Intermittent use of high-dose glucocorticoids and risk of fracture in Denmark:

A population-based case-control study

Andrea M. Burden, PhDMaastricht University

National Osteoporosis Society Conference 20167th November 2016

Birmingham, UK

Clinical Epidemiology

Glucocorticoids• Oral GCs are primarily prescribed for inflammatory

disorders• Chronic obstructive pulmonary disease (COPD), rheumatoid

arthritis, inflammatory bowel disease

• These indications often have frequent short-courses or tapering regimens for symptom management

• Difficult to accurately examine exposure in databases

Clinical Epidemiology

Rationale and Objective• Oral glucocorticoids (GCs) are associated with increased

fracture risk1

• Effect is dose dependent: • High-dose (≥15mg day) associated with high risk2

• Effect of the cumulative exposure to high doses is less clear

• We aimed to examine the effect of intermittent and long-term heavy use of GC on fracture risk

1 Amiche MA et al. Osteoporos Int. 2016; 27: 1709-182 van Staa TP et al. Rheumatology. 2000; 39: 1383-9

Clinical Epidemiology

Population and design• Danish National Database

• Information is available for inpatient visits, hospitalizations, A&E visits, prescriptions

• Case-control study • Cases (Fracture Patients: Osteoporotic [Hip, Vertebral, Humerus, Radius])

• All patients ≥18 years • Fracture during study period (1 JAN 1996 – 31 DEC 2011)• Index Date = date of initial fracture

• Controls (No Fracture)• Matched 1:1 on age (birth year) and sex• Received same date as matched case

Clinical Epidemiology

GC Exposure • Exposure to GCs was defined prior to index date as:

• Never User: no GC prescription before index (reference category)• Current User: prescription in 91 days before index (primary exposure group)• Also classified recent, past, and distant use

• Average daily dose: Total prednisone equivalent (mg)/time• High daily dose defined as ≥15mg per day

• Cumulative exposure: Total amount of prednisone equivalent (grams)

• Intermittent Exposure defined <1 gram cumulative exposure• High Exposure defined as ≥1gram cumulative exposure

• Equivalent to 3 short-courses of a high dose

Clinical Epidemiology

Statistical Analysis• Conditional logistic regression

• Odds Ratios (OR) and 95% Confidence Intervals (CI)• Adjusted for comorbidities and medication use

Clinical Epidemiology

CharacteristicCases

(N=376,858)Controls

(N=376,858)

N % N %

Female 259,080 68.8 547,781 53.9Mean Age (years, SD) 64.2 19.5 64.2 19.5History of Comorbidities (ever before)

Chronic Obstructive Pulmonary Disease 22,158 5.9 16,844 4.5

Rheumatoid Arthritis 7,191 1.9 5,303 1.4

Inflammatory Bowl Disease 7,722 2.1 6,054 1.6Medication Use (6-months prior to index)

Bisphosphonates 10,427 2.8 6,338 1.7

Inhaled Corticosteriods 12,311 3.3 10,832 2.9

Baseline Characteristics

Clinical Epidemiology

Osteoporotic fracture: cumulative doseExposure Cases Controls Adjusted OR (95% CI)Never GC Use 313,996 322,482 ReferenceCurrent GC Use 14,751 9,789 1.41 (1.36 – 1.45)

Cumulative dose <1 gram 3,104 2,579 1.17 (1.11 – 1.24)Cumulative dose ≥1 gram 11,647 7,210 1.55 (1.48 – 1.61)

Clinical Epidemiology

Osteoporotic fracture: daily doseExposure Cases Controls Adjusted OR (95% CI)Never GC Use 313,996 322,482 ReferenceCurrent GC Use 14,751 9,789 1.41 (1.36 – 1.45)

Daily Dose <7.5 mg 8,185 5,917 1.30 (1.25 – 1.35)Daily Dose 7.5-14.9 mg 4,062 2,613 1.43 (1.35 – 1.51)Daily Dose ≥15 mg 2,504 1,259 1.83 (1.71 – 1.97)

Clinical Epidemiology

Exposure Cases Controls Adjusted OR (95% CI)Never GC Use 313,996 322,482 ReferenceCurrent GC Use 14,751 9,789 1.41 (1.36 – 1.45)Daily Dose ≥15 mg 2,504 1,259 1.83 (1.71 – 1.97)

Cumulative <1g 503 383 1.24 (1.07 – 1.43)Cumulative ≥1g 2,001 876 2.10 (1.58 – 2.29)

*Adjusted for: COPD, history of fracture, rheumatoid arthritis, inflammatory bowel disease, secondary osteoporosis, inhaled corticosteroids, inhaled bronchodilators, antipsychotics, antidepressants, anxiolytics/hypnotics, anticonvulsants, and GC distant, past, recent use

Osteoporotic Fracture: daily and cumulative

Clinical Epidemiology

Exposure Cases Controls Adjusted OR (95% CI)Never GC Use 64,736 67,579 ReferenceCurrent GC Use 5,230 2,917 1.59 (1.50 – 1.67)Daily Dose ≥15 mg 1,054 349 2.54 (2.23 – 2.90)

Cumulative <1g 154 100 1.41 (1.07 – 1.84)Cumulative ≥1g 900 249 3.00 (2.58 – 3.50)

*Adjusted for: COPD, history of fracture, rheumatoid arthritis, inflammatory bowel disease, secondary osteoporosis, inhaled corticosteroids, inhaled bronchodilators, antipsychotics, antidepressants, anxiolytics/hypnotics, anticonvulsants, and GC distant, past, recent use

Hip Fracture: daily and cumulative

Clinical Epidemiology

Exposure Cases Controls Adjusted OR (95% CI)Never GC Use 30,044 32,463 ReferenceCurrent GC Use 2,163 790 2.54 (2.31 – 2.79)Daily Dose ≥15 mg 430 104 4.01 (3.17 – 5.07)

Cumulative <1g 63 29 2.17 (1.33 – 3.55)Cumulative ≥1g 367 75 4.69 (3.59 – 6.14)

*Adjusted for: COPD, history of fracture, rheumatoid arthritis, inflammatory bowel disease, secondary osteoporosis, inhaled corticosteroids, inhaled bronchodilators, antipsychotics, antidepressants, anxiolytics/hypnotics, anticonvulsants, and GC distant, past, recent use

Vertebral Fracture: daily and cumulative

Clinical Epidemiology

Interpretation• High daily-dose (≥15 mg) and high-exposure

(≥1 gram) independently associated a increased fracture risk

• Risk was only moderately increased in users with intermittent use (<1gram)

• Most substantial increase in fracture risk is among those with high-exposure to high-doses (≥1 gram at ≥15 mg per day)

• Clinicians should monitor these patients for fracture management

Clinical Epidemiology

Thank you for listening!

Thank you to collaborators:Prof. Dr Peter VestergaardDr. Frank de VriesAnnemariek Driessen, MSc

Clinical Epidemiology

Osteoporotic Fracture: daily and cumulative

Exposure Cases Controls Adjusted OR (95% CI)Never GC Use 313,996 322,482 ReferenceCurrent GC Use 14,751 9,789 1.41 (1.36 – 1.45)Daily Dose <7.5 mg

Cumulative <1g 2,132 1,831 1.15 (1.07 – 1.23)Cumulative ≥1g 6,053 4,086 1.37 (1.31 – 1.42)

Daily Dose 7.5-14.9 mgCumulative <1g 469 365 1.24 (1.07 – 1.44)Cumulative ≥1g 3,593 2,248 1.46 (1.38 – 1.55)

Daily Dose ≥15 mgCumulative <1g 503 383 1.24 (1.07 – 1.43)Cumulative ≥1g 2,001 876 2.10 (1.58 – 2.29)

*Adjusted for: COPD, history of fracture, rheumatoid arthritis, inflammatory bowel disease, secondary osteoporosis, inhaled corticosteroids, inhaled bronchodilators, antipsychotics, antidepressants, anxiolytics/hypnotics, anticonvulsants, and GC distant, past, recent use.

Clinical Epidemiology

Osteoporotic Fracture: cumulative dose sensitivity

Exposure Cases Controls Adjusted OR (95% CI)Never GC Use 313,996 322,482 ReferenceDistant GC Use 37,481 35,407 1.03 (1.02 – 1.05)Past GC Use 5,905 5,235 1.08 (1.03 – 1.12)Recent GC Use 4,725 3,945 1.13 (1.08 – 1.18)Current GC Use 14,751 9,789 1.41 (1.36 – 1.45)

Cumulative dose <1 gram 3,104 2,579 1.17 (1.11 – 1.24)Cumulative dose 1-4.9 gram 4,689 3,105 1.42 (1.35 – 1.49)Cumulative dose 5-9.9 gram 3,004 1,795 1.56 (1.46 – 1.66)Cumulative dose 10-24.9 gram 3,124 1,889 1.50 (1.41 – 1.60)Cumulative dose ≥25 gram 830 421 1.66 (1.47 – 1.89)

Clinical Epidemiology

Hip Fracture:Daily dose stratification

Exposure Cases Controls Adjusted OR (95% CI)Never GC Use 64,736 67,579 ReferenceDistant GC Use 8,639 8,610 0.96 (0.93 – 1.00) Past GC Use 1407 1,213 1.04 (0.96 – 1.14)Recent GC Use 1,330 1,023 1.19 (1.09 – 1.30)Current GC Use 5,230 2,917 1.59 (1.50 – 1.67)

Daily Dose <7.5 mg 2,628 1,699 1.39 (1,29 – 1.49)Daily Dose 7.5-14.9 mg 1,548 869 1.56 (1.42 – 1.72)Daily Dose ≥15 mg 1,054 349 2.54 (2.23 – 2.90)

Clinical Epidemiology

Exposure Cases Controls Adjusted OR (95% CI)Never GC Use 64,736 67,579 ReferenceDistant GC Use 8,639 8,610 0.96 (0.93 – 1.00) Past GC Use 1407 1,213 1.04 (0.96 – 1.14)Recent GC Use 1,330 1,023 1.19 (1.09 – 1.30)Current GC Use 5,230 2,917 1.59 (1.50 – 1.67)

Cumulative dose <1 gram 812 608 1.28 (1.14 – 1.43)Cumulative dose ≥1 gram 4,418 2,309 1.63 (1.49 – 1.78)

Hip Fracture:Cumulative dose stratification

Clinical Epidemiology

Exposure Cases Controls Adjusted OR (95% CI)Never GC Use 64,736 67,579 ReferenceDistant GC Use 8,639 8,610 0.96 (0.93 – 1.00) Past GC Use 1407 1,213 1.04 (0.96 – 1.14)Recent GC Use 1,330 1,023 1.19 (1.09 – 1.30)Current GC Use 5,230 2,917 1.59 (1.50 – 1.67)

Cumulative dose <1 gram 812 608 1.28 (1.14 – 1.43)Cumulative dose 1-4.9 gram 1,752 939 1.69 (1.55 – 1.84)Cumulative dose 5-9.9 gram 1,147 590 1.70 (1.53 – 1.90)Cumulative dose 10-24.9 gram 1,220 646 1.60 (1.44 – 1.78)Cumulative dose ≥25 gram 299 134 1.75 (1.39 – 2.19)

Hip Fracture:Cumulative dose sensitivity

Clinical Epidemiology

Exposure Cases Controls Adjusted OR (95% CI)Never GC Use 64,736 67,579 ReferenceCurrent GC Use 5,230 2,917 1.59 (1.50 – 1.67)Daily Dose <7.5 mg

Cumulative <1g 513 418 1.17 (1.02 – 1.35)Cumulative ≥1g 2,115 1,281 1.46 (1.32 – 1.62)

Daily Dose 7.5-14.9 mgCumulative <1g 145 90 1.61 (1.20 – 2.14)Cumulative ≥1g 1,403 779 1.56 (1.41 – 1.72)

Daily Dose ≥15 mgCumulative <1g 154 100 1.41 (1.07 – 1.84)Cumulative ≥1g 900 249 3.00 (2.58 – 3.50)

*Adjusted for: COPD, history of fracture, rheumatoid arthritis, inflammatory bowel disease, secondary osteoporosis, inhaled corticosteroids, inhaled bronchodilators, antipsychotics, antidepressants, anxiolytics/hypnotics, anticonvulsants, and GC distant, past, recent use.

Hip Fracture:daily and cumulative

Clinical Epidemiology

Exposure Cases Controls Adjusted OR (95% CI)Never GC Use 30,044 32,463 ReferenceDistant GC Use 3,745 3,103 1.24 (1.17 – 1.32) Past GC Use 637 450 1.38 (1.20 – 1.57)Recent GC Use 555 338 1.61 (1.38 – 1.87)Current GC Use 2,163 790 2.54 (2.31 – 2.79)

Daily Dose <7.5 mg 1,060 485 2.07 (1.84 – 2.34)Daily Dose 7.5-14.9 mg 673 201 2.89 (2.43 – 3.44)Daily Dose ≥15 mg 430 104 4.01 (3.17 – 5.07)

Vertebral Fracture:Daily dose stratification

Clinical Epidemiology

Exposure Cases Controls Adjusted OR (95% CI)Never GC Use 30,044 32,463 ReferenceDistant GC Use 3,745 3,103 1.24 (1.17 – 1.32) Past GC Use 637 450 1.38 (1.20 – 1.57)Recent GC Use 555 338 1.61 (1.38 – 1.87)Current GC Use 2,163 790 2.54 (2.31 – 2.79)

Cumulative dose <1 gram 376 212 1.81 (1.50 – 2.18)Cumulative dose ≥1 gram 1,887 578 2.36 (2.01 – 2.78)

Vertebral Fracture:Cumulative dose stratification

Clinical Epidemiology

Exposure Cases Controls Adjusted OR (95% CI)Never GC Use 30,044 32,463 ReferenceDistant GC Use 3,745 3,103 1.24 (1.17 – 1.32) Past GC Use 637 450 1.38 (1.20 – 1.57)Recent GC Use 555 338 1.61 (1.38 – 1.87)Current GC Use 2,163 790 2.54 (2.31 – 2.79)

Cumulative dose <1 gram 376 212 1.81 (1.50 – 2.18)Cumulative dose 1-4.9 gram 658 247 2.57 (2.18 – 3.03)Cumulative dose 5-9.9 gram 488 139 3.23 (2.63 – 3.98)Cumulative dose 10-24.9 gram 485 157 2.67 (2.19 – 3.26)Cumulative dose ≥25 gram 156 35 3.37 (2.27 – 5.00)

Vertebral Fracture:Cumulative dose sensitivity

Clinical Epidemiology

Exposure Cases Controls Adjusted OR (95% CI)Never GC Use 30,044 32,463 ReferenceCurrent GC Use 2,163 790 2.54 (2.31 – 2.79)Daily Dose <7.5 mg

Cumulative <1g 257 156 1.74 (1.40 – 2.16)Cumulative ≥1g 803 329 2.24 (1.93 – 2.59)

Daily Dose 7.5-14.9 mgCumulative <1g 56 27 1.90 (1.15 – 3.15)Cumulative ≥1g 617 174 3.06 (2.54 – 3.68)

Daily Dose ≥15 mgCumulative <1g 63 29 2.17 (1.33 – 3.55)Cumulative ≥1g 367 75 4.69 (3.59 – 6.14)

*Adjusted for: COPD, history of fracture, rheumatoid arthritis, inflammatory bowel disease, secondary osteoporosis, inhaled corticosteroids, inhaled bronchodilators, antipsychotics, antidepressants, anxiolytics/hypnotics, anticonvulsants, and GC distant, past, recent use.

Vertebral Fracture:daily and cumulative

Clinical Epidemiology

Exposure Cases Controls Adjusted OR (95% CI)Never GC Use 172,692 174,940 ReferenceDistant GC Use 19,160 17,862 1.05 (1.03 – 1.08)Past GC Use 2,961 2,719 1.05 (0.99 – 1.11)Recent GC Use 2,085 1,949 1.03 (0.96 – 1.10)Current GC Use 5,065 4,493 1.09 (1.05 – 1.14)

Daily Dose <7.5 mg 3,161 2,785 1.10 (1.04 – 1.16)Daily Dose 7.5-14.9 mg 1,229 1,111 1.08 (0.99 – 1.18)Daily Dose ≥15 mg 675 597 1.10 (0.98 – 1.24)

Radius Fracture:Daily dose stratification

Clinical Epidemiology

Exposure Cases Controls Adjusted OR (95% CI)Never GC Use 172,692 174,940 ReferenceDistant GC Use 19,160 17,862 1.05 (1.03 – 1.08)Past GC Use 2,961 2,719 1.05 (0.99 – 1.11)Recent GC Use 2,085 1,949 1.03 (0.96 – 1.10)Current GC Use 5,065 4,493 1.09 (1.05 – 1.14)

Cumulative dose <1 gram 1,440 212 1.03 (0.96 – 1.12)Cumulative dose ≥1 gram 3,625 3,137 1.08 (1.00 – 1.17)

Radius Fracture:Cumulative dose stratification

Clinical Epidemiology

Exposure Cases Controls Adjusted OR (95% CI)Never GC Use 172,692 174,940 ReferenceDistant GC Use 19,160 17,862 1.05 (1.03 – 1.08)Past GC Use 2,961 2,719 1.05 (0.99 – 1.11)Recent GC Use 2,085 1,949 1.03 (0.96 – 1.10)Current GC Use 5,065 4,493 1.09 (1.05 – 1.14)

Cumulative dose <1 gram 1,440 212 1.03 (0.96 – 1.12)Cumulative dose 1-4.9 gram 1,610 1,419 1.09 (1.01 – 1.18)Cumulative dose 5-9.9 gram 882 772 1.11 (1.00 – 1.23)Cumulative dose 10-24.9 gram 897 788 1.12 (1.01 – 1.25)Cumulative dose ≥25 gram 236 158 1.45 (1.70 – 1.80)

Radius Fracture:Cumulative dose sensitivity

Clinical Epidemiology

Exposure Cases Controls Adjusted OR (95% CI)Never GC Use 172,692 174,940 ReferenceCurrent GC Use 5,065 4,493 1.09 (1.05 – 1.14)Daily Dose <7.5 mg

Cumulative <1g 1,040 969 1.05 (0.95 – 1.15)Cumulative ≥1g 2,121 1,816 1.12 (1.05 – 1.20)

Daily Dose 7.5-14.9 mgCumulative <1g 197 190 1.04 (0.84 – 1.28)Cumulative ≥1g 1,032 921 1.09 (1.00 – 1.20)

Daily Dose ≥15 mgCumulative <1g 203 197 0.97 (0.79 – 1.19)Cumulative ≥1g 472 400 1.18 (1.02 – 1.36)

*Adjusted for: COPD, history of fracture, rheumatoid arthritis, inflammatory bowel disease, secondary osteoporosis, inhaled corticosteroids, inhaled bronchodilators, antidepressants, anxiolytics/hypnotics, anticonvulsants, and GC distant, past, recent use.

Radius Fracture:daily and cumulative