Pathophysiology of Osteoporosis

  • Serge Livio FerrariEmail author


The bone is a dynamic tissue that is continuously removed and replaced (i.e., remodeled) in order to (1) ensure adaptation of the skeleton to weight-bearing (shape is function), (2) repair microdamages (cracks) that result from mechanical stresses, and (3) allow for mobilization of calcium from the skeleton in order to maintain serum calcium homeostasis. Bone remodeling is initiated by the development and activation of osteoclasts, the bone-resorbing cell, which then release growth factors capable to activate osteoblasts, the bone-forming cell. The activities of bone removal and deposition are therefore coupled within each “bone multicellular unit” or BMU. After the completion of growth, the bone size and mineral content have reached its peak and will be maintained more or less unchanged during the adult life in absence of pathophysiological conditions thanks to moderate levels of bone remodeling that are perfectly balanced between resorption and formation within each BMU. In addition, the skeleton continuously responds to mechanical stimuli resulting from both muscle contraction and weight-bearing, by directly stimulating bone formation (i.e., without prior resorption), a process known as bone modeling. This process in particular is responsible for the increased bone diameter and bone mass observed in physically active individuals, furthermore in athletes. It is controlled by osteocytes, which are terminally differentiated osteoblasts that have lost their capacity to form new bone but are entrenched in the bone and form a dense network of “sensing” cells capable to respond to mechanical stimuli, as well as to microdamages, and control both modeling and local remodeling processes.


Bone Osteoblast Osteoclast Calcium homeostasis BMU Osteoporosis Osteoclastogenesis Osteoid Sclerostin Growth factor 


  1. 1.
    Hadjidakis DJ, Androulakis II. Bone remodeling. Ann N Y Acad Sci. 2006;1092:385–96.CrossRefGoogle Scholar
  2. 2.
    Bonewald LF. The amazing osteocyte. J Bone Miner Res. 2011;26(2):229–38.CrossRefGoogle Scholar
  3. 3.
    Seeman E, Delmas PD. Bone quality--the material and structural basis of bone strength and fragility. N Engl J Med. 2006;354(21):2250–61.CrossRefGoogle Scholar
  4. 4.
    Zebaze RM, Ghasem-Zadeh A, Bohte A, et al. Intracortical remodelling and porosity in the distal radius and post-mortem femurs of women: a cross-sectional study. Lancet. 2010;375(9727):1729–36.CrossRefGoogle Scholar
  5. 5.
    Farr JN, Fraser DG, Wang H, et al. Identification of senescent cells in the bone microenvironment. J Bone Miner Res. 2016;31(11):1920–9.CrossRefGoogle Scholar
  6. 6.
    Baron R, Rawadi G. Targeting the Wnt/beta-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology. 2007;148(6):2635–43.CrossRefGoogle Scholar
  7. 7.
    Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev. 2008;29(2):155–92.CrossRefGoogle Scholar
  8. 8.
    Bruzzaniti A, Baron R. Molecular regulation of osteoclast activity. Rev Endocr Metab Disord. 2006;7(1–2):123–39.PubMedGoogle Scholar
  9. 9.
    Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997;89(2):309–19.CrossRefGoogle Scholar
  10. 10.
    Eghbali-Fatourechi G, Khosla S, Sanyal A, Boyle WJ, Lacey DL, Riggs BL. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest. 2003;111(8):1221–30.CrossRefGoogle Scholar
  11. 11.
    Ma YL, Cain RL, Halladay DL, et al. Catabolic effects of continuous human PTH (1--38) in vivo is associated with sustained stimulation of RANKL and inhibition of osteoprotegerin and gene-associated bone formation. Endocrinology. 2001;142(9):4047–54.CrossRefGoogle Scholar
  12. 12.
    Heino TJ, Hentunen TA. Differentiation of osteoblasts and osteocytes from mesenchymal stem cells. Curr Stem Cell Res Ther. 2008;3(2):131–45.CrossRefGoogle Scholar
  13. 13.
    Murshed M, Harmey D, Millan JL, McKee MD, Karsenty G. Unique coexpression in osteoblasts of broadly expressed genes accounts for the spatial restriction of ECM mineralization to bone. Genes Dev. 2005;19(9):1093–104.CrossRefGoogle Scholar
  14. 14.
    Seeman E. Loading and bone fragility. J Bone Miner Metab. 2005;23(Suppl):23–9.CrossRefGoogle Scholar
  15. 15.
    Duque G. Bone and fat connection in aging bone. Curr Opin Rheumatol. 2008;20(4):429–34.CrossRefGoogle Scholar
  16. 16.
    Bonjour JP, Schurch MA, Chevalley T, Ammann P, Rizzoli R. Protein intake, IGF-1 and osteoporosis. Osteoporos Int. 1997;7(3):S36–42.CrossRefGoogle Scholar
  17. 17.
    Gong Y, Slee RB, Fukai N, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107(4):513–23.CrossRefGoogle Scholar
  18. 18.
    Brunkow ME, Gardner JC, Van Ness J, et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet. 2001;68(3):577–89.CrossRefGoogle Scholar
  19. 19.
    Staehling-Hampton K, Proll S, Paeper BW, et al. A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population. Am J Med Genet. 2002;110(2):144–52.CrossRefGoogle Scholar
  20. 20.
    van Bezooijen RL, Roelen BA, Visser A, et al. Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med. 2004;199(6):805–14.CrossRefGoogle Scholar
  21. 21.
    Poole KE, van Bezooijen RL, Loveridge N, et al. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J. 2005;19(13):1842–4.CrossRefGoogle Scholar
  22. 22.
    Bellido T, Ali AA, Gubrij I, et al. Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis. Endocrinology. 2005;146(11):4577–83.CrossRefGoogle Scholar
  23. 23.
    Keller H, Kneissel M. SOST is a target gene for PTH in bone. Bone. 2005;37(2):148–58.CrossRefGoogle Scholar
  24. 24.
    Ke HZ, Richards WG, Li X, Ominsky MS. Sclerostin and dickkopf-1 as therapeutic targets in bone diseases. Endocr Rev. 2012;33:747.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division of Bone DiseasesGeneva University Hospital and Faculty of MedicineGenevaSwitzerland

Personalised recommendations