Sympathetic β1-adrenergic signaling contributes to regulation of human bone metabolism

Sundeep Khosla, Matthew M Drake, Tammie L. Volkman, Brianne S. Thicke, Sara J. Achenbach, Elizabeth J. Atkinson, Michael Joseph Joyner, Clifford J. Rosen, David G Monroe, Joshua Farr

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

BACKGROUND: Evidence from rodent studies indicates that the sympathetic nervous system (SNS) regulates bone metabolism, principally via β2-adrenergic receptors (β2-ARs). Given the conflicting human data, we used multiple approaches to evaluate the role of the SNS in regulating human bone metabolism.

METHODS: Bone biopsies were obtained from 19 young and 19 elderly women for assessment of ADRB1, ADRB2, and ADRB3 mRNA expression. We examined the relationship of β-blocker use to bone microarchitecture by high-resolution peripheral quantitative CT in a population sample of 248 subjects. A total of 155 postmenopausal women were randomized to 1 of 5 treatment groups for 20 weeks: placebo; propranolol, 20 mg b.i.d.; propranolol, 40 mg b.i.d.; atenolol, 50 mg/day; or nebivolol, 5 mg/day. We took advantage of the β1-AR selectivity gradient of these drugs (propranolol [nonselective] << atenolol [relatively β1-AR selective] < nebivolol [highly β1-AR selective]) to define the β-AR selectivity for SNS effects on bone.

RESULTS: ADRB1 and ADRB2, but not ADRB3, were expressed in human bone; patients treated clinically with β1-AR-selective blockers had better bone microarchitecture than did nonusers, and relative to placebo, atenolol and nebivolol, but not propranolol, reduced the bone resorption marker serum C-telopeptide of type I collagen (by 19.5% and 20.6%, respectively; P < 0.01) and increased bone mineral density of the ultradistal radius (by 3.6% and 2.9%; P < 0.01 and P < 0.05, respectively).

CONCLUSIONS: These 3 independent lines of evidence strongly support a role for adrenergic signaling in the regulation of bone metabolism in humans, principally via β1-ARs.

TRIAL REGISTRATION: ClinicalTrials.gov NCT02467400.

FUNDING: This research was supported by the NIH (AG004875 and AR027065) and a Mayo Clinic Clinical and Translational Science Award (CTSA) (UL1 TR002377).

Original languageEnglish (US)
Pages (from-to)4832-4842
Number of pages11
JournalThe Journal of clinical investigation
Volume128
Issue number11
DOIs
StatePublished - Nov 1 2018

Fingerprint

Adrenergic Agents
Nebivolol
Bone and Bones
Propranolol
Atenolol
Sympathetic Nervous System
Placebos
Bone Resorption
Collagen Type I
Bone Density
Adrenergic Receptors
Rodentia
Biomarkers
Biopsy
Messenger RNA
Amberlite XAD-2 resin
Research
Pharmaceutical Preparations
Population

Keywords

  • Bone Biology
  • Osteoporosis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Sympathetic β1-adrenergic signaling contributes to regulation of human bone metabolism. / Khosla, Sundeep; Drake, Matthew M; Volkman, Tammie L.; Thicke, Brianne S.; Achenbach, Sara J.; Atkinson, Elizabeth J.; Joyner, Michael Joseph; Rosen, Clifford J.; Monroe, David G; Farr, Joshua.

In: The Journal of clinical investigation, Vol. 128, No. 11, 01.11.2018, p. 4832-4842.

Research output: Contribution to journalArticle

Khosla, Sundeep ; Drake, Matthew M ; Volkman, Tammie L. ; Thicke, Brianne S. ; Achenbach, Sara J. ; Atkinson, Elizabeth J. ; Joyner, Michael Joseph ; Rosen, Clifford J. ; Monroe, David G ; Farr, Joshua. / Sympathetic β1-adrenergic signaling contributes to regulation of human bone metabolism. In: The Journal of clinical investigation. 2018 ; Vol. 128, No. 11. pp. 4832-4842.
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abstract = "BACKGROUND: Evidence from rodent studies indicates that the sympathetic nervous system (SNS) regulates bone metabolism, principally via β2-adrenergic receptors (β2-ARs). Given the conflicting human data, we used multiple approaches to evaluate the role of the SNS in regulating human bone metabolism.METHODS: Bone biopsies were obtained from 19 young and 19 elderly women for assessment of ADRB1, ADRB2, and ADRB3 mRNA expression. We examined the relationship of β-blocker use to bone microarchitecture by high-resolution peripheral quantitative CT in a population sample of 248 subjects. A total of 155 postmenopausal women were randomized to 1 of 5 treatment groups for 20 weeks: placebo; propranolol, 20 mg b.i.d.; propranolol, 40 mg b.i.d.; atenolol, 50 mg/day; or nebivolol, 5 mg/day. We took advantage of the β1-AR selectivity gradient of these drugs (propranolol [nonselective] << atenolol [relatively β1-AR selective] < nebivolol [highly β1-AR selective]) to define the β-AR selectivity for SNS effects on bone.RESULTS: ADRB1 and ADRB2, but not ADRB3, were expressed in human bone; patients treated clinically with β1-AR-selective blockers had better bone microarchitecture than did nonusers, and relative to placebo, atenolol and nebivolol, but not propranolol, reduced the bone resorption marker serum C-telopeptide of type I collagen (by 19.5{\%} and 20.6{\%}, respectively; P < 0.01) and increased bone mineral density of the ultradistal radius (by 3.6{\%} and 2.9{\%}; P < 0.01 and P < 0.05, respectively).CONCLUSIONS: These 3 independent lines of evidence strongly support a role for adrenergic signaling in the regulation of bone metabolism in humans, principally via β1-ARs.TRIAL REGISTRATION: ClinicalTrials.gov NCT02467400.FUNDING: This research was supported by the NIH (AG004875 and AR027065) and a Mayo Clinic Clinical and Translational Science Award (CTSA) (UL1 TR002377).",
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AU - Drake, Matthew M

AU - Volkman, Tammie L.

AU - Thicke, Brianne S.

AU - Achenbach, Sara J.

AU - Atkinson, Elizabeth J.

AU - Joyner, Michael Joseph

AU - Rosen, Clifford J.

AU - Monroe, David G

AU - Farr, Joshua

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N2 - BACKGROUND: Evidence from rodent studies indicates that the sympathetic nervous system (SNS) regulates bone metabolism, principally via β2-adrenergic receptors (β2-ARs). Given the conflicting human data, we used multiple approaches to evaluate the role of the SNS in regulating human bone metabolism.METHODS: Bone biopsies were obtained from 19 young and 19 elderly women for assessment of ADRB1, ADRB2, and ADRB3 mRNA expression. We examined the relationship of β-blocker use to bone microarchitecture by high-resolution peripheral quantitative CT in a population sample of 248 subjects. A total of 155 postmenopausal women were randomized to 1 of 5 treatment groups for 20 weeks: placebo; propranolol, 20 mg b.i.d.; propranolol, 40 mg b.i.d.; atenolol, 50 mg/day; or nebivolol, 5 mg/day. We took advantage of the β1-AR selectivity gradient of these drugs (propranolol [nonselective] << atenolol [relatively β1-AR selective] < nebivolol [highly β1-AR selective]) to define the β-AR selectivity for SNS effects on bone.RESULTS: ADRB1 and ADRB2, but not ADRB3, were expressed in human bone; patients treated clinically with β1-AR-selective blockers had better bone microarchitecture than did nonusers, and relative to placebo, atenolol and nebivolol, but not propranolol, reduced the bone resorption marker serum C-telopeptide of type I collagen (by 19.5% and 20.6%, respectively; P < 0.01) and increased bone mineral density of the ultradistal radius (by 3.6% and 2.9%; P < 0.01 and P < 0.05, respectively).CONCLUSIONS: These 3 independent lines of evidence strongly support a role for adrenergic signaling in the regulation of bone metabolism in humans, principally via β1-ARs.TRIAL REGISTRATION: ClinicalTrials.gov NCT02467400.FUNDING: This research was supported by the NIH (AG004875 and AR027065) and a Mayo Clinic Clinical and Translational Science Award (CTSA) (UL1 TR002377).

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