Skip to main content

Advertisement

SpringerLink
Log in

Evolving Concepts in Neurogenic Osteoporosis

  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Convincing evidence has accumulated of regulation of bone by the central nervous system. The neural connection between brain and bone is mediated centrally by classic neurotransmitters and several neuropeptides, and peripherally by many of the same neurotransmitters and neuropeptides, albeit with actions opposite to their central effects. Pharmacologic blockade of ß2-adrenergic receptors or disruption of the gene encoding them increases bone mass, whereas increased activity of the sympathetic nervous system (SNS) contributes to bone loss. Brainstem serotonergic neurons regulate SNS activity and its modulation by leptin. Physiologic stimulation of osteoblastic nicotinic receptors results in proliferation and deposition of bone, whereas higher levels inhibit osteoblast function. Activation of sensory nerves has a centrally mediated action on bone, albeit poorly understood. The relative importance of, and interactions between autonomic, sensory, and peripheral nervous system actions on bone mass are also not clear in healthy individuals, and less so in pathologic states.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Iwamoto J, Matsumoto H, Takeda T: Efficacy of risedronate against hip fracture in patients with neurological diseases: a meta-analysis of randomized controlled trials. Curr Med Res Opin 2008, 24:1379–1384.

    Article  CAS  PubMed  Google Scholar 

  2. Dudley-Javoroski S, Shields RK: Muscle and bone plasticity after spinal cord injury: review of adaptations to disuse and to electrical muscle stimulation. J Rehabil Res Dev 2008, 45:283–296.

    Article  PubMed  Google Scholar 

  3. Haziza M, Kremer R, Benedetti A, Trojan DA: Osteoporosis in a postpolio clinic population. Arch Phys Med Rehabil 2007, 88:1030–1035.

    Article  PubMed  Google Scholar 

  4. Marrie RA, Cutter G, Tyry T, Vollmer T: A cross-sectional study of bone health in multiple sclerosis. Neurology 2009, 73:1394–1398.

    Article  PubMed  Google Scholar 

  5. Sato Y, Honda Y, Iwamoto J: Etidronate for fracture prevention in amyotrophic lateral sclerosis: a randomized controlled trial. Bone 2006, 39:1080–1086.

    Article  CAS  PubMed  Google Scholar 

  6. Eser P, Frotzler A, Zehnder Y, et al.: Relationship between the duration of paralysis and bone structure: a pQCT study of spinal cord injured individuals. Bone 2004, 34:869–880.

    Article  CAS  PubMed  Google Scholar 

  7. Zaidi M: Skeletal remodeling in health and disease. Nat Med 2007, 13:791–801

    Article  CAS  PubMed  Google Scholar 

  8. Elefteriou F: Regulation of bone remodeling by the central and peripheral nervous system. Arch Biochem Biophys 2008, 473:231–236.

    Article  CAS  PubMed  Google Scholar 

  9. Gajda M, Litwin JA, Tabarowski Z, et al.: Development of rat tibia innervation: colocalization of autonomic nerve fiber markers with growth-associated protein 43. Cells Tissues Organs 2010, 191:489–499.

    Article  CAS  PubMed  Google Scholar 

  10. Hill EL, Elde R: Distribution of CGRP-, VIP-, D beta H-, SP-, and NPY-immunoreactive nerves in the periosteum of the rat. Cell Tissue Res 1991, 264:469–480.

    Article  CAS  PubMed  Google Scholar 

  11. Takeda S, Elefteriou F, Levasseur R, et al.: Leptin regulates bone formation via the sympathetic nervous system. Cell 2002, 111:305–317.

    Article  CAS  PubMed  Google Scholar 

  12. Elefteriou F, Ahn JD, Takeda S, et al.: Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 2005, 434:514–520.

    Article  CAS  PubMed  Google Scholar 

  13. • Bouxsein ML, Devlin MJ, Glatt V, et al.: Mice lacking beta-adrenergic receptors have increased bone mass but are not protected from deleterious skeletal effects of ovariectomy. Endocrinology 2009, 150:144–152. This report provided evidence that ß1- and/or ß3-adrenergic receptors may also influence bone metabolism in as yet unknown ways, as suggested by findings that disruption of genes for the ß1-, ß2-, and ß3-adrenergic receptors led to a phenotype in which bone loss caused by ovariectomy was not prevented, in contrast to the protection afforded by deletion of the ß2-adrenergic receptor alone.

    Article  CAS  PubMed  Google Scholar 

  14. Hamrick MW, Ferrari SL: Leptin and the sympathetic connection of fat to bone. Osteoporos Int 2008, 19:905–912.

    Article  CAS  PubMed  Google Scholar 

  15. • Yadav VK, Oury F, Suda N, et al.: A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell 2009, 138:976–989. Through targeting deletions of serotonin receptor subtypes to serotonergic neurons, this report provides genetic evidence that leptin modulates serotonergic neurotransmission arising in the arcuate nucleus and projecting to sites that include those modulating sympathetic tone, providing a neurophysiologic and neuroanatomic context for interpreting other work linking serotonergic signaling, or drugs that alter it, to bone mass and metabolism.

    Article  CAS  PubMed  Google Scholar 

  16. Bab I, Ofek O, Tam J, et al.: Endocannabinoids and the regulation of bone metabolism. J Neuroendocrinol 2008, 20(Suppl 1):69–74.

    Article  CAS  PubMed  Google Scholar 

  17. Zengin A, Zhang L, Herzog H, et al.: Neuropeptide Y and sex hormone interactions in humoral and neuronal regulation of bone and fat. Trends Endocrinol Metab 2010, 21:411–418.

    Article  CAS  PubMed  Google Scholar 

  18. Marenzana M, Chenu C: Sympathetic nervous system and bone adaptive response to its mechanical environment. J Musculoskelet Neuronal Interact 2008, 8:111–120.

    CAS  PubMed  Google Scholar 

  19. • Shi Y, Oury F, Yadav VK, et al.: Signaling through the M(3) muscarinic receptor favors bone mass accrual by decreasing sympathetic activity. Cell Metab 2010, 11:231–238. By selectively deleting each of four isoforms of the muscarinic ACh receptor in mice (M1-M4), the involvement of these receptors in bone cells and/or the CNS in determining bone mass was evaluated. Only the M3 receptor altered bone mass, and this occurred through a central effect by which ACh reduced SNS activity. Importantly, this work suggests that the low level expression of muscarinic receptors in bone cells does not contribute to the control of rates of bone resorption or formation.

    Article  CAS  PubMed  Google Scholar 

  20. Wiens M, Etminan M, Gill SS, Takkouche B: Effects of antihypertensive drug treatments on fracture outcomes: a meta-analysis of observational studies. J Intern Med 2006, 260:350–362.

    Article  CAS  PubMed  Google Scholar 

  21. Kondo H, Nifuji A, Takeda S, et al.: Unloading induces osteoblastic cell suppression and osteoclastic cell activation to lead to bone loss via sympathetic nervous system. J Biol Chem 2005, 280:30192–30200.

    Article  CAS  PubMed  Google Scholar 

  22. Fu Q, Levine BD, Pawelczyk JA, et al.: Cardiovascular and sympathetic neural responses to handgrip and cold pressor stimuli in humans before, during and after spaceflight. J Physiol 2002, 544:653–664.

    Article  CAS  PubMed  Google Scholar 

  23. Mano T: Autonomic neural functions in space. Curr Pharm Biotechnol 2005, 6:319–324.

    Article  CAS  PubMed  Google Scholar 

  24. Yirmiya R, Bab I: Major depression is a risk factor for low bone mineral density: a meta-analysis. Biol Psychiatry 2009, 66:423–432.

    Article  PubMed  Google Scholar 

  25. Haney EM, Chan BK, Diem SJ, et al.: Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men. Arch Intern Med 2007, 167:1246–1251.

    Article  PubMed  Google Scholar 

  26. Ziere G, Dieleman JP, van der Cammen TJ, et al.: Selective serotonin reuptake inhibiting antidepressants are associated with an increased risk of nonvertebral fractures. J Clin Psychopharmacol 2008, 28:411–417.

    Article  CAS  PubMed  Google Scholar 

  27. Mizushima T, Tajima F, Nakamura T, et al.: Muscle sympathetic nerve activity during cold pressor test in patients with cerebrovascular accidents. Stroke 1998, 29:607–612.

    CAS  PubMed  Google Scholar 

  28. Marshall AT, Crisp AJ: Reflex sympathetic dystrophy. Rheumatology (Oxford) 2000, 39:692–695.

    Article  CAS  Google Scholar 

  29. Ziemssen T, Reichmann H: Cardiovascular autonomic dysfunction in Parkinson’s disease. J Neurol Sci 2010, 289:74–80.

    Article  CAS  PubMed  Google Scholar 

  30. Alexander MS, Biering-Sorensen F, Bodner D, et al.: International standards to document remaining autonomic function after spinal cord injury. Spinal Cord 2009, 47:36–43.

    Article  CAS  PubMed  Google Scholar 

  31. Wong PK, Christie JJ, Wark JD: The effects of smoking on bone health. Clin Sci (Lond) 2007, 113:233–241.

    Article  CAS  Google Scholar 

  32. Walker LM, Preston MR, Magnay JL, et al.: Nicotinic regulation of c-fos and osteopontin expression in human-derived osteoblast-like cells and human trabecular bone organ culture. Bone 2001, 28:603–608.

    Article  CAS  PubMed  Google Scholar 

  33. Rothem DE, Rothem L, Soudry M, et al.: Nicotine modulates bone metabolism-associated gene expression in osteoblast cells. J Bone Miner Metab 2009, 27:555–561.

    Article  CAS  PubMed  Google Scholar 

  34. • Sato T, Abe T, Chida D, et al.: Functional role of acetylcholine and the expression of cholinergic receptors and components in osteoblasts. FEBS Lett 2010, 584:817–824. These studies of cultured, bone marrow–derived osteoblasts revealed that during differentiation several isoforms of both nicotinic and muscarinic ACh receptors are expressed. Genes encoding enzymatic machinery needed to synthesize ACh were also expressed in these cells.

    Article  CAS  PubMed  Google Scholar 

  35. En-Nosse M, Hartmann S, Trinkaus K, et al.: Expression of non-neuronal cholinergic system in osteoblast-like cells and its involvement in osteogenesis. Cell Tissue Res 2009, 338:203–215.

    Article  CAS  PubMed  Google Scholar 

  36. Fajardo NR, Pasiliao RV, Modeste-Duncan R, et al.: Decreased colonic motility in persons with chronic spinal cord injury. Am J Gastroenterol 2003, 98:128–134.

    Article  PubMed  Google Scholar 

  37. Zhang P, Tanaka SM, Jiang H, et al.: Diaphyseal bone formation in murine tibiae in response to knee loading. J Appl Physiol 2006, 100:1452–1459.

    Article  PubMed  Google Scholar 

  38. Sample SJ, Behan M, Smith L, et al.: Functional adaptation to loading of a single bone is neuronally regulated and involves multiple bones. J Bone Miner Res 2008, 23:1372–1381.

    Article  PubMed  Google Scholar 

  39. Wu Q, Sample SJ, Baker TA, et al.: Mechanical loading of a long bone induces plasticity in sensory input to the central nervous system. Neurosci Lett 2009, 463:254–257.

    Article  CAS  PubMed  Google Scholar 

  40. Lewin GR, Moshourab R: Mechanosensation and pain. J Neurobiol 2004, 61:30–44.

    Article  PubMed  Google Scholar 

  41. Ding Y, Arai M, Kondo H, Togari A: Effects of capsaicin-induced sensory denervation on bone metabolism in adult rats. Bone 2010, 46:1591–1596.

    Article  CAS  PubMed  Google Scholar 

  42. Goto T, Nakao K, Gunjigake KK, et al.: Substance P stimulates late-stage rat osteoblastic bone formation through neurokinin-1 receptors. Neuropeptides 2007, 41:25–31.

    Article  CAS  PubMed  Google Scholar 

  43. Wang L, Zhao R, Shi X, et al.: Substance P stimulates bone marrow stromal cell osteogenic activity, osteoclast differentiation, and resorption activity in vitro. Bone 2009, 45:309–320.

    Article  CAS  PubMed  Google Scholar 

  44. De Felipe C, Herrero JF, O’Brien JA, et al.: Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature 1998, 392:394–397.

    Article  PubMed  Google Scholar 

  45. Wedemeyer C, Neuerburg C, Pfeiffer A, et al.: Polyethylene particle-induced bone resorption in substance P-deficient mice. Calcif Tissue Int 2007, 80:268–274.

    Article  CAS  PubMed  Google Scholar 

  46. Liu D, Li H, Zhao CQ, et al.: Changes of substance P-immunoreactive nerve fiber innervation density in the sublesional bones in young growing rats at an early stage after spinal cord injury. Osteoporos Int 2008, 19:559–569.

    Article  CAS  PubMed  Google Scholar 

  47. Zaidi M, Chambers TJ, Gaines Das RE, et al.: A direct action of human calcitonin gene-related peptide on isolated osteoclasts. J Endocrinol 1987, 115:511–518.

    Article  CAS  PubMed  Google Scholar 

  48. Schinke T, Liese S, Priemel M, et al.: Decreased bone formation and osteopenia in mice lacking alpha-calcitonin gene-related peptide. J Bone Miner Res 2004, 19:2049–2056.

    Article  CAS  PubMed  Google Scholar 

  49. Oh-hashi Y, Shindo T, Kurihara Y, et al.: Elevated sympathetic nervous activity in mice deficient in alphaCGRP. Circ Res 2001, 89:983–990.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors wish to acknowledge support from the VA Rehabilitation Research and Development Service grants B4162C and B3347K.

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

  1. Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, NY, 10468, USA

    Weiping Qin, William A. Bauman & Christopher P. Cardozo

Authors
  1. Weiping Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William A. Bauman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher P. Cardozo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Weiping Qin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Qin, W., Bauman, W.A. & Cardozo, C.P. Evolving Concepts in Neurogenic Osteoporosis. Curr Osteoporos Rep 8, 212–218 (2010). https://doi.org/10.1007/s11914-010-0029-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11914-010-0029-9

Keywords

Search

Navigation