A look behind the scenes: the risk and pathogenesis of primary osteoporosis

This article has been updated

Key Points

  • The pathogenesis of primary osteoporosis is complex and influenced by both environmental and genetic factors

  • Oxidative stress, apoptosis, sex-steroid deficiency and macroautophagy are age-related risk factors that contribute to the pathogenesis of osteoporosis

  • Lifestyle-related factors, such as inadequate intake of calcium and vitamin D, physical inactivity, smoking and excessive alcohol consumption are important risk factors for osteoporosis

  • Mutations in several genes can cause different monogenic disorders characterized by decreased bone mineral density and increased bone fragility

  • The contribution of genetic factors to polygenic osteoporosis is determined by the presence of variants in many genes, each with a small effect size

Abstract

Osteoporosis is a common disorder, affecting hundreds of millions of people worldwide, and characterized by decreased bone mineral density and increased fracture risk. Known nonheritable risk factors for primary osteoporosis include advanced age, sex-steroid deficiency and increased oxidative stress. Age is a nonmodifiable risk factor, but the influence of a person's lifestyle (diet and physical activity) on their bone structure and density is modifiable to some extent. Heritable factors influencing bone fragility can be monogenic or polygenic. Osteogenesis imperfecta, juvenile osteoporosis and syndromes of decreased bone density are discussed as examples of monogenic disorders associated with bone fragility. So far, the factors associated with polygenic osteoporosis have been investigated mainly in genome-wide association studies. However, epigenetic mechanisms also contribute to the heritability of polygenic osteoporosis. Identification of these heritable and nonheritable risk factors has already led to the discovery of therapeutic targets for osteoporosis, which emphasizes the importance of research into the pathogenetic mechanisms of osteoporosis. Accordingly, this article discusses the many heritable and nonheritable factors that contribute to the pathogenesis of primary osteoporosis. Although osteoporosis can also develop secondary to many other diseases or their treatment, a discussion of the factors that contribute only to secondary osteoporosis is beyond the scope of this Review.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Overview of BMD values during life, indicating the importance of peak bone mass and the subsequent rate of decline in BMD in the development of primary osteoporosis.
Figure 2: Ageing-associated changes that contribute to bone fragility.
Figure 3: Factors that influence the development of osteoporosis.
Figure 4: Genes associated with either BMD or fracture risk.124

Change history

  • 24 April 2015

    In the version of this article initially published online, Figure 3 contained a typographical error (alchohol instead of alcohol). The error has been corrected for the print, HTML and PDF versions of the article.

References

  1. 1

    Abrahamsen, B., van Staa, T., Ariely, R., Olson, M. & Cooper, C. Excess mortality following hip fracture: a systematic epidemiological review. Osteoporos. Int. 20, 1633–1650 (2009).

    Article  CAS  Google Scholar 

  2. 2

    van den Bergh, J. P., van Geel, T. A. & Geusens, P. P. Osteoporosis, frailty and fracture: implications for case finding and therapy. Nat. Rev. Rheumatol. 8, 163–172 (2012).

    Article  CAS  Google Scholar 

  3. 3

    Melton, L. J. 3rd. How many women have osteoporosis now? J. Bone Miner. Res. 10, 175–177 (1995).

    Article  Google Scholar 

  4. 4

    Randell, A. et al. Direct clinical and welfare costs of osteoporotic fractures in elderly men and women. Osteoporos. Int. 5, 427–432 (1995).

    Article  CAS  Google Scholar 

  5. 5

    Kanis, J. A. & Johnell, O. Requirements for DXA for the management of osteoporosis in Europe. Osteoporos. Int. 16, 229–238 (2005).

    Article  CAS  Google Scholar 

  6. 6

    Bachrach, L. K. Acquisition of optimal bone mass in childhood and adolescence. Trends Endocrinol. Metab. 12, 22–28 (2001).

    Article  CAS  Google Scholar 

  7. 7

    Sapir-Koren, R. & Livshits, G. Osteocyte control of bone remodeling: is sclerostin a key molecular coordinator of the balanced bone resorption-formation cycles? Osteoporos. Int. (2014).

  8. 8

    Zuo, C. et al. Osteoblastogenesis regulation signals in bone remodeling. Osteoporos. Int. 23, 1653–1663 (2012).

    Article  CAS  Google Scholar 

  9. 9

    Garnero, P. The contribution of collagen crosslinks to bone strength. Bonekey Rep. 1, 182 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Alliston, T. Biological regulation of bone quality. Curr. Osteoporos. Rep. 12, 366–375 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    Sroga, G. E. & Vashishth, D. Effects of bone matrix proteins on fracture and fragility in osteoporosis. Curr. Osteoporos. Rep. 10, 141–150 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Bouxsein, M. L. & Karasik, D. Bone geometry and skeletal fragility. Curr. Osteoporos. Rep. 4, 49–56 (2006).

    Article  Google Scholar 

  13. 13

    Almeida, M. Aging mechanisms in bone. Bonekey Rep. 1, 102 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14

    Manolagas, S. C. From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. Endocr. Rev. 31, 266–300 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    de Boer, J. et al. Premature aging in mice deficient in DNA repair and transcription. Science 296, 1276–1279 (2002).

    Article  CAS  Google Scholar 

  16. 16

    Tyner, S. D. et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 415, 45–53 (2002).

    Article  CAS  Google Scholar 

  17. 17

    Nojiri, H. et al. Cytoplasmic superoxide causes bone fragility owing to low-turnover osteoporosis and impaired collagen cross-linking. J. Bone Miner. Res. 26, 2682–2694 (2011).

    Article  CAS  Google Scholar 

  18. 18

    Smietana, M. J., Arruda, E. M., Faulkner, J. A., Brooks, S. V. & Larkin, L. M. Reactive oxygen species on bone mineral density and mechanics in Cu, Zn superoxide dismutase (Sod1) knockout mice. Biochem. Biophys. Res. Commun. 403, 149–153 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Ambrogini, E. et al. FoxO-mediated defense against oxidative stress in osteoblasts is indispensable for skeletal homeostasis in mice. Cell Metab. 11, 136–146 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Almeida, M. Unraveling the role of FoxOs in bone—insights from mouse models. Bone 49, 319–327 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Almeida, M., Han, L., Martin-Millan, M., O'Brien, C. A. & Manolagas, S. C. Oxidative stress antagonizes Wnt signaling in osteoblast precursors by diverting β-catenin from T cell factor- to forkhead box O-mediated transcription. J. Biol. Chem. 282, 27298–27305 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Essers, M. A. et al. Functional interaction between β-catenin and FOXO in oxidative stress signaling. Science 308, 1181–1184 (2005).

    Article  CAS  Google Scholar 

  23. 23

    Migliaccio, E. et al. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402, 309–313 (1999).

    Article  CAS  Google Scholar 

  24. 24

    Nemoto, S. & Finkel, T. Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway. Science 295, 2450–2452 (2002).

    Article  CAS  Google Scholar 

  25. 25

    Giorgio, M. et al. Electron. transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell 122, 221–233 (2005).

    Article  CAS  Google Scholar 

  26. 26

    Pacini, S. et al. p66SHC promotes apoptosis and antagonizes mitogenic signaling in T cells. Mol. Cell Biol. 24, 1747–1757 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Bartell, S. M. et al. Deletion of the redox amplifier p66shc decreases ROS production in murine bone and increases osteoblast resistance to oxidative stress and bone mass [abstract]. J. Bone Miner. Res. 26 (Suppl. 1), S85 (2011).

    Google Scholar 

  28. 28

    Maier, B. et al. Modulation of mammalian life span by the short isoform of p53. Genes Dev. 18, 306–319 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Wang, X. et al. p53 functions as a negative regulator of osteoblastogenesis, osteoblast-dependent osteoclastogenesis, and bone remodeling. J. Cell Biol. 172, 115–125 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Jilka, R. L. et al. Dysfunctional osteocytes increase RANKL and promote cortical pore formation in their vicinity: a mechanistic explanation for the development of cortical porosity with age [abstract]. J. Bone Miner. Res. 27 (Suppl. 1), S348 (2012).

    Google Scholar 

  31. 31

    Jilka, R. L. et al. Dysapoptosis of osteoblasts and osteocytes increases cancellous bone formation but exaggerates bone porosity with age. J. Bone Miner. Res. 29, 103–117 (2014).

    Article  CAS  Google Scholar 

  32. 32

    Tomkinson, A., Gevers, E. F., Wit, J. M., Reeve, J. & Noble, B. S. The role of estrogen in the control of rat osteocyte apoptosis. J. Bone Miner. Res. 13, 1243–1250 (1998).

    Article  CAS  Google Scholar 

  33. 33

    Almeida, M. et al. Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J. Biol. Chem. 282, 27285–27297 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Tomkinson, A., Reeve, J., Shaw, R. W. & Noble, B. S. The death of osteocytes via apoptosis accompanies estrogen withdrawal in human bone. J. Clin. Endocrinol. Metab. 82, 3128–3135 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Frost, H. M. Micropetrosis. J. Bone Joint Surg. Am. 42-A, 144–150 (1960).

  36. 36

    Busse, B. et al. Decrease in the osteocyte lacunar density accompanied by hypermineralized lacunar occlusion reveals failure and delay of remodeling in aged human bone. Aging Cell 9, 1065–1075 (2010).

    Article  CAS  Google Scholar 

  37. 37

    Carpentier, V. T. et al. Increased proportion of hypermineralized osteocyte lacunae in osteoporotic and osteoarthritic human trabecular bone: implications for bone remodeling. Bone 50, 688–694 (2012).

    Article  Google Scholar 

  38. 38

    Manolagas, S. C., O'Brien, C. A. & Almeida, M. The role of estrogen and androgen receptors in bone health and disease. Nat. Rev. Endocrinol. 9, 699–712 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Seeman, E. Periosteal bone formation—a neglected determinant of bone strength. N. Engl. J. Med. 349, 320–323 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    Martin-Millan, M. et al. The estrogen receptor-α in osteoclasts mediates the protective effects of estrogens on cancellous but not cortical bone. Mol. Endocrinol. 24, 323–334 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Nakamura, T. et al. Estrogen prevents bone loss via estrogen receptor α and induction of Fas ligand in osteoclasts. Cell 130, 811–823 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Chiang, C. et al. Mineralization and bone resorption are regulated by the androgen receptor in male mice. J. Bone Miner. Res. 24, 621–631 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Notini, A. J. et al. Osteoblast deletion of exon 3 of the androgen receptor gene results in trabecular bone loss in adult male mice. J. Bone Miner. Res. 22, 347–356 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Sinnesael, M. et al. Androgen receptor (AR) in osteocytes is important for the maintenance of male skeletal integrity: evidence from targeted AR disruption in mouse osteocytes. J. Bone Miner. Res. 27, 2535–2543 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Almeida, M. et al. Estrogens attenuate oxidative stress and the differentiation and apoptosis of osteoblasts by DNA-binding-independent actions of the ERα. J. Bone Miner. Res. 25, 769–781 (2010).

    CAS  PubMed  Google Scholar 

  46. 46

    Kousteni, S. et al. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 104, 719–730 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Kousteni, S. et al. Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science 298, 843–846 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Marathe, N., Rangaswami, H., Zhuang, S., Boss, G. R. & Pilz, R. B. Pro-survival effects of 17β-estradiol on osteocytes are mediated by nitric oxide/cGMP via differential actions of cGMP-dependent protein kinases I and II. J. Biol. Chem. 287, 978–988 (2012).

    Article  CAS  Google Scholar 

  49. 49

    Seeman, E. Pathogenesis of bone fragility in women and men. Lancet 359, 1841–1850 (2002).

    Article  Google Scholar 

  50. 50

    Kaufman, J. M. & Vermeulen, A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr. Rev. 26, 833–876 (2005).

    Article  CAS  Google Scholar 

  51. 51

    Shahnazari, M. et al. Bone turnover markers in peripheral blood and marrow plasma reflect trabecular bone loss but not endocortical expansion in aging mice. Bone 50, 628–637 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Syed, F. A. et al. Effects of chronic estrogen treatment on modulating age-related bone loss in female mice. J. Bone Miner. Res. 25, 2438–2446 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Zebaze, R. M. et al. Intracortical remodelling and porosity in the distal radius and post-mortem femurs of women: a cross-sectional study. Lancet 375, 1729–1736 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Manolagas, S. C. & Parfitt, A. M. For whom the bell tolls: distress signals from long-lived osteocytes and the pathogenesis of metabolic bone diseases. Bone 54, 272–278 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Hocking, L. J., Whitehouse, C. & Helfrich, M. H. Autophagy: a new player in skeletal maintenance? J. Bone Miner. Res. 27, 1439–1447 (2012).

    Article  CAS  Google Scholar 

  56. 56

    Kim, K. H. & Lee, M. S. Autophagy—a key player in cellular and body metabolism. Nat. Rev. Endocrinol. 10, 322–337 (2014).

    Article  CAS  Google Scholar 

  57. 57

    Zhang, L. et al. Pathway-based genome-wide association analysis identified the importance of regulation-of-autophagy pathway for ultradistal radius BMD. J. Bone Miner. Res. 25, 1572–1580 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  58. 58

    Rubinsztein, D. C., Marino, G. & Kroemer, G. Autophagy and aging. Cell 146, 682–695 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Selman, C. et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140–144 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Chang, Y. Y. et al. Nutrient-dependent regulation of autophagy through the target of rapamycin pathway. Biochem. Soc. Trans. 37, 232–236 (2009).

    Article  CAS  Google Scholar 

  61. 61

    DeSelm, C. J. et al. Autophagy proteins regulate the secretory component of osteoclastic bone resorption. Dev. Cell 21, 966–974 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Liu, F. et al. Suppression of autophagy by FIP200 deletion leads to osteopenia in mice through the inhibition of osteoblast terminal differentiation. J. Bone Miner. Res. 28, 2414–2430 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Onal, M. et al. Suppression of autophagy in osteocytes mimics skeletal aging. J. Biol. Chem. 288, 17432–17440 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Bonjour, J. P., Kraenzlin, M., Levasseur, R., Warren, M. & Whiting, S. Dairy in adulthood: from foods to nutrient interactions on bone and skeletal muscle health. J. Am. Coll. Nutr. 32, 251–263 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Christodoulou, S., Goula, T., Ververidis, A. & Drosos, G. Vitamin D and bone disease. Biomed. Res. Int. 2013, 396541 (2013).

    Article  CAS  Google Scholar 

  66. 66

    Eisman, J. A. & Bouillon, R. Vitamin D: direct effects of vitamin D metabolites on bone: lessons from genetically modified mice. Bonekey Rep. 3, 499 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Rajendran, P. et al. Antioxidants and human diseases. Clin. Chim. Acta 436C, 332–347 (2014).

  68. 68

    Shen, C. L. et al. Fruits and dietary phytochemicals in bone protection. Nutr. Res. 32, 897–910 (2012).

    Article  CAS  Google Scholar 

  69. 69

    Li, J. J. et al. Fruit and vegetable intake and bone mass in Chinese adolescents, young and postmenopausal women. Public Health Nutr. 16, 78–86 (2013).

    Article  CAS  Google Scholar 

  70. 70

    New, S. A. et al. Dietary influences on bone mass and bone metabolism: further evidence of a positive link between fruit and vegetable consumption and bone health? Am. J. Clin. Nutr. 71, 142–151 (2000).

    Article  CAS  Google Scholar 

  71. 71

    Prynne, C. J. et al. Fruit and vegetable intakes and bone mineral status: a cross sectional study in 5 age and sex cohorts. Am. J. Clin. Nutr. 83, 1420–1428 (2006).

    Article  CAS  Google Scholar 

  72. 72

    Zalloua, P. A. et al. Impact of seafood and fruit consumption on bone mineral density. Maturitas 56, 1–11 (2007).

    Article  Google Scholar 

  73. 73

    Heaney, R. P. & Layman, D. K. Amount and type of protein influences bone health. Am. J. Clin. Nutr. 87, 1567S–1570S (2008).

    Article  CAS  Google Scholar 

  74. 74

    Sebastian, A. Dietary protein content and the diet's net acid load: opposing effects on bone health. Am. J. Clin. Nutr. 82, 921–922 (2005).

    Article  CAS  Google Scholar 

  75. 75

    Bonjour, J. P. Nutritional disturbance in acid-base balance and osteoporosis: a hypothesis that disregards the essential homeostatic role of the kidney. Br. J. Nutr. 110, 1168–1177 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Bushinsky, D. A. Metabolic alkalosis decreases bone calcium efflux by suppressing osteoclasts and stimulating osteoblasts. Am. J. Physiol. 271, F216–F222 (1996).

    Article  CAS  Google Scholar 

  77. 77

    Leeuwenburgh, C. & Heinecke, J. W. Oxidative stress and antioxidants in exercise. Curr. Med. Chem. 8, 829–838 (2001).

    Article  CAS  Google Scholar 

  78. 78

    Ozcivici, E. et al. Mechanical signals as anabolic agents in bone. Nat. Rev. Rheumatol. 6, 50–59 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Rochefort, G. Y., Pallu, S. & Benhamou, C. L. Osteocyte: the unrecognized side of bone tissue. Osteoporos. Int. 21, 1457–1469 (2010).

    Article  CAS  Google Scholar 

  80. 80

    Balemans, W. et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum. Mol. Genet. 10, 537–543 (2001).

    Article  CAS  Google Scholar 

  81. 81

    Balemans, W. et al. Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J. Med. Genet. 39, 91–97 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Li, X. et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J. Biol. Chem. 280, 19883–19887 (2005).

    Article  CAS  Google Scholar 

  83. 83

    Semenov, M., Tamai, K. & He, X. SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J. Biol. Chem. 280, 26770–26775 (2005).

    Article  CAS  Google Scholar 

  84. 84

    Boudin, E., Fijalkowski, I., Piters, E. & Van Hul, W. The role of extracellular modulators of canonical Wnt signaling in bone metabolism and diseases. Semin. Arthritis Rheum. 43, 220–240 (2013).

    Article  CAS  Google Scholar 

  85. 85

    Wang, Y. et al. Wnt and the Wnt signaling pathway in bone development and disease. Front. Biosci. (Landmark Ed.) 19, 379–407 (2014).

    Article  CAS  Google Scholar 

  86. 86

    Maurel, D. B., Boisseau, N., Benhamou, C. L. & Jaffre, C. Alcohol and bone: review of dose effects and mechanisms. Osteoporos. Int. 23, 1–16 (2012).

    Article  CAS  Google Scholar 

  87. 87

    Ronis, M. J., Mercer, K. & Chen, J. R. Effects of nutrition and alcohol consumption on bone loss. Curr. Osteoporos. Rep. 9, 53–59 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  88. 88

    Chen, J. R. et al. A role for ethanol-induced oxidative stress in controlling lineage commitment of mesenchymal stromal cells through inhibition of Wnt/β-catenin signaling. J. Bone Miner. Res. 25, 1117–1127 (2010).

    Article  CAS  Google Scholar 

  89. 89

    Chen, J. R., Shankar, K., Nagarajan, S., Badger, T. M. & Ronis, M. J. Protective effects of estradiol on ethanol-induced bone loss involve inhibition of reactive oxygen species generation in osteoblasts and downstream activation of the extracellular signal-regulated kinase/signal transducer and activator of transcription 3/receptor activator of nuclear factor-κB ligand signaling cascade. J. Pharmacol. Exp. Ther. 324, 50–59 (2008).

    Article  CAS  Google Scholar 

  90. 90

    Kanis, J. A. et al. Smoking and fracture risk: a meta-analysis. Osteoporos. Int. 16, 155–162 (2005).

    Article  CAS  Google Scholar 

  91. 91

    Ward, K. D. & Klesges, R. C. A meta-analysis of the effects of cigarette smoking on bone mineral density. Calcif. Tissue Int. 68, 259–270 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Yoon, V., Maalouf, N. M. & Sakhaee, K. The effects of smoking on bone metabolism. Osteoporos. Int. 23, 2081–2092 (2012).

    Article  CAS  Google Scholar 

  93. 93

    Marini, J. C. & Blissett, A. R. New genes in bone development: what's new in osteogenesis imperfecta. J. Clin. Endocrinol. Metab. 98, 3095–3103 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Sillence, D. O., Senn, A. & Danks, D. M. Genetic heterogeneity in osteogenesis imperfecta. J. Med. Genet. 16, 101–116 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    OMIM® Online Mendelian Inheritance in Man®. An Online Catalog of Human Genes and Genetic Disorders [online], (2015).

  96. 96

    Van Dijk, F. S. & Sillence, D. O. Osteogenesis imperfecta: Clinical diagnosis, nomenclature and severity assessment. Am. J. Med. Genet. A 164, 1470–1481 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  97. 97

    Lazarus, S., Zankl, A. & Duncan, E. L. Next-generation sequencing: a frameshift in skeletal dysplasia gene discovery. Osteoporos. Int. 25, 407–422 (2014).

    Article  CAS  Google Scholar 

  98. 98

    Warman, M. L. et al. Nosology and classification of genetic skeletal disorders: 2010 revision. Am. J. Med. Genet. A 155A, 943–968 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    van Dijk, F. S. et al. EMQN best practice guidelines for the laboratory diagnosis of osteogenesis imperfecta. Eur. J. Hum. Genet. 20, 11–19 (2012).

    Article  CAS  Google Scholar 

  100. 100

    Lazarus, S., Moffatt, P., Duncan, E. L. & Thomas, G. P. A brilliant breakthrough in OI type V. Osteoporos. Int. 25, 399–405 (2014).

    Article  CAS  Google Scholar 

  101. 101

    Eyre, D. R. & Weis, M. A. Bone collagen: new clues to its mineralization mechanism from recessive osteogenesis imperfecta. Calcif. Tissue Int. 93, 338–347 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Gebken, J. et al. Increased cell surface expression of receptors for transforming growth factor-β on osteoblasts from patients with Osteogenesis imperfecta. Pathobiology 68, 106–112 (2000).

    Article  CAS  Google Scholar 

  103. 103

    Grafe, I. et al. Excessive transforming growth factor-β signaling is a common mechanism in osteogenesis imperfecta. Nat. Med. 20, 670–675 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Lapunzina, P. et al. Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta. Am. J. Hum. Genet. 87, 110–114 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Keupp, K. et al. Mutations in WNT1 cause different forms of bone fragility. Am. J. Hum. Genet. 92, 565–574 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Laine, C. M. et al. WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta. N. Engl. J. Med. 368, 1809–1816 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Fahiminiya, S. et al. Whole-exome sequencing reveals a heterozygous LRP5 mutation in a 6-year-old boy with vertebral compression fractures and low trabecular bone density. Bone 57, 41–46 (2013).

    Article  CAS  Google Scholar 

  108. 108

    Korvala, J. et al. Mutations in LRP5 cause primary osteoporosis without features of OI by reducing Wnt signaling activity. BMC Med. Genet. 13, 26 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Crabbe, P. et al. Missense mutations in LRP5 are not a common cause of idiopathic osteoporosis in adult men. J. Bone Miner. Res. 20, 1951–1959 (2005).

    Article  CAS  Google Scholar 

  110. 110

    van Dijk, F. S. et al. PLS3 mutations in X-linked osteoporosis with fractures. N. Engl. J. Med. 369, 1529–1536 (2013).

    Article  CAS  Google Scholar 

  111. 111

    Fahiminiya, S. et al. Osteoporosis caused by mutations in PLS3: clinical and bone tissue characteristics. J. Bone Miner. Res. 29, 1805–1814 (2014).

    Article  CAS  Google Scholar 

  112. 112

    Laine, C. M. et al. Primary osteoporosis without features of OI in children and adolescents: clinical and genetic characteristics. Am. J. Med. Genet. A 158A, 1252–1261 (2012).

    Article  Google Scholar 

  113. 113

    Gong, Y. et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107, 513–523 (2001).

    Article  CAS  Google Scholar 

  114. 114

    Narumi, S. et al. Various types of LRP5 mutations in four patients with osteoporosis-pseudoglioma syndrome: identification of a 7.2-kb microdeletion using oligonucleotide tiling microarray. Am. J. Med. Genet. A 152A, 133–140 (2010).

    Article  CAS  Google Scholar 

  115. 115

    Balemans, W. & Van Hul, W. The genetics of low-density lipoprotein receptor-related protein 5 in bone: a story of extremes. Endocrinology 148, 2622–2629 (2007).

    Article  CAS  Google Scholar 

  116. 116

    Puig-Hervas, M. T. et al. Mutations in PLOD2 cause autosomal-recessive connective tissue disorders within the Bruck syndrome—osteogenesis imperfecta phenotypic spectrum. Hum. Mutat. 33, 1444–1449 (2012).

    Article  CAS  Google Scholar 

  117. 117

    Shaheen, R. et al. Mutations in FKBP10 cause both Bruck syndrome and isolated osteogenesis imperfecta in humans. Am. J. Med. Genet. A 155A, 1448–1452 (2011).

    Article  CAS  Google Scholar 

  118. 118

    Schwarze, U. et al. Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen. Hum. Mol. Genet. 22, 1–17 (2013).

    Article  CAS  Google Scholar 

  119. 119

    Peacock, M., Turner, C. H., Econs, M. J. & Foroud, T. Genetics of osteoporosis. Endocr. Rev. 23, 303–326 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Siris, E. S. et al. Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women: results from the National Osteoporosis Risk Assessment. JAMA 286, 2815–2822 (2001).

    Article  CAS  Google Scholar 

  121. 121

    Duncan, E. L. & Brown, M. A. Clinical review 2: Genetic determinants of bone density and fracture risk—state of the art and future directions. J. Clin. Endocrinol. Metab. 95, 2576–2587 (2010).

    Article  CAS  Google Scholar 

  122. 122

    Ralston, S. H. & Uitterlinden, A. G. Genetics of osteoporosis. Endocr. Rev. 31, 629–662 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Duncan, E. L. et al. Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. PLoS Genet. 7, e1001372 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Estrada, K. et al. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat. Genet. 44, 491–501 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Medina-Gomez, C. et al. Meta-analysis of genome-wide scans for total body BMD in children and adults reveals allelic heterogeneity and age-specific effects at the WNT16 locus. PLoS Genet. 8, e1002718 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Richards, J. B. et al. Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 371, 1505–1512 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Rivadeneira, F. et al. Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat. Genet. 41, 1199–1206 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Styrkarsdottir, U. et al. Multiple genetic loci for bone mineral density and fractures. N. Engl. J. Med. 358, 2355–2365 (2008).

    Article  CAS  Google Scholar 

  129. 129

    Styrkarsdottir, U. et al. European bone mineral density loci are also associated with BMD in East-Asian populations. PLoS ONE 5, e13217 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Zhang, L. et al. Multistage genome-wide association meta-analyses identified two new loci for bone mineral density. Hum. Mol. Genet. 23, 1923–1933 (2014).

    Article  CAS  Google Scholar 

  131. 131

    Moayyeri, A. et al. Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium. Hum. Mol. Genet. 23, 3054–3068 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Oei, L. et al. Genome-wide association study for radiographic vertebral fractures: a potential role for the 16q24 BMD locus. Bone 59, 20–27 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Oei, L. et al. A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus. J. Med. Genet. 51, 122–131 (2014).

    Article  Google Scholar 

  134. 134

    Chew, S. et al. Homozygous deletion of the UGT2B17 gene is not associated with osteoporosis risk in elderly Caucasian women. Osteoporos. Int. 22, 1981–1986 (2011).

    Article  CAS  Google Scholar 

  135. 135

    Deng, F. Y. et al. Genome-wide copy number variation association study suggested VPS13B gene for osteoporosis in Caucasians. Osteoporos. Int. 21, 579–587 (2010).

    Article  CAS  Google Scholar 

  136. 136

    Yang, T. L. et al. Genome-wide copy-number-variation study identified a susceptibility gene, UGT2B17, for osteoporosis. Am. J. Hum. Genet. 83, 663–674 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Holroyd, C., Harvey, N., Dennison, E. & Cooper, C. Epigenetic influences in the developmental origins of osteoporosis. Osteoporos. Int. 23, 401–410 (2012).

    Article  CAS  Google Scholar 

  138. 138

    Vrtacnik, P., Marc, J. & Ostanek, B. Epigenetic mechanisms in bone. Clin. Chem. Lab. Med. 52, 589–608 (2014).

    Article  CAS  Google Scholar 

  139. 139

    Delgado-Calle, J., Garmilla, P. & Riancho, J. A. Do epigenetic marks govern bone mass and homeostasis? Curr. Genomics 13, 252–263 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Cohen-Kfir, E. et al. Sirt1 is a regulator of bone mass and a repressor of Sost encoding for sclerostin, a bone formation inhibitor. Endocrinology 152, 4514–4524 (2011).

    Article  CAS  Google Scholar 

  141. 141

    Redfern, A. D. et al. RNA-induced silencing complex (RISC) proteins PACT, TRBP, and Dicer are SRA binding nuclear receptor coregulators. Proc. Natl Acad. Sci. USA 110, 6536–6541 (2013).

    Article  Google Scholar 

  142. 142

    van Wijnen, A. J. et al. MicroRNA functions in osteogenesis and dysfunctions in osteoporosis. Curr. Osteoporos. Rep. 11, 72–82 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  143. 143

    Gamez, B., Rodriguez-Carballo, E. & Ventura, F. MicroRNAs and post-transcriptional regulation of skeletal development. J. Mol. Endocrinol. 52, R179–197 (2014).

    Article  CAS  Google Scholar 

  144. 144

    Delgado-Calle, J. et al. DNA methylation contributes to the regulation of sclerostin expression in human osteocytes. J. Bone Miner. Res. 27, 926–937 (2012).

    Article  CAS  Google Scholar 

  145. 145

    Delgado-Calle, J. et al. Role of DNA methylation in the regulation of the RANKL-OPG system in human bone. Epigenetics 7, 83–91 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Gelb, B. D., Shi, G. P., Chapman, H. A., & Desnick, R. J. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 273, 1236–1238 (1996).

    Article  CAS  Google Scholar 

  147. 147

    Fijalkowski, I., Boudin, E., Mortier, G. & van Hul, W. Sclerosing bone dysplasias: leads toward novel osteoporosis treatments. Curr. Osteoporos. Rep. 12, 243–251 (2014).

    Article  Google Scholar 

  148. 148

    Tella, S. H. & Gallagher, J. C. Biological agents in management of osteoporosis. Eur. J. Clin. Pharmacol. (2014).

  149. 149

    McClung, M. R. et al. Romosozumab in postmenopausal women with low bone mineral density. N. Engl. J. Med. 370, 412–420 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. 150

    Recker, R. et al. A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density. J. Bone Miner. Res. 30, 216–224 (2015).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors' research is supported by grants G.0197.12N and G.0065.10N to W.V.H. from the Research Foundation—Flanders (FWO) and by the SYBIL (Systems biology for the functional validation of genetic determinants of skeletal diseases) project. SYBIL is funded by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602300 to W.V.H. In addition, E.B. holds a postdoctoral fellowship funded by the FWO.

Author information

Affiliations

Authors

Contributions

G.H. and E.B. contributed equally to this work. G.H. and E.B. researched the data for the article. All authors (G.H., E.B., W.V.H.) contributed substantially to discussions of the article content, writing the article, and review or editing of the manuscript before submission.

Corresponding author

Correspondence to Wim Van Hul.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hendrickx, G., Boudin, E. & Van Hul, W. A look behind the scenes: the risk and pathogenesis of primary osteoporosis. Nat Rev Rheumatol 11, 462–474 (2015). https://doi.org/10.1038/nrrheum.2015.48

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing