The autonomic nervous system and bone health in chronic kidney disease

Abstract

Besides the well-known role of hormonal factors in mineral and bone metabolism, the sympathetic nervous system participates in this regulation by inhibiting bone formation and promoting bone resorption, primarily via β-adrenergic receptors expressed on osteoblasts. Conversely, the parasympathetic system, through cholinergic signalling, inhibits osteoclast activity, promoting bone formation and maintaining skeletal homeostasis. This review presents the role of the autonomic nervous system, with particular focus on the potential role of β-blockers, especially β1-selective blockers, in modulating bone health in people with normal kidney function and those with CKD. While early studies with non-selective β-blockers like propranolol showed mixed results, recent findings in postmenopausal women suggested that β1-selective β-blockers could enhance bone density by modulating sympathetic activity. Trial emulation using large databases and eventually randomized controlled trials are needed to test the hypothesis that β-blockade can favourably impact bone disease in patients with kidney failure.

1 ∣. INTRODUCTION

The skeleton, the largest organ in the human body, plays a role that extends far beyond the traditional functions of support, locomotion and protection. The skeleton is a crucial reservoir of minerals, particularly calcium and phosphorus, essential for various cellular activities and physiological processes. The bones can release these minerals into and take them up from the circulation, maintaining mineral homeostasis and supporting metabolic functions.¹ It also exerts a buffer function, especially of acid loads. Moreover, the bone regulates glucose metabolism and systemic energy balance.² Beyond these metabolic functions, the bone interacts with the brain and the autonomous nervous system. One established mechanism of this interaction involves osteocalcin.³ This peptide hormone, primarily produced by osteoblasts, plays a significant role in bone metabolism and exerts other functions beyond the skeletal system. Osteocalcin can cross the blood–brain barrier, and once in the brain, it exerts neural actions, including the regulation of oligodendrocyte myelination, which is crucial for the proper insulation of nerve fibres and efficient neural transmission.

A complex interplay of genetic, hormonal and environmental factors tightly regulates skeletal structure and function.⁴ Environmental factors, particularly mechanical forces from locomotion and gravity, are crucial in bone formation and adaptation to physical activity.^4,5 This is primarily achieved through the basic multicellular units of osteoblasts and osteoclasts, which carry out bone formation and resorption. Along with endocrine control, central regulation of bone mass is fundamental.^6,7 The regulatory axis between the nervous system and the bone is an expanding and fruitful research area.

Innervation is one of the most important pathways in the mechanical regulation of bone growth,⁸ an effect achieved via muscle movement, which provides the necessary compression or tension to bones. The bone is a dynamic tissue that adapts to the changing demands of growth, physiological conditions like lactation,⁹ mechanosensing and mechanical strain, and variations of calcium and phosphate in the internal and external milieu. Osteoblasts and osteoclasts form a functional network that ensures continuous bone remodelling. This process is regulated locally by autocrine factors and systemically by a complex system involving several hormones. Bone metabolism is regulated by a complex interactome,¹⁰ and the nervous system participates in this regulation through multiple bidirectional pathways. The hypothalamus plays a crucial role. Its semipermeable blood–brain barrier allows the detection and integration of signals from peripheral tissues via the circulatory system and neural networks, and efferent neuronal discharges complete the brain-bone link.¹¹

Notwithstanding the critical role of the autonomic system in bone physiology¹² and the pervasive nature of chronic kidney disease—bone mineral disorder (CKD-BMD),¹³ neural mechanisms of bone regulation in CKD have received scarce attention. Understanding these mechanisms may highlight additional therapeutic interventions, making this issue clinically relevant.

Given this background, the present review first focuses on the physiological relevance of central and autonomic nervous system control of bone mass and then discusses the alterations of these control mechanisms in CKD, a condition characterized by markedly enhanced sympathetic activity and suppressed parasympathetic activity.¹⁴

2 ∣. PHYSIOLOGICAL REGULATION OF BONE HEALTH BY THE AUTONOMIC AND CENTRAL NERVOUS SYSTEMS

Bone remodelling, a continuous process involving the removal and replacement of bone tissue, maintains the integrity and function of the skeleton.¹⁵ Osteoclasts, derived from haematopoietic cells, resorb bone, while osteoblasts, originating from mesenchymal cells, form new bone. Osteoblasts can differentiate into osteocytes, which act as mechanosensory and endocrine cells, playing a crucial role in bone remodelling. While the regulation of bone remodelling by endocrine, paracrine, and mechanical factors is well-established, more recent research has focused on the role of neural control in this process.⁷ Observations in mutant mouse models of obesity have been crucial for discovering the central regulation of bone mass.¹⁶ Short-chain fatty acids generated by the gut microbiota cross the blood–brain barrier, enhance central sympathetic function¹⁷ and probably modulate parathyroid function.¹⁸

2.1∣. The autonomic nervous system

The autonomic nervous system (ANS) is integral to how the central nervous system (CNS) processes information from the environment and the body’s internal state, relaying signals through autonomic and somatic motor pathways.¹² The ANS is divided into the sympathetic and parasympathetic systems. The sympathetic system primarily uses norepinephrine, while the parasympathetic system uses acetylcholine as neurotransmitters.

Sensory nerves in the skeleton release neurotransmitters like substance P¹⁹ and calcitonin gene-related peptide²⁰ responding to mechanical stimuli involved in pain sensations from bone trauma or disease.²¹ These nerves, originating from the dorsal root ganglia, detect various environmental stimuli and relay signals to the brain for processing.²² The periosteum and trabecular bone are richly innervated, with sensory fibres including myelinated A fibres and small-diameter C fibres,²³ contributing to pain sensation associated with bone injuries.

Sympathetic nerves innervate the skeleton⁸ coordinated by brain stem and hypothalamus neurons, responding to stressors like exercise and cold to maintain homeostasis.⁸ Preganglionic neurons in the spinal cord synapse with postganglionic neurons in the sympathetic chain. Postganglionic neurons, which are noradrenergic and peptidergic, project to the skeleton,²⁴ with fibres found in the periosteum and bone marrow.²⁵ Both bone compartments receive noradrenergic fibres (often associated with the vasculature) and non-adrenergic vesicular acetylcholine transporter (VAChT)- and vasoactive intestinal polypeptide-immunoreactive fibres.²⁵ Sympathetic periosteal fibres branch within the bone marrow and compact bone, as shown by immunoreactivity for tyrosine hydroxylase, dopamine β-hydroxylase, or neuropeptide Y (NPY),²⁶ which are markers of sympathetic nerves. In general, the areas of mineralized bone that undergo the greatest mechanical stress and load have the highest metabolic rate and bone turnover. They are also the most vascularized bone areas and display the highest density of sympathetic and sensory nerve fibres.

The parasympathetic system innervates the skeleton through cholinergic fibres.²⁷ Cranial nerves from the brain stem and sacral preganglionic neurons innervate different body regions. Parasympathetic neurons in the bone microenvironment, identified by VAChT and ChAT markers, communicate IL-1 signals for bone mass accrual.²⁸ These neurons help mediate CNS signals affecting bone density and health, with IL-1 influencing bone remodelling.

Neuronal circuitries between the central nervous system and the skeleton. An advanced technique using the pseudorabies virus has allowed tracing multisynaptic connections and revealed a circuit linking autonomic spinal and brain areas to femoral nerve fibres via sympathetic and parasympathetic neurons.²⁹ The studies on the autonomic nervous system’s effects on bone cells are collectively presented in Table 1.

TABLE 1.

Summary of Autonomic Nervous System Effects on Bone Cells.

Aspect of regulation	Description	Reference
Sympathetic regulation
β2-Adrenergic Receptors	Prominent in osteoblasts; stimulation promotes osteoclastogenesis and inhibits bone formation, leading to bone loss. Mice lacking β2 receptors have high bone mass	30
α2-Adrenergic Receptors	α2A, α2B and α2C receptor transcripts detected at low levels in bone tissues; β receptors are main adrenergic receptors in bone remodelling	31
NE and β2 Receptors	NE stimulation of β2 receptors promotes osteoclastogenesis via RANKL in osteoblasts, involving ATF4 and PKA	32
FoxO1 and Sympathetic Outflow	Mice lacking FoxO1 in dopamine β-hydroxylase-positive neurons show low sympathetic outflow and high bone mass, similar to β receptor knock-out mice	33
Norepinephrine Transporter (NET)	Controls NE release by re-uptake into presynaptic neurons; NET-deficient mice exhibit low bone mass. Osteoblasts and osteocytes express NET, acting as a catabolic sink for NE	34,35
Cannabinoid Receptor 1 (CB1)	Induces presynaptic inhibition of NE release; CB1-deficient mice show low bone mass with reduced bone formation and increased resorption	36-38
Neuropeptide Y (NPY)	Released during stress, via Y1R and Y2R receptors inhibits bone formation. NPY−/− and Y2R-deficient mice show exaggerated bone loss under stress	39-42
Parasympathetic regulation
Acetylcholine (ACh)	Primary neurotransmitter; cholinergic receptors (nAChRs and mAChRs) detected in osteoclasts and osteoblasts	43,44
Cholinergic Signalling	Targets osteoclasts, inhibiting activity; nAChR agonists upregulate osteoclast apoptosis, AChE inhibitors inhibit bone resorption	28,45
Central IL-1 and Parasympathetic Outflow	Inhibition of central IL-1 signalling reduces parasympathetic outflow, leading to low bone mass and increased resorption	28,46

2.2 ∣. Sympathetic regulation of bone remodelling

Various preclinical observations show that osteoblasts and osteoclasts express various subtypes of α and β-adrenergic receptors, with β2 receptors being the most prominent receptors in osteoblasts. Their activation inhibits bone formation and promotes osteoclastogenesis, leading to bone loss³⁰ (Figure 1). Moreover, β1 receptors also are expressed in human bone cells,⁴⁷ and it has been shown that their blockade improves bone microarchitecture, reduces bone resorption and increases bone mineral density.⁴⁸

FIGURE 1.

Autonomic control of bone formation and resorption. Noradrenergic nerve terminals in bone release norepinephrine at the vicinity of osteoblasts and stimulate the β1 and 2 adrenergic receptors which results in reduced bone formation. β2 adrenergic receptors are also present in osteocytes where they contribute to enhance osteoclastogenesis via RANKL. The norepinephrine transporter (NET, not shown in the Figure) plays a crucial role in regulating bone metabolism by controlling the levels of norepinephrine available in the synaptic cleft. NET is responsible for reuptake norepinephrine into presynaptic neurons, thereby terminating its action. When NET function is impaired, as seen in norepinephrine transporter-deficient models, there is an increase in norepinephrine levels due to reduced reuptake. This leads to enhanced sympathetic signalling, resulting in decreased bone formation and increased bone resorption. The Receptor Activator for Nuclear Factor kappa-B (RANKL) synthesized in osteoblasts activates osteoclasts. This leads to inhibition of bone formation and increased RANKL expression, leading to osteoclast formation and increased bone resorption. Cannabinoid receptor 1 (CB, not shown) signalling is known to transmit retrograde signals that can restrain norepinephrine release and transiently stimulate bone formation following an acute challenge. Neuropeptide Y (NPY), acting through Y1 receptors on osteoblasts, suppresses osteoblast activity (=). The parasympathetic system, via acetylcholine and acetylcholine receptors in osteoclasts, promotes apoptosis of these cells, thereby reducing bone resorption. Conversely, acetylcholine esterase, which degrades acetylcholine, increases bone resorption. (modified by Ref. [14]). Sclerostin, made by osteocytes, inhibits osteoblast function (=).

Transcripts of α2A and, to a lesser extent, α2B and α2C adrenergic receptors are detected at low levels in bone tissues.³² Their weak expression suggests that β-adrenergic receptors are the primary adrenergic receptors mediating sympathetic nerve action on bone remodelling.

Norepinephrine stimulation of β2 receptors impacts bone remodelling by promoting osteoclastogenesis via the release of Receptor Activator of Nuclear Factor Kappa B Ligand (RANKL) from osteoblasts (Figure 1), which involves activating transcription factor 4 and protein kinase A.³³ On the other hand, this neurotransmitter is also an established agonist for β1 receptors.⁴⁹

Experimental alteration of skeletal sympathetic nerves confirms the role of endogenous norepinephrine on bone remodelling. Mice lacking Forkhead Box O1, a fundamental transcription factor for development and differentiation, in dopamine β-hydroxylase-positive neurons show low sympathetic outflow and a high bone mass phenotype, similar to mice with double knockout for β adrenergic receptors.³⁴

Control of sympathetic outflow. Sympathetic nerves release norepinephrine at synaptic terminals to stimulate postsynaptic target cells. Feedback mechanisms involving presynaptic α-adrenergic receptors, the norepinephrine transporter, the cannabinoid system and the Neuropeptide Y (NPY)-ergic system control the intensity and duration of this signal. The norepinephrine transporter (NET) controls the amount of norepinephrine released by sympathetic neurons by reuptake into presynaptic neurons, clearing 80%–90% of it. Pharmacological NET blockade leads to acute NE spillover, but long-term inhibition depletes intracellular NE storage, which may result in low systemic levels of NE. Male NET-deficient mice exhibit low bone mass because, in face of low circulating NE levels, NE in the synaptic cleft remains elevated.³⁵ Differentiated osteoblasts and osteocytes express NET and can uptake and catabolize norepinephrine, acting as a catabolic sink, and thereby buffer the catabolic action of sympathetic nerves on the skeleton.³⁵

The cannabinoid receptor 1 (CB1) induces presynaptic inhibition of norepinephrine release.³⁶ CB1 and CB2 receptors are coupled to Gi/o proteins, with CB1 being mainly expressed in presynaptic neurons and CB2 in peripheral tissues, including bone cells.³⁷ Mice lacking CB1 exhibit reduced bone formation, increased bone resorption and low bone mass.³⁸ However, CB1-deficient mice on different genetic backgrounds show varying bone phenotypes, complicating the understanding of CB1’s role in bone remodelling.

2.3 ∣. Parasympathetic regulation of bone remodelling (pre-clinical studies)

Acetylcholine is the primary neurotransmitter of the parasympathetic nervous system. Table 2, which includes pertinent literature references, presents an exhaustive series of acetylcholine receptors, mRNAs and transporters expressed in bone cells.

TABLE 2.

Adrenergic and acetylcholine receptors and mRNAs expressed in bone cells [Correction added on 26 Feb 2025, after first online publication: Table 2 caption was corrected.].

Cells investigated and (model)	Receptor/Enzyme	Reference
Monocytes (mice)	γ, δ and ε α2 adrenergic receptors, α10 receptors and β2 nicotinic acetylcholine receptors(nAChR); β1 muscarinic AChR (β1 MAChR)	28
Bone marrow-derived osteoclasts (mice)	γ, δ, ε, α2 adrenergic receptors, β2 and β4 nicotinic AChR; β1 mAChR	28
	α2–7 adrenergic receptors, α9–10 adrenergic receptors, β2–3 nAChR	50
Differentiated Research Animal Workshop (RAW)264.7 cells:	α1–5, 7, 9 and 10 nAChR	45
Osteoblasts (mouse calvaria)	β2, β4, α4, α7 nAChR; α1, β1, γ, δ, MACh1R, MACh2R, MACh4; Acetylcholine esterase (AChE), Vascular Acetyl-choline transporter (VAChT), Choline acetyl transferase (ChAT) and Choline transporter 1 (CHT1)	28
Osteoblasts (human) and osteosarcoma (MG63 line)	α4 nAChR	51
Sarcoma Osteogenic line 2 (SaOS2) cells	Carnitine acetyltransferase; MAch3R and MACh 5R; α3, α5, α9, α10, β2 nAChR; Butyrylcholinesterase (BChE)	43
Mouse Calvaria 3, Type 3 (MC3T3) cells	Carcinoembryonic Antigen Choline Transporte (CarChT), VAChT, ChAT, (α1), α2, α3, α5, β2 and β4 nAChR; MACh1R, MACh4R; AChE and BChE	43,52
Differentiated Osteoblasts (mice) in MC3T3 cells:	CarChT, VAChT (α1), α6, α7, δ, ε, β2, β3 and β4 nAChR; MACh1R, M2AchR, MACh4R; AChE and BChE	43,52
Calvarial osteoblasts	AChE, VAChT; α1, α6, α7, β1, β4, δ and ε-nAChRs; MACh1R, M2AChR, MACH4R	21,53

Note: Receptors types, transporters and other abbreviations are given when first mentioned. Quoted references (last column) indicate detailed reports on receptors, pertinent transporters and mRNAs expressed in bone cells.

Cholinergic receptors are divided into nicotinic (nA-ChRs) and muscarinic (mAChRs) receptors. Cholinergic receptors are composed of multiple subunits, and their RNA transcripts are detected in osteoclasts and osteoblasts, with α2nAChR being the most abundant in osteoclasts.⁴³ mAChR M4 subtype expression is detected in immature and differentiated osteoblasts.⁴⁴

Cholinergic signalling targets osteoclasts, inhibiting their activity (Figure 1). nAChR agonists upregulate osteoclast apoptosis, and acetylcholine inhibitors like pyridostigmine inhibit bone resorption in vivo.²⁸ Nicotine reduces proinflammatory bone marrow monocyte and osteoclast activity,⁴⁵ and double-knockout α2nAChR mice display low bone mass with high osteoclast numbers.⁴⁵

Parasympathetic signalling also regulates bone homeostasis via central mechanisms. This is illustrated by the action of donepezil, a central parasympathetic agonist of acetylcholine, which inhibits sympathetic outflow and increases bone mass.⁴⁶ On the other hand, inhibition of central interleukin-1 signalling reduces parasympathetic outflow to the heart and skeleton, as shown by reduced skeletal VAChT protein expression. Mice with central IL-1 receptor inhibition exhibit low bone mass and increased bone resorption, not reversed by peripheral acetylcholine inhibition.²⁸ This suggests a central IL-1-driven regulation of bone remodelling via the parasympathetic system.

2.4 ∣. Factors impacting hypothalamic and peripheral control of bone mass (Figure 2)

FIGURE 2.

Neuropeptide I (NPY) inhibits bone formation via hypothalamic centers. Furthermore, this peptide peripherally inhibits bone formation by reducing osteoblast proliferation. Leptin, a NPY-interacting adipokine, acts on the hypothalamus to regulate bone metabolism through central pathways. In the arcuate nuclei of the hypothalamus, leptin signalling increases the expression of cocaine- and amphetamine-regulated transcript (CART), which subsequently inhibits the synthesis of receptor activator of nuclear factor kappa-B ligand (RANKL). This inhibition can lead to decreased bone resorption by osteoclasts. In addition to NPY and Leptin, parasympathetic signalling also regulates bone homeostasis via central mechanisms because ACh inhibits sympathetic outflow, thereby favouring osteoclastogenesis and bone resorption via peripheral beta2 adrenergic receptors (see text). Central interleukin-1 (IL-1) signalling reduces parasympathetic outflow and tilts the balance toward sympathetic activity predominance, an effect favouring increased bone resorption.

NPY is a neurotransmitter released by sympathetic nerves during stress, affecting both central and peripheral nervous systems.³⁹ NPY signals through five receptors, with Y1R and Y2R involved in bone homeostasis.⁴⁰ NPY inhibits bone formation both centrally in the hypothalamus and peripherally via Y1 receptors in osteoblasts. NPY-deficient and Y2R-deficient mice exhibit exaggerated bone loss under stress, indicating NPY’s protective role.⁴¹ NPY signalling also responds to gonadal failure-induced bone loss.⁴² Leptin, an adipokine, increases the expression of cocaine- and amphetamine-regulated transcript (CART) in the arcuate nuclei of the hypothalamus, which subsequently inhibits the synthesis of the receptor activator of nuclear factor kappa-B ligand (RANKL).⁵⁴ This inhibition can lead to decreased bone resorption by osteoclasts. Leptin and NPY interact in a complex way to regulate the metabolism of cancellous and cortical bone, respectively. While the Y2-mediated anabolic pathway stimulates both cortical and cancellous bone formation, the leptin-mediated pathway has opposing effects on cortical and cancellous bone, diminishing the production of cortical bone while stimulating that of cancellous bone.⁵⁵ The hypothalamus is involved in this interaction, where leptin inhibits NPY expression and release⁵⁵ (Figure 2). The preclinical evidence linking leptin,³⁰ and NPY⁵⁶ to bone disease has significant implications for understanding and treating bone disorders. Both leptin and NPY are involved in the pathogenesis of osteoporosis, a condition characterized by reduced bone mass and increased fracture risk. Patients with anorexia nervosa have low serum leptin levels that correlate directly to low body mass index and percent body fat,⁵⁷ contributing to osteoporosis. Conversely, reduced NPY levels can enhance bone formation and increase bone mass, potentially offering a therapeutic target for osteoporosis. Leptin excess is associated with inflammation and cartilage degradation in osteoarthritis and rheumatoid arthritis,⁵⁸ while NPY can modulate pain and inflammation in rheumatoid arthritis.⁵⁹

3 ∣. CHANGES IN THE INTERACTION OF AUTONOMIC NERVE FUNCTION, LEPTIN AND NEUROPEPTIDE Y WITH BONE IN CKD

At the outset, we searched pertinent literature in PubMed to identify clinical reports in this field. The search criteria used are detailed in Table 3. The search yielded 84 papers; among these, only one study investigated an association between autonomic function measured by heart rate variability and biomarkers of bone metabolism, while the remaining 83 were not pertinent to the issue under investigation. The study was based on 134 patients with kidney failure, including pre-dialysis and dialysis patients.⁶⁰ Circulating PTH, FGF23 and bone-specific alkaline phosphatase were associated with some metrics of time-domain RR-interval variability but not with frequency-domain parameters. However, the lack of internal consistency of study findings and low quality of reporting make it difficult to interpret. Well-designed observational studies, including cross-sectional and longitudinal analyses of autonomic function metrics (validated parasympathetic and sympathetic function measurements) and bone structure, as assessed by bone histology or bone mineral density, remain a clinical research priority.

TABLE 3.

‘Search Criteria for the Review’.

Original papers dealing with the autonomic system inflammation link were searched in PubMed by using the string:
(((‘Autonomic Nervous System’[Mesh] OR ‘Sympathetic Nervous System’[Mesh] OR ‘Parasympathetic Nervous System’[Mesh] OR ‘Neuropeptide Y’[Mesh] OR ‘Leptin’[Mesh]) AND (‘Bone and Bones’[Mesh] OR ‘Bone Remodelling’[Mesh] OR ‘Bone Density’[Mesh] OR ‘Osteoclasts’[Mesh] OR ‘Osteoblasts’[Mesh])) AND (Chronic Kidney Disease OR Chronic Renal Insufficiency OR ‘Kidney Failure, Chronic’[Mesh] OR End-Stage Renal Disease OR ‘Renal Dialysis’[Mesh])) OR ((autonomic system OR sympathetic nervous system OR parasympathetic nervous system OR neuropeptide Y OR leptin) AND (bone OR bone remodelling OR bone density OR osteoclasts OR osteoblasts) AND (chronic kidney disease OR chronic renal insufficiency OR end-stage renal disease OR renal dialysis))
Original papers dealing with the effect of betablockers on bone disease in CKD were searched with the string:
((‘Beta-Blockers’[Mesh] OR beta-blockers OR beta-adrenergic blockers OR beta-adrenergic antagonists) AND (‘Bone and Bones’[Mesh] OR ‘Bone Remodelling’[Mesh] OR ‘Bone Density’[Mesh] OR bone OR bone remodelling OR bone density OR osteoclasts OR osteoblasts) AND (‘Chronic Kidney Disease’[Mesh] OR ‘Chronic Renal Insufficiency’[Mesh] OR ‘Kidney Failure, Chronic’[Mesh] OR ‘End-Stage Renal Disease’[Mesh] OR ‘Renal Dialysis’[Mesh] OR chronic kidney disease OR chronic renal insufficiency OR end-stage renal disease OR renal dialysis))

As to leptin and NPY, in a cross-sectional study of end-stage kidney disease in patients receiving haemodialysis therapy,⁶¹ serum leptin levels were inversely related to serum intact parathyroid hormone (PTH) and bone alkaline phosphatase levels in male persons, suggesting leptin may reduce bone turnover. This relationship was not observed in female persons, indicating potential sex-specific mechanisms. Further exploring the influences on bone health of sympathetic system neurotransmitters in a study in patients on haemodialysis,⁶² an inverse relationship between NPY levels and serum bone-specific alkaline phosphatase was observed, generating the hypothesis that NPY may contribute to low bone turnover in such patients independently of PTH.

In addition to these neurohormonal factors, changes in autonomic function may indirectly affect bone in CKD patients due to alterations in skeletal muscle innervation, mass and function, which reduce mechanosensing and mechanical strain.^63,64

4 ∣. POTENTIAL INTERVENTIONS ON THE AUTONOMIC SYSTEM THAT MAY FAVOURABLY IMPACT BONE HEALTH IN CKD

CKD-MBD is a systemic disorder commonly seen in patients with CKD. It is characterized by abnormalities in mineral metabolism, bone turnover and vascular or soft tissue calcification. These disturbances result from impaired kidney function, leading to calcium, phosphate, parathyroid hormone (PTH), Fibroblast Growth Factor 23 (FGF23)/Klotho imbalances and subnormal 1,25 (OH)₂ vitamin D levels. CKD-MBD significantly increases the risk of fractures, cardiovascular disease and mortality in CKD patients.

The autonomic nervous system regulates bone remodelling and mineral metabolism. Understanding how the autonomic system interacts with CKD-MBD can open new avenues for therapeutic interventions that improve bone health and reduce cardiovascular risk in CKD patients. Potential interventions targeting the autonomic system could modulate sympathetic and parasympathetic activity to favourably impact bone remodelling and mineral metabolism in CKD-MBD.

In CKD⁶⁵ and kidney failure,⁶⁶ the sympathetic nervous system activity attains the highest levels among chronic diseases, and this alteration is coupled with parasympathetic inhibition.⁶⁷ These abnormal activities not only contribute to hypertension and increased cardiovascular morbidity and mortality but also impact fundamental biological functions like innate immunity, inflammation⁶⁸ and bone health.⁴⁸ The autonomic system-bone interaction is of relevance in that it may underlie still unexplored pathways for preserving bone health and curing bone disease in the CKD population.

4.1 ∣. Beta-blockers and bone disease in patients on haemodialysis therapy

Table 3 details the search strategy for identifying original papers on beta-blockade in haemodialysis patients. This search yielded 34 original papers, 23 of which were not pertinent to the studied issue. No study reported information on patients with pre-dialysis CKD. The remaining 11 papers, focusing on dialysis patients, are discussed below (Table 4).

TABLE 4.

Clinical Studies on Beta-Blockers and Bone Health in CKD.

Study	Design and participants	Key findings	Limitations	Reference
Caro et al., 1978	Retrospective case–control; 9 on propranolol, 25 controls	Lower PTH and alkaline phosphatase; less radiological evidence of osteodystrophy in propranolol group	Small sample size; did not account for confounding variables like vitamin D; short follow-up	69
Brancaccio et al., 1978	Retrospective case–control; 33 on propranolol, 33 controls	Lower prevalence of radiological bone resorption in propranolol group	Retrospective design; limited participant number; short follow-up	70
Coevoet et al., 1980	Non-randomized; 9 on propranolol, 6 on metoprolol	Propranolol reduced PTH by 50% and calcitonin by 30%; metoprolol ineffective	Non-randomized; small sample size; no control group	71
Pizzarelli et al., 1982	Retrospective case–control; well-matched control group	No significant differences in bone resorption or biochemical markers	Retrospective design; limited participant number	72
Anumas et al., 2023; Hashimoto et al., 2024	Retrospective case–control; 128 and 291 participants, respectively	No significant difference in bone mineral density among patients on/off beta-blockers	Retrospective design; potential for confounding factors	73,74

In the late seventies, two pioneering studies^69,70 about the effects of propranolol, an unselective beta-adrenergic blocker, on bone disease in patients undergoing haemodialysis therapy stimulated interest in the autonomic control of the bone in these patients and patients with CKD in general. The first study, a retrospective case–control study by Caro et al.⁶⁹ compared nine patients receiving propranolol for hypertension or angina pectoris with 25 similar patients not taking the drug. The results showed that serum PTH and alkaline phosphatase concentrations were lower in patients receiving propranolol, and they had less radiological evidence of renal osteodystrophy. The authors suggested that propranolol might be helpful as an adjunct therapy in reversing or preventing renal osteodystrophy. However, there was no precise information on bone disease type and degree of severity. In another retrospective case–control, Brancaccio et al. compared 33 patients on haemodialysis receiving propranolol treatment with 33 control patients not taking the drug.⁷⁰ Their findings, published in the format of a Letter to the Editor, were in agreement with those of Caro et al., with a lower prevalence of bone resorption, which was semi-quantitatively assessed by X-ray, but available methodological details were limited. The possibility that beta blockade can effectively reduce PTH secretion was confirmed by Coevoet et al. in a non-randomized study, in which nine patients with advanced CKD sequentially received a continuous I.V. infusion of propranolol and, after a two-week washout period, an I.V. infusion of metoprolol (a β1-selective β-blocker) in six of same patients [Correction added on 26 Feb 2025, after first online publication: The preceding sentence was corrected.].⁷¹ Remarkably, plasma PTH was reduced by 50% and calcitonin by 30% in response to propranolol, while metoprolol was ineffective. The contrast between the responses to propranolol and metoprolol was interpreted as implying that PTH and calcitonin secretion are modulated through specific beta2 receptors. The studies by Caro and Brancaccio were retrospective in nature and had limited sample sizes. Caro’s study compared patients on propranolol with patients who did not receive the drug. However, the authors did not account for other variables that might influence PTH levels and bone health, such as vitamin D sterols. Moreover, neither study followed the patients for a sufficient time period allowing the authors to determine long-term effects of propranolol on renal osteodystrophy, not to mention the precise type of it. In the Coevoet et al. study, the infusion of propranolol and metoprolol was not randomized. Furthermore, metoprolol was administered only in six patients, and the study did not include a control group.⁷¹ These shortcomings and a subsequent retrospective case–control study in patients on haemodialysis by Pizzarelli et al.,⁷² that found no significant differences in x-ray-assessed bone resorption or biochemical markers of bone disease compared to a well-matched control group, quickly waned any interest in the potential of β-blockers for the treatment of renal osteodystrophy in patients with CKD in the nephrology community. The findings by Pizzarelli et al. are in line with two more recently published, relatively large retrospective case–control studies,^73,74 where no significant difference in bone mineral density was found among patients receiving haemodialysis therapy who were on and off β-blockers, respectively. The discordant findings between the early and these more recent studies underscore the need for well-designed, large-scale studies to provide definitive answers and guide clinical practice in this patient population.

4.2 ∣. Has the hypothesis that β-blockers protect the bone in CKD been prematurely abandoned?

Postmenopausal osteoporosis and bone disease in CKD and patients on dialysis therapy share similar features, including increased bone resorption, decreased bone density and the need for vitamin D in those with vitamin D insufficiency.^75,76 Both conditions result in reduced bone strength and elevated fracture risk associated with calcium and phosphate metabolism imbalances. In postmenopausal women, oestrogen decline accelerates bone resorption, while in patients with CKD, impaired kidney function disrupts mineral metabolism, leading to renal osteodystrophy. Despite several similarities, the primary causes differ, with postmenopausal osteoporosis driven mainly by hormonal changes and CKD-related bone disease driven by complex disturbances secondary to kidney function impairment. Yet, the similarities support the hypothesis that treatments effective in post-menopausal osteoporosis may favourably impact bone disease in patients with CKD.

In 2014, a meta-analysis by Toulis et al., based on sixteen studies on the general population,⁷⁷ showed that fracture risk was approximately 15% lower in patients treated with β-blockers than in control subjects independent of gender, fracture site and dose. Interestingly, this risk reduction was associated with the use of β1-selective blockers.

The potential role of the autonomic nervous system in postmenopausal osteoporosis has been highlighted in a carefully conducted clinical study by Khosla et al.⁴⁸ published in 2018. Given previous conflicting human data, these investigators used multiple approaches to evaluate the role of the sympathetic system in regulating human bone metabolism. They obtained bone biopsies from 19 young and 19 elderly women to assess adrenergic receptors β1, β2 and β3 mRNA expression. They subsequently examined the relationship of β-blocker use to bone microarchitecture by high-resolution peripheral quantitative computed tomography in a population sample of 248 subjects. One hundred and fifty-five postmenopausal women were randomized to five 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. They took advantage of the β1-selectivity gradient of these drugs, from a non-selective compound like propranolol to a relatively β1-selective compound like atenolol and a highly β1-selective β-blocker like nebivolol to define the β-adrenergic selectivity for sympathetic nervous system effects on bone. β1, β2, but not β3 adrenergic receptors were expressed in human bone. In the randomized clinical trial, patients treated with β1-adrenergic 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. In this well-articulated study, three independent lines of evidence – namely, the expression of β1 and β2 adrenergic receptors in human bones, the favourable impact of beta-blockade on bone microarchitecture and the β1-adrenergic selectivity of the effect of β-blockers on the bone—strongly support a role for adrenergic signalling in the regulation of bone metabolism in humans, principally via β1-adrenergic receptors.

Collectively, the response to β-blockers in osteoporosis has shown contrasting outcomes (Table 5). In postmenopausal women, β-blockers, mainly those selective for β1-adrenergic receptors, clearly improved bone microarchitecture by inhibiting bone resorption, while earlier studies in patients on haemodialysis using propranolol, a non-selective β-blocker, produced mixed results. Some studies indicated a reduction in PTH levels and bone resorption. In contrast, others failed to observe significant differences in bone mineral density or biochemical markers of bone disease in postmenopausal women. No long-term randomized trial on bone fractures has been performed in this population. Small sample sizes, lack of randomization and short follow-up periods limit the interpretation of the results of the early studies. The use of propranolol, which is non-selective, may have contributed to the mixed results.

TABLE 5.

Comparison of β1-Selective and Non-Selective Beta-Blockers effects on bone health. See main text and reference.⁴⁸

Aspect	β1-Selective Beta-Blockers (Atenolol, Nebivolol)	Non-Selective Beta-Blocker (Propranolol)	Reference
Receptor selectivity	Primarily targets β1-adrenergic receptors	Targets both β1 and β2-adrenergic receptors	73
Bone microarchitecture	Improved bone microarchitecture compared to nonusers	No significant improvement compared to placebo	73
Bone resorption marker	Reduced serum C-telopeptide of type I collagen	No reduction in serum C-telopeptide of type I collagen	73

4.3 ∣. Need for additional studies

The performance of new studies should be carefully considered to capture the actual effects of β-blockers on bone health in CKD. Randomized controlled trials are essential to minimize bias and confounding factors. Evaluating the impact of β-blockers on bone disease in the CKD setting is relevant because treating renal osteodystrophy remains an issue, particularly in the presence of osteopenia and osteoporosis. Although the treatment and prevention of osteitis fibrosa, that is, high bone turnover disease, and to a lesser degree also that of osteomalacia, are generally effective in patients with CKD, the treatment and prevention of low turnover, adynamic bone disease, and concomitant osteoporosis remain a major problem.⁷⁸ Prospective trials should test the effects of selective β-blockers (e.g., atenolol, nebivolol), excluding nonselective blockers like propranolol, which are probably either less effective or ineffective. Long-term longitudinal follow-up is crucial to assess the sustained impact of β-blockers on bone health. Comprehensive outcome measures should be evaluated including bone mineral density, bone turnover markers with no or minimal renal clearance⁷⁹ (e.g., serum bone-specific alkaline phosphatase [bAP] and trimeric procollagen type 1N-terminal propeptide [P1NP] for bone formation, and tartrate-resistant acid phosphatase 5b [TRAP 5b] for bone resorption), serum PTH, and most importantly, clinical endpoints like fracture incidence. Markers with a renal clearance, like C-telopeptide of type I collagen [β-CDX], should not be adopted.

Subgroup analyses based on factors such as age, sex, duration of dialysis and baseline bone health status can identify populations that may benefit the most from β-blocker therapy. However, long-term randomized clinical trials testing β-blockers are challenging to organize due to the complexity of this patient population and cost reasons. β-blockers are decade-old drugs, and the pharma industry, the primary funding source for randomized controlled clinical trials, is highly unlikely to support such studies.

A pragmatic solution is to use trial emulation in large-scale databases. This can guide clinical practice and inform future trials, potentially funded by major agencies if bone health benefits from β-blockers are suggested. The trial emulation aims to evaluate the impact of selective β-blockers like atenolol or nebivolol on fracture incidence (hip, vertebral and major fractures) among patients with kidney failure not on dialysis. Patients with severe bone disease unrelated to CKD should be excluded, as well as those on non-selective β-blockers and those with less than 1 year of follow-up. Secondary outcomes include changes in bone mineral density, bone turnover markers and PTH levels.

Several databases could be utilized. The US Renal Data System (USRDS) provides comprehensive patient data, including medication use and fractures.^80,81 The Dialysis Outcomes and Practice Patterns Study (DOPPS) collects international dialysis patient data on β-blocker use and fractures.^82,83 The CKD-DOPPS study⁸⁴ offers similar information. The National Health and Nutrition Examination Survey (NHANES) includes bone density and medication data.⁸⁵ Medicare Claims Data⁸⁶ provides healthcare utilization and outcomes for older adults with CKD. The Clinical Practice Research Datalink (CPRD) and The Health Improvement Network (THIN) in Europe offer longitudinal records.⁸⁷

The methodology involves identifying CKD stages 3–5 or haemodialysis patients from databases, applying criteria to refine cohorts and classifying based on selective β-blocker use. Data on fractures, bone density and markers would be extracted. Propensity score matching or inverse probability weighting would balance characteristics between groups. Statistical analyses include Cox models for fracture risk and mixed models for bone density and markers, adjusting for confounders like age, sex, kidney function, comorbidities and medications.

Collaboration with database custodians is crucial for extracting data on demographics, medication, outcomes and lab results. Addressing missing values and outliers ensures data quality. Propensity score matching would pair β-blocker users with similar non-users. Outcome analyses involve time-to-event for fracture risk and longitudinal for bone density and markers. Sensitivity analyses test robustness with different matching and adjustments. This approach could guide clinical practice and inform future studies in this population.

Overall, the hypothesis that β-blockers protect bone health in patients with CKD before and after initiation of haemodialysis therapy may have been prematurely abandoned due to the limitations of previous studies. New, well-designed studies are needed to explore the potential benefits of β1-selective β-blockers in this population, considering the promising results in postmenopausal women. Renewed investigation efforts could lead to significant advancements in the management of bone disease in patients with kidney failure, ultimately improving their quality of life and clinical outcomes.

5 ∣. PERSPECTIVE

The interplay between the autonomic nervous system and bone health is an emerging field that offers additional insights into the regulation of skeletal integrity and function. The sympathetic and parasympathetic systems, traditionally known for regulating cardiovascular and metabolic functions, are at present recognized as key players in bone metabolism. By releasing norepinephrine, the sympathetic nervous system inhibits osteoblast activity and promotes osteoclastogenesis, resulting in a decrease of bone mass. This adrenergic signalling is mediated primarily through β2-adrenergic receptors on bone cells, highlighting a direct pathway through which the nervous system can affect bone mineral density and strength. Conversely, through cholinergic signalling, the parasympathetic system appears to counterbalance these effects by inhibiting osteoclast activity and promoting bone formation, thus maintaining skeletal homeostasis. Acetylcholine per se reduces bone resorption, and the use of acetylcholine esterase inhibitors has been associated with a lower risk of hip fractures in elderly people with Alzheimer’s dementia.⁸⁸ Recognition of the autonomic regulation of bone health offers new opportunities for therapeutic interventions in CKD, where bone and mineral metabolism is severely impaired. The mineral and bone disorder exacerbates bone loss, making the modulation of autonomic pathways a potential strategy for mitigating bone disease. Within this context, the putative favourable impact on bone health of selective β1-adrenergic receptor blockers deserves attention. While early studies with non-selective β-blockers like propranolol in patients on haemodialysis showed inconsistent results, the effects on the bone of β1-selective β-blockers still need to be explored. The promising outcomes observed in post-menopausal women treated with β1-selective β-blockers suggest that these drugs may reduce resorption and enhance bone density. If validated in patients with kidney failure, this could significantly advance their bone disease management. However, well-designed studies are essential to truly understand and harness β-blockers’ potential in this context. Such studies should focus on the pharmacological effects of β-blockers and consider the broader autonomic regulation of bone health, integrating insights from both sympathetic and parasympathetic pathways.

In conclusion, the role of the autonomic nervous system in bone health is a complex issue. It remains a multifaceted area of research that holds great promise for developing novel therapeutic strategies. By exploring the effects of both sympathetic and parasympathetic systems on bone metabolism and further investigating the potential place of β-blockers in modulating these effects one could pave the way for innovative treatments that improve bone health and quality of life for patients with CKD and those undergoing haemodialysis. Combining basic science and clinical research insights, this holistic approach is essential for advancing our understanding of bone health and developing effective interventions.

DATA AVAILABILITY STATEMENT

This review has no original data to share.