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

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).

Keywords: Bone Biology; Osteoporosis.

Figure 1. Effects of a β₁-AR agonist (dobutamine) and a β₂-AR agonist (salmeterol) on gene expression in hFOB cells.

Relative mRNA levels of (A) RANKL (also known as TNFSF11), (B) OPG (also known as TNFRSF11B), (C) ADRB1, and (D) ADRB2 in hFOB cells treated for 2 hours with vehicle, dobutamine (β₁-AR agonist), or salmeterol (β₂-AR agonist). See Methods for experimental details. n = 6 per treatment, with comparisons between vehicle and treatment groups using a 2-sample t test. **P < 0.01 and ***P < 0.001.

Figure 2. CONSORT flow diagram for the interventional study.

The study flow diagram shows the number of subjects assessed for eligibility as well as the number randomized, allocated, lost to follow-up, and included in the final analysis.

Figure 3. Percentage of change from baseline in bone resorption and bone formation markers in the study subjects following the assigned treatments.

Percentage of change from baseline after 20 weeks of treatment in serum levels of (A) CTx, (B) PINP, (C) TRAP5b, and (D) osteocalcin. ANCOVA P values are indicated, and when these were less than 0.05, individual groups were compared with the placebo-treated group using the Dunnett’s 2-tailed t test. *P < 0.05, **P < 0.01, and ***P < 0.001. As per the CONSORT flow diagram in Figure 2, the sample sizes for the week-20 analyses were as follows: placebo, n = 29; propranolol 20 mg b.i.d., n = 26; propranolol 40 mg b.i.d., n = 25; atenolol 50 mg/day, n = 25; and nebivolol 5 mg/day, n = 24.

Figure 4. Percentage of change from baseline in BMD in the study subjects following the assigned treatments.

Percentage of BMD change from baseline following 20 weeks of treatment at the (A) ultradistal radius, (B) distal radius, (C) femur neck, and (D) lumbar spine. ANCOVA P values are indicated, and when these were less than 0.05, individual groups were compared with the placebo-treated group using a Dunnett’s 2-tailed t test. *P < 0.05 and **P < 0.01. As per the CONSORT flow diagram in Figure 2, the sample sizes for the week-20 analyses were as follows: placebo, n = 29; propranolol 20 mg b.i.d., n = 26; propranolol 40 mg b.i.d., n = 25; atenolol 50 mg/day, n = 25; and nebivolol 5 mg/day, n = 24.