent [
15, 17
], the relationship with the
cumulative exposure is less well established [
15, 17
].
To minimize fracture risk, clinical practice guidelines
recommend that osteoporosis pharmacotherapy should be given
to patients that are expected to receive a daily dose of 5 to
7.5 mg of prednisone equivalent for 3–6 months [
10, 18–20
].
However, in a real-world setting, patients with inflammatory
conditions often receive intermittent short courses (7–14 days)
of high doses (40–60 mg per day), or a continuous low (...truncated)