The Effects of Inhaled Glucocorticoids on the Postmenopausal Skeleton
| Status: | Not yet recruiting |
|---|---|
| Conditions: | Osteoporosis |
| Therapuetic Areas: | Rheumatology |
| Healthy: | No |
| Age Range: | 60 - Any |
| Updated: | 7/11/2015 |
| Start Date: | March 2015 |
| End Date: | November 2018 |
| Contact: | Emily M Stein, MD |
| Email: | es2029@cumc.columbia.edu |
| Phone: | 212-305-0220 |
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.
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.
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.
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.
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
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