Introduction

The mammalian skeleton is kept mechanically sound in adults through the process of bone remodeling [1], which is driven by the coordinated and interdependent actions of osteoblasts, the bone-forming cells, and osteoclasts, the bone-resorbing cells [2]. Paracrine and cell-cell interactions couple the differentiation and activity of these two cell lineages. Thanks to the high vascularity and rich innervation of bones, hormones and neuroendocrine factors also link the process of bone remodeling to the function of other tissues, positioning the skeleton as an integral component of the complex homeostatic system of vertebrates [3, 4]. Bone cells receive cues from glands including the parathyroid gland (PTH); pancreas (insulin); and gonads (estradiol, testosterone, and inhibins) and from sympathetic nerves (norepinephrine). They also secrete hormones such as osteocalcin or FGF23 that regulate the function of other organs like the pancreas, kidneys, or the gonads [5–8, 9•, 10, 11], supporting the endocrine nature of the skeleton. In line with these inter-organ cross-talks, several centers within the central nervous system have been shown to control bone remodeling, and recent results in rats and mice suggest that the vestibular system, known for its role in regulating postural reflexes for balance, participates in the maintenance of bone mass, independent of its effects on locomotion. This review focuses on the regulation of adult bone homeostasis by the vestibular system and on the contribution of the sympathetic nervous system (SNS) to this process.

Bone Homeostasis Regulation by the Sympathetic Nervous System

The control of bone remodeling by the sympathetic nervous system (SNS) was discovered after the identification of leptin as an inhibitor of bone formation acting via a central relay [9•]. Leptin-deficient mice (the ob/ob mice) were indeed characterized by hypogonadism, hypercorticosteronemia, and increased vertebral cancellous bone mass, and leptin-responsive neurons in the ventromedial hypothalamus were shown to be required for normal bone remodeling. Four main observations suggested that sympathetic nerve activation, downstream of hypothalamic centers, was the mechanism by which such centers affect bone remodeling: (1) the high bone mass phenotype of leptin-deficient mice was accompanied by a low sympathetic tone [9•]; (2) electrical stimulation of ventromedial hypothalamic neurons [12] and leptin injection into the third ventricle area resulted in enhanced sympathetic tone [13]; (3) bones are innervated, as evidenced by immunological reactivity to various neuropeptides [14–19] and retrograde neuronal labeling [20]; and (4) the post-synaptic beta2-adrenergic receptors (β2AR) are expressed and functional in osteoblasts [6, 21, 22].

Based on these observations, different mouse genetic models and pharmacological approaches were then used to further address the contribution of sympathetic nerves to bone remodeling. Dopamine beta-hydroxylase (Dbh) is the gene encoding the enzyme that generates norepinephrine and epinephrine (the ligands for adrenergic receptors). Mice lacking Dbh, as well as mice lacking Adrb2 (the gene encoding the β2AR), displayed a high bone mass in adults [6, 23••]. In these models, there was an absence of the endocrine and metabolic changes observed in the ob/ob or Dbh−/− mice, thus excluding them as mediators of their bone phenotypes. Furthermore, leptin intracerebroventricular infusion failed to decrease bone mass in mice lacking the β2AR, demonstrating that the SNS, via the β2AR, mediates the central anti-osteogenic effect of leptin [6, 23••].

Drugs stimulating the β2ARs, such as the βAR agonists isoproterenol or clenbuterol, and drugs blocking β2AR signaling, such as the non-selective βAR blocker propranol, decrease and increase bone mass, respectively, in mice and rats [6, 24, 25•, 26]. In addition, lack of the norepinephrine transporter (Net), which functions in presynaptic neurons to reuptake norepinephrine and to control the duration and intensity of sympathetic signaling led to a low bone mass phenotype, suggesting  that an endogenous homeostatic system exists to control or buffer the deleterious effect of sympathetic activation on the skeleton [27]. Collectively, these results provided multiple independent evidence that the SNS plays a critical role in the regulation of bone mass, at least in rodents. In humans, the observed association between the use of β-blockers and reduced fracture risk, and higher bone mineral density, further supported these results and their clinical relevance [27, 28] although this not a universal observation [29, 30]. The recording of higher SNS activity by microneurography at the peroneal nerve in postmenopausal women compared to premenopausal women was associated with reduced trabecular bone volume fraction and thickness by peripheral quantitative computed tomography (pQCT), suggesting here again that high sympathetic outflow leads to bone loss in humans [31].

Numerous conditions disturb the balance of bone remodeling, leading to a progressive decrease in bone mass, quality, architectural integrity, and mechanical properties. Aging is one such condition contributing to osteoporosis and bone fragility, independent of gonadal function. Oxidative stress is thought to be a main contributor to the deterioration of bone mass observed with aging [32, 33]. However, astronauts, who are relatively young and extremely fit individuals, also suffer bone loss. In such case, a reduction in dynamic load experienced by bone appears to be the main causal factor, as evidenced by human and animal studies in space and unloading studies on earth [34, 35, 36•]. While the contribution of mechanical signals is well-established, the involvement of the SNS in this process is now to be considered as an additional contributory factor. Indeed, anti-resorptives such as bisphosphonates, exercise regimens that mechanically load the skeleton, and nutritional supplementation countermeasures to prevent bone loss in space are still not fully effective, suggesting the existence of additional factors causing bone loss in weightlessness conditions [37–41]. What is especially interesting is that aged individuals and astronauts have at least three pathophysiological changes in common: a dysfunction of the vestibular system [42, 43•], an increase in SNS activity [44–46], and bone loss [42, 47]. The observations that vestibular dysfunction alter sympathetic outflow and that sympathetic nerve activity regulates bone remodeling begged the question as to whether the vestibular system had an influence on bone homeostasis.

The SNS is a Major Pathway for Vestibular Signal Outputs

The vestibular system is an integral part of the labyrinth that lies in the otic capsule in the petrous portion of the temporal bone. It is a sensory organ commonly known as the organ of balance and spatial orientation. Through three semicircular canals and two otolithic sensors (Fig. 1), it detects head orientation and motion, as well as body motion in the three dimensions. This system is studied in humans largely in the context of vestibular pathology like Menière’s disease, and more generally in all vestibular causes of vertigo, in order to elucidate the process of vestibular compensation and related pharmacological targets for balance recovery. Previous studies demonstrated its contribution to the regulation of posture, respiration, heart rate, and blood pressure in animals [48–51] and humans [52, 53], and via anatomic projections from vestibular nuclei to brainstem autonomic centers [54, 55]. All vestibular inputs transit via the vestibular nucleus to the brain through specific neuronal pathways, according to their function. For instance, oculomotor control and postural reflexes for balance involve the brainstem [56], whereas body and self-motion perception for balance and voluntary motor control involve cortical neurons [57, 58]. While high latency responses (>18 ms) are relayed to preganglionic sympathetic neurons through neurons in the caudal medullary raphe nuclei [59–61] and in the subretrofacial nuclei [61], short latency responses transit through the vestibulo-spinal axis in the lateral tegmental field [62] or through the subretrofacial neurons in the rostral ventrolateral medulla [63, 64]. Moreover, higher integrative centers, such as the hypothalamus [65–68], the nucleus of the solitary tract [55, 69], and the cerebellum [70] are also involved in the vestibulo-sympathetic responses [71, 72•, 73, 74], as demonstrated by the orthostatic hypotension observed in cats with bilateral vestibular destruction [75].

Fig. 1
figure 1

Model of the control of bone homeostasis by the vestibular system

Full size image

Vestibular Outputs Participate to Bone Homeostasis Regulation Through the Sympathetic Nervous System

Retrospective studies highlighted a relationship between bone mineral density in aged patients and balance control [76, 77••]. From these studies, it was concluded that a reduction in balance control in aged individuals led to an increase in the risk of falls, and in turn, to an increase in bone fracture incidence. Further, it was suggested that balance disorders in aged individuals might be a result of loss of bone mineral density in the petrous bone surrounding the vestibular organ. However, the association between petrous bone density and vestibular function is not supported, and in the absence of additional data, the possibility that vestibular dysfunction may independently affect bone homeostasis and increase the rate of fracture upon aging was not considered.

This potential effect of vestibular dysfunction on bone density and homeostasis was prompted by the observation that sympathetic outflow is increased following alteration of vestibular signals in weightlessness, as noted above, and that sympathetic activation leads to bone loss. Levasseur et al. first reported a reduction in bone mineral density of the femoral metaphysis in rats after 1 month of chemically induced vestibular deficiency [78, 79]. This model used bilateral transtympanic sodium arsenilate injections to disturb vestibular function, causing vestibular deficiency that was accompanied with a series of abnormal spontaneous behaviors. These original results were confirmed in another study in rats, in which bone parameters were further assessed by uCT and histomorphometry [80•]. In addition, this study demonstrated that propranolol reduces the bone loss induced by transtympanic bilateral sodium arsenilate injections, supporting the contribution of sympathetic signaling to the effect of vestibular alterations on bone mass [80•].

Sodium arsenilate transtympanic injections are assumed to induce vestibular damage [81] and to promote degeneration of the eighth cranial nerve [82]. However, contrary to the high dose previously used, the low dose of sodium arsenilate used in studies examining bone loss did not induce changes in vestibular structure or nerve degeneration [83]. This observation suggested that low-dose sodium arsenilate modulates vestibular function, at least transiently and sufficiently to disturb bone homeostasis. In addition, these lesions did not reduce locomotor activity, and did not increase TNFα serum levels, thus excluding reduced mechanical loading and chronic systemic inflammation as mechanisms by which vestibular lesions cause bone loss [80•, 84, 85••]. This does not exclude the possibility that the alteration in vestibular function may change the “perception” of bone loading so that the threshold for initiating a modeling or remodeling response is increased.

This model of vestibular dysfunction was later adapted to mice with the purpose of using genetic loss of function models to further address the mechanism(s) involved in the interactions between vestibular neurons and bone cells. Here again, bilateral sodium arsenilate transtympanic injections induced bone loss in cancellous bone in femoral diaphyses but not in the vertebrae (L3-L4), as observed in rats with vestibular deficiency. This regionalized effect of vestibular deficiency on weight-bearing bones and on the trabecular bone compartment is reminiscent to the patterning of sympathetic nerve activity in response to various vestibular stimulation [73, 86•, 87–92] and suggests that central centers and peripheral sympathetic nerves innervate and control bone remodeling differentially among various skeletal elements. These results might also be relevant to data from Sample et al. [93], who showed evidence that load-induced response of a single bone is neuronally regulated and induce adaptive responses in other skeletal elements.

The cellular changes induced by vestibular lesions, i.e., an increase in osteoclast density and a reduction in osteoblast number were partly reminiscent to the phenotypes observed following isoproterenol treatment [6, 85••], supporting the hypothesis that vestibular deficiency induces bone loss, at least in part, via sympathetic nerve activation. This specific question was further addressed by the use of mice lacking the β2AR, globally or specifically on osteoblasts. Both mutant mice subjected to bilateral vestibular arsenilate injections were resistant to bone loss, supporting the notion that sympathetic nerves mediate the effect of vestibular deficiency on bone remodeling [85••]. The resistance of the osteoblast-specific β2AR-deficient mice also suggested that the osteoblast is the main target of this vestibulo-sympathetic axis and excluded the contribution of changes in blood flow or other mechanisms to bone loss induced by vestibular lesions.

Does Vestibular Aging Contribute to Osteoporosis?

Considering the retrospective studies mentioned above, linking balance control and fracture risk in aged individuals and the data from animal models, we propose the hypothesis that vestibular aging contributes to age-related bone loss. A vestibulo-sympathetic reflex attenuation with aging has indeed been well documented and correlates with degeneration of the vestibular system. First, in humans, the density of hair cells and sensorial cells of the vestibular system decreases with age [94, 95]. Hair cells themselves can also undergo morphological changes with age, such as cilia disarrangement, increased cilia fragility, and development of giant cilia [95, 96]. The neuronal structures relaying vestibular signals can be affected with time as well, as revealed by a decrease in Scarpa’s ganglion cell number [97] and a decline in the number of primary neurons of the human vestibular system [98] in both aged humans and rats [99–101]. A prospective trial conducted with 70 healthy individuals traced a time-course of vestibular information integration and led to the conclusion that vestibular information reached a peak at the age of 40–49 years old and then decreased. This observation was independent of gender influence and has been attributed to aging of the vestibular system and absence of correction [102]. Additionally, the age-related changes in vestibulo-ocular and vestibulo-spinal reflexes have also been attributed to morphological degeneration of the vestibular system (i.e., hair cells loss, changes in synapse morphology, electrophysiologic alterations) [103–106]. The absence or decrease of postural effect on breathing frequency in the elderly, as compared to young individuals, also demonstrated that aging impairs vestibular-mediated activation of ventilation in humans [107]. In addition, morphological changes associated with aging of the otolith organs are associated with altered vestibular-mediated activation of the cardiorespiratory system, as evidenced by the attenuation in muscle-sympathetic nerve responses in aged subjects [108]. Otolith stimulation elicits differential activation of sympathetic nerve activity and vascular responses to muscle and skin in humans [73, 86•, 87–92]. Head-down rotation in 40 healthy subjects did not change mean arterial pressure and heart rate in younger or older subjects but renal blood velocity and vascular conductance significantly decreased in young subjects whereas these parameters did not change in older subjects. These data led to the conclusion that vestibulo-sympathetic functions are attenuated in older humans [109].

Returning to the analogy of bone loss between aged subjects and astronauts, the absence of gravity in space triggers a reduction in motoneuron excitability by the otolithic system (gravity sensor of the vestibule) [110]. Similar to aged subjects, remodeling of synaptic connections in vestibular sensorial hair cells and an increase in the number and the size of synaptic knobs have been reported in adult rats during short-term space missions [111, 112]. The vestibulo-spinal and vestibulo-ocular reflexes are also altered in these conditions [113–115].

While unloading, radiation, and nutritional deficiencies are all thought to contribute to bone loss in space, it is not known if alterations in the vestibulo-sympathetic axis contribute to weightlessness-induced bone loss. Interestingly, some of the vestibular deficits or alterations observed in these conditions disappear with time (phenomenon of compensation), while others, including balance, eye movements in response to head rotations in the dark, navigational abilities, and spatial memory, remain permanently altered [116–120]. In mice, bilateral vestibular sodium arsenilate lesions induce a vestibular syndrome and bone loss after a month, but bone mass returns to normal 3 or 6 months after lesions [85••]. Although this result would suggest the existence of compensation and by extension, a transient and clinically irrelevant effect on bone in humans, it remains to be addressed whether or not the vestibular structural and functional changes induced by long-term weightlessness in space or by a single sodium arsenilate injection on earth in mice/rats share similarities.

Conclusions

The data reviewed herein suggest that deleterious alterations in vestibular function leading to increased sympathetic outflow upon aging may contribute to age-related bone loss. These data also suggest that a similar pathogenic mechanism is at play in younger individuals during weightlessness or other vestibular dysfunctions, in addition to the well-accepted bone unloading that occurs in space. Although two retrospective studies in aged patients with osteoporosis support this speculation [76, 77••], it remains to be further addressed in preclinical models and in humans. Although the vestibular system has defined neuronal projections to brainstem neurons that control sympathetic outflow, the precise central nervous system pathways and neurotransmitters specifically involved in the observed bone loss induced by vestibular alterations remain to be explored. These findings also have clinical implications for patients with a history of vestibular pathologies such as labyrinthectomy, antibiotic treatment (aminoglycosides and platinum-based chemotherapy), vestibular neuritis, or Ménière’s disease. Interestingly, autistic children also suffer from vestibular dysfunction [121, 122] and decreased bone mineral density, and present with higher fracture risk than age-matched controls [123, 124]. Alterations of the vestibulo-sympathetic axis may thus have many potential pathophysiological consequences on the skeleton, which need to be further investigated to better understand the complexity of bone homeostasis and to identify new therapies to improve bone mass.