Dose Response and Receptor Selectivity of Beta-blocker Effects on Bone Metabolism

This study is designed to answer the question as to whether the sympathetic nervous system is an important determinant of bone metabolism in humans.

Study Overview

• Status: Completed
• Conditions: Osteoporosis, Age-Related
• Intervention / Treatment: Drug: placebo; Drug: Atenolol; Drug: Nebivolol; Drug: Propranolol

Detailed Description

In postmenopausal women, who have increased sympathetic outflow, to test the hypothesis that treatment with low doses of a non-selective β-blocker (propranolol) will increase serum markers of bone formation and reduce markers of bone resorption (Aim 1a); and using increasingly β1-AR (adrenergic receptor) selective blockers (atenolol and nebivolol), to better define the β-adrenergic receptor selectivity (β1 versus β2) in the regulation of bone turnover by sympathetic outflow in humans.

• Study Type: Interventional
• Enrollment (Actual): 165
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

• Inclusion Criteria:

  • at least 5 yrs since their last menses
  • Follicle Stimulating Hormone (FSH) > 20 IU/L

• Exclusion Criteria:

  • Abnormality in any of the screening laboratory studies
  • Presence of significant liver or renal disease
  • Malignancy (including myeloma)
  • Malabsorption
  • Diabetes
  • Hypoparathyroidism
  • Hyperparathyroidism
  • Acromegaly
  • Cushing's syndrome
  • Hypopituitarism
  • Severe chronic obstructive pulmonary disease
  • Undergoing treatment with any medications that affect bone turnover, including the following:
• adrenocorticosteroids (> 3 months at any time or > 10 days within the previous yr)
• anticonvulsant therapy (within the previous year)
• pharmacological doses of thyroid hormone (causing decline of thyroid stimulating hormone below normal)
• calcium supplementation of > 1200 mg/d (within the preceding 3 months)
• bisphosphonates (within the past 3 yrs)
• denosumab
• estrogen (E) therapy within the past year
• treatment with a selective E receptor modulator within the past year
• teriparatide within the past yr

• anti-hypertensive therapy

  • Clinical history of osteoporotic fracture (vertebral, hip, or distal forearm
  • Recent (within the past 6 months) fracture
  • Serum 25-hydroxyvitamin D levels of < 20 ng/ml
  • Resting blood pressure >140/90 mm Hg or those with hypotension (systolic blood pressure <110 mm Hg), heart rate < 60 bpm
  • History of asthma

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo; Sugar pill 2/day for 20 weeks; The once daily groups will receive a placebo as the second dose	Drug: placebo; placebo
Active Comparator: Atenolol; Atenolol 50 mg 1/day for 20 weeks	Drug: Atenolol; beta blocker
Active Comparator: Nebivolol; Nebivolol 5 mg/day for 20 weeks	Drug: Nebivolol; beta blocker
Active Comparator: Propranolol 40 mg; Propranolol 20 mg bid for 20 weeks	Drug: Propranolol; beta blocker
Active Comparator: Propranolol 80 mg; Propranolol 40 mg bid for 20 weeks	Drug: Propranolol; beta blocker

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ratio of serum bone formation to bone resorption marker	Serum bone formation marker (PINP)/serum bone resorption marker (CTX)	20 weeks

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Investigators: Principal Investigator: Sundeep Khosla, MD, Mayo Clinic

Publications and helpful links

General Publications

• Khosla S, Drake MT, Volkman TL, Thicke BS, Achenbach SJ, Atkinson EJ, Joyner MJ, Rosen CJ, Monroe DG, Farr JN. Sympathetic beta1-adrenergic signaling contributes to regulation of human bone metabolism. J Clin Invest. 2018 Nov 1;128(11):4832-4842. doi: 10.1172/JCI122151. Epub 2018 Oct 2.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2015
• Primary Completion (Actual): October 26, 2017
• Study Completion (Actual): April 1, 2018

Study Registration Dates

• First Submitted: June 4, 2015
• First Submitted That Met QC Criteria: June 9, 2015
• First Posted (Estimate): June 10, 2015

Study Record Updates

• Last Update Posted (Actual): February 6, 2019
• Last Update Submitted That Met QC Criteria: February 4, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: bone formation
• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic; Osteoporosis; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic Agonists; Adrenergic beta-Agonists; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Adrenergic beta-1 Receptor Agonists; Propranolol; Nebivolol; Atenolol
• Other Study ID Numbers: 14-004305

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No