The Effects of Inhaled Glucocorticoids on the Postmenopausal Skeleton

NCT ID: NCT02357277

Last Updated: 2017-07-18

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE4
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-03-31
• Study Completion Date: 2018-11-30

Brief Summary

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.

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.

Conditions

Osteoporosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: DOUBLE

Study Groups

Budesonide 360 mcg

Budesonide dry powder inhaler 2 puffs of 90 mcg twice daily for 4 weeks

Group Type: EXPERIMENTAL

Budesonide

Intervention Type: DRUG

inhaled glucocorticoid budesonide as dry powder inhaler

Budesonide 720 mcg

Budesonide dry powder inhaler 2 puffs of 180 mcg twice daily for 4 weeks

Group Type: EXPERIMENTAL

Budesonide

Intervention Type: DRUG

inhaled glucocorticoid budesonide as dry powder inhaler

Placebo

Placebo inhaler 2 puffs twice daily for 4 weeks

Group Type: PLACEBO_COMPARATOR

Placebo Inhaler

Intervention Type: OTHER

inhaled placebo

Interventions

Budesonide

inhaled glucocorticoid budesonide as dry powder inhaler

Intervention Type: DRUG

Placebo Inhaler

inhaled placebo

Intervention Type: OTHER

Other Intervention Names

Pulmicort flexhaler

Eligibility Criteria

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

• Minimum Eligible Age: 60 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Columbia University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Emily M Stein, MD

Role: PRINCIPAL_INVESTIGATOR

Columbia University

Other Identifiers

AAAO5309

Identifier Type: -

Identifier Source: org_study_id