The Effects of Inhaled Glucocorticoids on the Postmenopausal Skeleton

July 14, 2017 updated by: Columbia University

There are over 10 million individuals with asthma using inhaled glucocorticoids (IGCs) in the United States. While oral GCs are recognized to have destructive skeletal effects, far less is known about the effects of IGCs. This gap in our knowledge is of critical importance, not only because of the prevalence, chronic nature and long duration of IGC use, but also because several studies have found that patients using IGCs are at increased risk of fracture. Fracture risk is greatest in postmenopausal (PM) women, in whom IGCs may augment negative effects of estrogen loss and aging.

The investigators hypothesize that initiation of IGCs in IGC naïve PM women will lead to decreased bone formation and uncoupling of bone turnover, a potential mechanism for the effect of IGCs on the skeleton.

To test our hypothesis, the investigators will perform a randomized, controlled 4 week study of the acute effects of commonly used doses of budesonide (360 or 720 mcg) on bone turnover and circulating osteoblast precursors in 60 treatment naïve, non-asthmatic, PM women. These studies are of high clinical significance because there are currently no guidelines regarding screening, prevention or treatment for osteoporosis in patients using IGCs, nor is IGC use taken into account when calculating fracture risk in PM women, the group at highest risk of fracture. High quality evidence for low volumetric bone mineral density (BMD) and abnormal bone quality in PM women using IGCs has the potential to change clinical practice by supporting specific interventions to prevent bone loss and fractures.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

The investigators will study acute biochemical and hormonal responses over 4 weeks to commonly prescribed moderate and high doses of budesonide one of the most widely prescribed IGCs, and the preferred drug for Medicare and Medicaid. Sixty treatment naïve PM non-asthmatic women will be randomized to one of 3 groups (20/group): placebo, budesonide 360 or 720 mcg/day. IGCs will be self-administered as 2 puffs twice daily. Budesonide will be provided as Pulmicort flexhaler. At the baseline visit, subjects will be taught proper technique for self-administration of the inhaled medications, including mouth rinsing after each dose. Since dry powder formulations will be used, spacer devices are not required. Women will be assessed at baseline, 1,2, and 4 weeks. This time period and schedule was chosen to ensure adequate time for IGCs to reach peak levels, and to assess the bone metabolic response. Given the 4-6 hr half-life of budesonide, steady state pharmacokinetics will be reached at one week. The investigators will monitor medication adherence using the inhaler's device counter. Visits will be conducted in the Metabolic Bone Diseases Unit. To measure systemic absorption, serum steroid levels will be directly measured.To assess the effects of IGC and dose on the hypothalamic-pituitary-adrenal (HPA) axis, morning (AM) cortisol will be measured at each visit and urinary free cortisol at baseline and 4 weeks.

Study Type

Interventional

Phase

  • Phase 4

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

60 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Age ≥ 60 years or at least > 5 years postmenopause (defined as 1 year without a menstrual period)
  • No asthma and no history of GC use, either oral or inhaled

Exclusion Criteria:

  • Use of oral GCs for > 4 weeks per year in the past 3 years
  • History of smoking, to rule out overlapping chronic obstructive pulmonary disease (COPD)
  • Other metabolic bone diseases (e.g. hyperparathyroidism, Paget's disease, osteogenesis imperfecta)
  • Gastrointestinal Disease (malabsorption, celiac disease, inflammatory bowel disease)
  • Endocrinopathies (i.e. untreated thyroid disease, Cushing's syndrome, prolactinoma,)
  • Current use of osteoporosis medication (hormone replacement therapy (HRT), raloxifene, bisphosphonates, denosumab)
  • Current or past use of teriparatide
  • estimated glomerular filtration rate (eGFR)< 45 ml/min calculated by MDRD112 to accommodate mild declines in renal function due to aging
  • History of malignancy, except for cured skin cancers
  • Diabetes, (HbA1c>6) as this disease is also associated with decreased bone formation
  • Osteoporosis by Dual-energy X-ray Absorptiometry (DXA) at any site or an asymptomatic vertebral fracture

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Budesonide 360 mcg
Budesonide dry powder inhaler 2 puffs of 90 mcg twice daily for 4 weeks
Drug: Budesonide
inhaled glucocorticoid budesonide as dry powder inhaler
Other Names:
  • Pulmicort flexhaler
Experimental: Budesonide 720 mcg
Budesonide dry powder inhaler 2 puffs of 180 mcg twice daily for 4 weeks
Drug: Budesonide
inhaled glucocorticoid budesonide as dry powder inhaler
Other Names:
  • Pulmicort flexhaler
Placebo Comparator: Placebo
Placebo inhaler 2 puffs twice daily for 4 weeks
Other: Placebo Inhaler
inhaled placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Osteocalcin
Time Frame: Baseline and 4 weeks
The primary outcome will be the within-group change in serum osteocalcin from baseline to 4-weeks based on intention-to-treat analyses.
Baseline and 4 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Columbia University

Investigators

  • Principal Investigator: Emily M Stein, MD, Columbia University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2015

Primary Completion (Anticipated)

November 1, 2017

Study Completion (Anticipated)

November 1, 2018

Study Registration Dates

First Submitted

February 3, 2015

First Submitted That Met QC Criteria

February 5, 2015

First Posted (Estimate)

February 6, 2015

Study Record Updates

Last Update Posted (Actual)

July 18, 2017

Last Update Submitted That Met QC Criteria

July 14, 2017

Last Verified

July 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AAAO5309

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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