Sympathetic β1-adrenergic signaling contributes to regulation of human bone metabolism
Open accessAbstract
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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In an earlier identically designed beta-blocker RCT, β1-selective blockers lowered bone resorption and raised radius BMD, but not central-site BMD, likely because DXA at the radius is more precise.
“We observed similar findings in a previous, identically designed RCT of beta-blockers where relatively β1-selective blockers reduced bone resorption and increased BMD at the radius, but not central sites, presumably because of the greater precision for the dual-energy X-ray absorptiometry (DXA) measurements at the radius29.”
From Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial (2024) · cites this paper as [29]
The paper reports that atenolol and nebivolol reduced the bone-resorption marker CTx, and its Discussion (page unavailable) reports significant BMD gains at the ultradistal radius but no significant changes at the femur neck or spine. Our copy does not attribute the difference between sites to greater precision of radius DXA measurements, so that proposed explanation is unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredP1NP and CTx in serum were quantified using validated standard assays.
“As we have established29,39,40, serum P1NP and CTx were measured with standard, validated assays: P1NP by radioimmunoassay (Orion Diagnostica, coefficient of variation <9%); and CTx by one-step ELISA (Nordic Bioscience Diagnostics, coefficient of variation <8%).”
From Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial (2024) · cites this paper as [29]
A licensed X-ray technician with long experience performed the DXA scans, and phantom scans checked for drift.
“DXA scans of the lumbar spine (L1–L4), hip (femoral neck) and radius were obtained at baseline and 20 weeks (study endpoint) using the Lunar iDXA (GE Medical Systems; Encore software v.12.2) in the Mayo Clinic CRTU by a licensed X-ray technician with long-term experience29,39,40. Phantoms were scanned to detect potential drift and results were appended to a quality control database.”
From Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial (2024) · cites this paper as [29]
The methods passage (section labeled “Cell culture studies”; page unavailable) reports DXA measurements at baseline and 20 weeks, but does not identify who performed the scans. Searches for a licensed or experienced technician and for phantom scans or drift checks found no passage addressing those details. (LLM, conf=0.74)
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References 43 · Cited by 132
Research works printed but not linked: 1
- [40]40. Baker JG. The selectivity of beta-adrenoceptor ago- nists at human beta1-, beta2-and beta3-adreno- ceptors. Br J Pharmacol. 2010;160(5):1048-1061.
- Authors
- Khosla, S., Drake, M. T., Volkman, T. L., Thicke, B. S., Achenbach, S. J., Atkinson, E. J., Joyner, M. J., Rosen, C. J., Monroe, D. G., & Farr, J. N.
- Affiliations
- Mayo Clinic (US)
- Maine Medical Center Research Institute (US)
- Corresponding author
- Khosla, Sundeep
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2018-10-02
- Volume
- 128
- Issue
- 11
- Pages
- 4832-4842
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC6205387
- OpenAlex
- W2889322815
- Cited by
- 132
- References
- 43
- Citations by year
- 2026: 21 · 2025: 23 · 2024: 22 · 2023: 13 · 2022: 10 · 2021: 15 · 2020: 16 · 2019: 10 · 2018: 1 · 2017: 1
- FWCI
- 11.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG004875)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR027065)
- National Center for Advancing Translational Sciences (UL1 TR002377)
- Topics
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- sympathetic nervous system, beta1-adrenergic receptor, beta2-adrenergic receptor, beta3-adrenergic receptor, bone metabolism, bone microarchitecture, beta-blockers, propranolol, atenolol, nebivolol, bone resorption, C-terminal telopeptide, bone mineral density, postmenopausal women, ADRB1, ADRB2
- MeSH terms
- Adrenergic beta-Antagonists, Adult, Aged, Bone and Bones, Bone Resorption, Cell Line, Female, Humans, Middle Aged, Peptides, Sympathetic Nervous System, Signal Transduction, Receptors, Adrenergic, beta-1, Receptors, Adrenergic, beta-2, Receptors, Adrenergic, beta-3, Collagen Type I
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