Is There An Association Between Inhaled Corticosteroids And Bone Density In Postmenopausal Women

1
Is There An Association Between Inhaled
Corticosteroids And Bone Density In
Postmenopausal Women?

• Thang Nguyen, M.D.
• Reviewer David Thom, MD, PhD

2
Outline

• Elmstahl S, Ekstrom H, Galvard H, Johnell O,
  Gerhardsson de Verdier M, Norjavaara E. Is there
  an association between inhaled corticosteroids
  and bone density in postmenopausal women?J
  Allergy Clin Immunol. 2003 Jan111(1)91-6.
• Jones A, Fay JK, Burr M, Stone M, Hood K, Roberts
  G. Inhaled corticosteroid effects on bone
  metabolism in asthma and mild chronic obstructive
  pulmonary disease (Cochrane Review). In The
  Cochrane Library, Issue 2, 2003. Oxford Update
  Software.
• Wong CA, Walsh LJ, Smith CJ, Wisniewski AF, Lewis
  SA, Hubbard R, Cawte S, Green DJ, Pringle M,
  Tattersfield AE. Inhaled corticosteroid use and
  bone-mineral density in patients with
  asthma.Lancet. 2000 Apr 22355(9213)1399-403.

3
Background

• Osteoporosis
• bone resorption gt bone formation gt bone loss.
• Corticosteroids
• inhibit osteoblastic function
• reduce of osteoblast life span
• Systemic steroids at high doses
• vertebral fracture and hip fracture

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Background

• Inhaled corticosteroids
• main therapy for asthma
• adrenal suppression, skin thinning, increased
  cataract formation, decreased linear growth in
  children, metabolic changes and behavioral
  abnormalities

5
Elmstahl S, Ekstrom H, Galvard H, Johnell O,
Gerhardsson de Verdier M, Norjavaara E. Is there
an association between inhaled corticosteroids
and bone density in postmenopausal women?J
Allergy Clin Immunol. 2003 Jan111(1)91-6.
6
Design

• Retrospective cohort study
• Postmenopausal women
• 155 subjects exposed to ICs
• 106 exposed to ICs only
• 49 exposed to ICs and OCs
• 674 non-exposed control subjects
• Demographics similar to underlying population

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Design

• Health questionnaire
• Medical history and medication use
• History of steroid use (type, route, dose,
  duration)
• Risk factors for BMD (e.g., smoking, physical
  activity)
• Steroid use was verified for all exposed subjects
  via medical record review
• Medical record review of random 5 controls
  found 98 without steroid use
• BMD measurements in wrist

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Analysis

• Students t-test used to assess differences in
  BMD between groups
• ANOVA and linear regression used to adjust for
  age
• Stratification by cumulative does, duration,
  current daily dose
• Not clear if used 1-tailed or 2-tailed p-values

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Results

• Mean duration of use was 8.2 years, range 1.5-26
  years
• Mean annual duration of inhalation 8.5-12 months
• Mean daily dose was 853 ug and 23 used doses gt
  1000 ug/day
• Budesonide most common
• 49 of 155 also used oral or intra-articular
  steroids in addition to inhaled steroid (OC)

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Results

• Mean BMD values in IC group vs. controls
• No differences between exposed and control
• Same when adjusted for years of steroid use, age,
  and annual duration of IC use

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Results

• Mean BMD values in OC vs. IC only
• BMD for OC lt IC (0.408 v. 0.434 p0.044)
• Difference only seen in 3 subgroups
• Cumulative dose lt4000mg
• Duration of exposure gt 6.3 years
• Current daily dose gt 1000 mg

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Results

• Same distribution of risk factors for exposed and
  control subjects.
• BMD higher in subjects with medium to heavy
  physical activity vs. light activity.
• Women on gt 1000 ug daily less physically active
  than those on lt 1000 ug daily.

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Discusssion

• Confounding factors
• Selection bias unlikely
• Other studies support and contradict their
  conclusions.
• Need for prospective study

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Critique

• Selection bias study sample similar to
  underlying population
• Unexposed and exposed groups similar in all
  important respects except for the exposure.
• Information bias-outcomes identified in the same
  way for both groups
• Did not examine fracture rates
• Controlled for confounding
• External validity

15

• Jones A, Fay JK, Burr M, Stone M, Hood K, Roberts
  G. Inhaled corticosteroid effects on bone
  metabolism in asthma and mild chronic obstructive
  pulmonary disease (Cochrane Review). In The
  Cochrane Library, Issue 2, 2003. Oxford Update
  Software.

16
Design

• Search
• Cochrane Airways Group trials register
• electronic reference databases
• UK National Research Register
• bibliographies of included studies
• contacted pharmaceutical companies
• Selection Criteria
• Quality and Validity Assessment

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Results

• Seven studies of IC and BMD
• Study subjects age less than 60 and
• The malefemale ratio was 21
• Mean duration of inhaled steroid use was 2-3
  years
• No differences in BMD and fracture rates
• Osteocalcin
• No differences at conventional doses of IC
• Decreased at experimental doses

18
Wong CA, Walsh LJ, Smith CJ, Wisniewski AF, Lewis
SA, Hubbard R, Cawte S, Green DJ, Pringle M,
Tattersfield AE. Inhaled corticosteroid use and
bone-mineral density in patients with
asthma.Lancet. 2000 Apr 22355(9213)1399-403.
19
Design

• 196 adults with asthma (119 women)
• Age 20-40 years
• Inhaled corticosteroid regularly for at least 6
  months
• Limited exposure to systemic steroids
• Questionnaires
• BMD measurements

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Results

• Median duration of inhaled corticosteroid
  treatment 6 years (range 0.5-24)
• Median cumulative dose was 876 mg (87-4380)
• Negative association between cumulative dose of
  inhaled corticosteroid and bone-mineral density
  at the
• lumbar spine (L2-L4)
• femoral neck
• trochanter
• Before and after adjustments

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Conclusion

• Conflicting evidence
• No correlation mostly
• Higher doses more detrimental
• Consider preventive therapy