Help your patients strengthen their bones
iBoneAcademy is your source for scientific information on osteoporosis. Here you can access disease state education slides and video presentations to learn more about fractures and osteoporosis management.
Globally, approximately 274 million women ≥ 50 years of age are expected to be at high risk of a fragility fracture by 2040.1 Learn more about the pathophysiology of osteoporosis, the pathways that regulate bone homeostasis, and how these pathways may contribute to osteoporosis.
The basic science behind a fragility fracture is revealed here, with a specific focus on understanding the cellular mechanisms influencing bone formation. Sclerostin, a negative regulator of bone formation that inhibits WNT signaling, is introduced.#usa-785-81330
The RANK ligand pathway plays a key role in postmenopausal bone loss and osteoporosis. Watch the video to learn how declining estrogen levels following menopause affect RANK ligand expression and osteoclast-mediated bone resorption.#usa-785-81347
1. Odén A, et al. Osteoporos Int. 2015;26:2243-2248. 2. International Osteoporosis Foundation. https://www.osteoporosis.foundation/health-professionals/about-osteoporosis. Accessed January 18, 2021. 3. Lin C, et al. J Bone Miner Res. 2009;24:1651-1661. 4. Li X, et al. J Biol Chem. 2005;280:19883-19887. 5. Kostenuik PJ. Curr Opin Pharmacol. 2005;5:618-625. 6. Eghbali-Fatourechi G, et al. J Clin Invest. 2003;111:1221-1230. 7. Ardawi MSM, et al. J Bone Miner Res. 2011;26:2812-2822. 8. Szulc P, et al. J Bone Miner Res. 2013;28:1760-1770. 9. Winkler DG, et al. EMBO J. 2003;22:6267-6276. 10. Camacho PM, et al. Endocr Pract. 2020;26(suppl 1):1-46.
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But after a simple fall from standing height,1,2 the difference between a momentary mishap and a fracture may be more than an accident3-5 and is potentially a result of compromised bone strength.3-5 A fragility fracture, also often referred to as a low-trauma fracture,1,5,6 could reflect a deficit in bone mass and structural integrity,5,7 the main determinants of bone strength.8 This deficit occurs when bone formation by osteoblasts fails to counterbalance bone resorption by osteoclasts.7 Every three seconds, someone in the world experiences a low-trauma clinical fracture,9 a fragility fracture that causes immediate pain and disability.6,10 Clinical fractures happen anywhere in the skeleton and include nonvertebral2,11 and symptomatic vertebral fractures.9 These fractures can result in a substantial burden to individuals and society.10 Any such fracture signals increased risk for a subsequent clinical fracture.2 After a clinical fracture, one in 4 women will sustain another fracture in the next 5 years.12 A clinical fracture signals a need for immediate action to reduce the risk of further fractures.5 Improving bone mass, structure, and strength can help protect against further fractures.5,7
The skeleton is a dynamic organ with a capacity to change its mass and structure7,13 by way of multiple signaling pathways that regulate bone formation and resorption.13-15 Extensive crosstalk among osteocytes, osteoblasts, and osteoclasts affects signaling via these pathways.14 Osteocytes can limit bone formation by secreting Wnt antagonists.16 Of these, sclerostin is a key negative regulator of bone formation in adults.14,17 Under conditions of reduced weight bearing18 or postmenopausal estrogen deficiency,19,20 osteocytes secrete more sclerostin. At the cellular level, sclerostin interferes with Wnt coreceptor signaling,18,21 thus reducing the amount of new bone being formed by osteoblasts.18 Sclerostin also increases osteoclast formation and resorptive activity indirectly by increasing the expression of RANKL and decreasing the expression of OPG in osteoblast lineage cells.22 Under conditions of mechanical loading, as in exercise23,24 or with PTH19,23 and estrogen signaling,19,20 osteocytes secrete less sclerostin, allowing Wnt to bind to its coreceptors,16 resulting in signaling associated with increased bone formation by osteoblasts.16 These responses are part of the body’s diverse repertoire for regulating bone mass.14
1. Prentice A, Schoenmakers I, Laskey MA, de Bono S, Ginty F, Goldberg GR. Nutrition and bone
growth and development. Proc Nutr Soc. 2006;65:348-60.
2. Center JR, Bliuc D, Nguyen TV, Eisman JA. Risk of subsequent fracture after low-trauma fracture in men and women. JAMA. 2007;297:387-94.
3. Bouxsein ML, Seeman E. Quantifying the material and structural determinants of bone strength. Best Pract Res Clin Rheumatol. 2009;23:741-53.
4. Raisz LG. Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest. 2005;115:3318-25.
5. Boonen S, Singer AJ. Osteoporosis management: impact of fracture type on cost and quality of life in patients at risk for fracture I. Curr Med Res Opin. 2008;24:1781-8.
6. Abimanyi-Ochom J, Watts JJ, Borgström F, et al. Changes in quality of life associated with fragility fractures: Australian arm of the International Cost and Utility Related to Osteoporotic Fractures Study (AusICUROS). Osteoporos Int. 2015;26:1781-90.
7. Seeman E, Delmas PD. Bone quality: the material and structural basis of bone strength and fragility. N Engl J Med. 2006;354:2250-61.
8. Seeman E. Bone quality: the material and structural basis of bone strength. J Bone Miner Metab. 2008;26:1-8.
9. Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int. 2006;17:1726-33.
10. U.S. Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services, Office of the Surgeon General, 2004.
11. van Helden S, Cals J, Kessels F, Brink P, Dinant GJ, Geusens P. Risk of new clinical fractures within 2 years following a fracture. Osteoporos Int. 2006;17:348-54.
12. Bliuc D, Nguyen ND, Nguyen TV, Eisman JA, Center JR. Compound risk of high mortality following osteoporotic fracture and refracture in elderly women and men. J Bone Miner Res. 2013;28:2317-24.
13. Raggatt LJ, Partridge NC. Cellular and molecular mechanisms of bone remodeling. J Biol Chem. 2010;285:25103-8.
14. Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med. 2013;19:179-92.
15. Blau JE, Collins MT. The PTH-Vitamin D-FGF23 axis. Rev Endocr Metab Disord. 2015;16:165-74.
16. Robling AG, Niziolek PJ, Baldridge LA, et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem. 2008;283:5866-75.
17. 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;199:805-14.
18. Lin C, Jiang X, Dai Z, et al. Sclerostin mediates bone response to mechanical unloading through antagonizing Wnt/beta-catenin signaling. J Bone Miner Res. 2009;24:1651-61.
19. Mirza FS, Padhi ID, Raisz LG, Lorenzo JA. Serum sclerostin levels negatively correlate with parathyroid hormone levels and free estrogen index in postmenopausal women. J Clin Endocrinol Metab. 2010;95:1991-7.
20. Jia HB, Ma JX, Ma XL, et al. Estrogen alone or in combination with parathyroid hormone can decrease vertebral MEF2 and sclerostin expression and increase vertebral bone mass in ovariectomized rats. Osteoporos Int. 2014;25:2743-54.
21. Li X, Zhang Y, Kang H, et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem. 2005;280:19883-7.
22. Wijenayaka AR, Kogawa M, Lim HP, Bonewald LF, Findlay DM, Atkins GJ. Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway. PLoS One. 2011;6(10):e25900.
23. Ke HZ, Richards WG, Li X, Ominsky MS. Sclerostin and Dickkopf-1 as therapeutic targets in bone diseases. Endocr Rev. 2012;33:747-83.
24. Kontulainen S, Sievänen H, Kannus P, Pasanen M, Vuori I. Effect of long-term impact- loading on mass, size, and estimated strength of humerus and radius of female racquet- sports players: a peripheral quantitative computed tomography study between young and old starters and controls. J Bone Miner Res. 2002;17:2281-9.
Discoveries in bone biology have revealed the role of the RANK ligand pathway in osteoclast-mediated bone loss and postmenopausal osteoporosis.
Osteoporosis is a significant health burden, compromising the strength of bones and increasing the risk for fracture.
Menopause is a key turning point in the skeletal health of women.
Following menopause, declines in estrogen often lead to excessive bone remodeling activity and accelerated bone loss.
Bone loss following menopause results from an imbalance of osteoclast and osteoblast activity.
Osteoclasts are the specialized cells that resorb bone, and osteoblasts are the cells that form new bone.
The discovery of the RANK ligand pathway has been an important advance in our understanding of bone remodeling.
RANK ligand, a protein expressed by osteoblasts, plays a key role in osteoclast formation, function, and survival through interaction with its receptor, RANK, that is expressed on the surface of osteoclasts.
Osteoprotegerin, or OPG, another protein secreted by osteoblasts, is a natural inhibitor of RANK ligand and plays a role in regulating bone resorption.
At the initiation of bone remodeling, lining cells move apart to expose the bone surface, become osteoblasts, and begin expressing RANK ligand.
RANK ligand binds to RANK on osteoclast precursors, which initiates cell fusion and the formation of mature, multinucleated osteoclasts.
RANK ligand continues to bind to RANK on mature osteoclasts.
The binding of RANK ligand to RANK is essential for osteoclast formation, function, and survival.
Following bone resorption, osteoblasts migrate into the pit.
Osteoblasts fill the pit with new bone matrix.
Some osteoblasts become embedded within the matrix and eventually turn into osteocytes, while others become new lining cells on the bone surface.
In the final stage of remodeling, newly created bone matrix mineralizes and the bone returns to a resting state.
The process of bone remodeling is regulated by factors including estrogen and OPG.
Estrogen limits the amount of RANK ligand expression by osteoblasts and OPG blocks the binding of RANK ligand to RANK, thereby reducing osteoclast activity.
In postmenopausal women, reduced levels of estrogen lead to increased expression of RANK ligand by osteoblasts.
Excessive RANK ligand overwhelms OPG, leading to more osteoclasts, increased bone remodeling activity, and greater bone loss.
Osteoblasts continue to deposit new bone matrix, but they can not replace all of the resorbed bone. Therefore, resorption pits may not be completely refilled, which over time leads to thinning and weakening of bone.
The progressive loss of bone following menopause reduces the structural integrity and strength of the skeleton.
Bone loss may go undetected for many years until the occurrence of a fracture, a potentially serious and debilitating outcome of postmenopausal osteoporosis.
In summary, in postmenopausal women, as estrogen declines, RANK ligand expression increases. Elevated RANK ligand levels lead to increased osteoclast formation, function and survival. Greater osteoclast activity increases bone loss, weakens bone architecture, and can ultimately lead to fracture.
We now understand the underlying biological mechanism of the increase in bone resorption that follows menopause.
RANK ligand is a key link between reduced estrogen levels and osteoclast-mediated bone loss.
Kostenuik PJ. Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength. Curr Opin Pharmacol. 2005;5:618-625.
Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423:337-342.
US Department of Health and Human Services: Bone Health and Osteoporosis: A Report of the Surgeon General. Washington DC.F 2004.
Riggs BL, Parfitt AM. Drugs used to treat osteoporosis: the critical need for a uniform nomenclature based on their action on bone remodeling. J Bone Miner Res. 2005;20:177-184.
Raisz LG. Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest. 2005;115:3318-3325.
Seeman E, Delmas PD. Bone quality--the material and structural basis of bone strength and fragility. N Engl J Med. 2006;354:2250-2261.
Chavassieux P, Seeman E, Delmas PD. Insights into material and structural basis of bone fragility from diseases associated with fractures: how determinants of the biomechanical properties of bone are compromised by disease. Endocr Rev. 2007;28:151-164.
Morgan EF, Barnes GL, Einhorn TA. The Bone Organ System: Form and Function. In: Marcus R, Feldman D, Nelson DA, Rosen CJ, eds. Osteoporosis. 3rd ed. New York, NY: Elsevier Academic Press; 2008:3-25.
Lacey DL, Tan HL, Lu J, et al. Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo. Am J Pathol. 2000;157:435-448.
Dempster DW. Anatomy and Functions of the Adult Skeleton. In: Favus M, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 6th ed. Washington, DC: ASBMR; 2006:7-11.
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;111:1221-1230.
NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285:785-795.
World Health Organization. Technical Report Series 921: Prevention and Management of Osteoporosis: Report of a WHO Scientific Group. Geneva, Switzerland. 2003.
Hodgson SF, Watts NB, Bilezikian JP, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 ed, with selected updates for 2003. Endocr Pract. 2003;9:544-564.
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;29:155-192.
The human skeleton gives the body its shape and provides physical support for the system contained within.1 It also forms part of the musculoskeletal system that enables us to move.1 The structure of bone is optimized so that it is strong but relatively lightweight.
The interior of bone is composed of bone marrow.2 It is surrounded by two major types of bone tissue: cortical bone, or the hard outer shell of bone; and trabecular bone, the spongy-looking center.2 The amount of each type of tissue in bone is dependent on the function of that bone.2
The basic unit of cortical or compact bone is the osteon.2 It is composed of successive concentric lamellae.2 This structure contributes to bone strength by resisting bending.2
Cells called osteocytes are distributed within the concentric lamellae.2 Osteocytes form a complex network3 that is thought to be important in maintaining the viability and structural integrity of bone.4
At the center of the osteon is the Haversian canal. These canals contain blood vessels and nerves.2 The blood vessels within bone facilitate the exchange between osteocytes and the blood.2
Trabecular bone is present in the interior of some bones and resists compression.2 Osteocytes are also contained within its structure and again play an important role in sensing local changes in strain.5 Trabeculae are covered in a layer of flattened lining cells that are thought to be involved in the dynamic process by which bone is formed and broken down.2
Bone marrow is found within the interior of bones. The surrounding trabeculae and vascular network provide structural support, nutrition and a waste removal system for the heterogeneous group of cells found within this space.6 Bone marrow is a site for haemopoiesis, the process by which the cellular components of blood are formed.6
Bone is a dynamic tissue that is continually being built, broken down and rebuilt in a process called bone remodeling.3
Bone tissue is broken down and resorbed by multinucleated cells known as osteoclasts.3 These cells are derived from monocytes which originate within bone marrow.7 Osteoclasts play an important role in liberating minerals and other molecules stored within the bone matrix.8,9
Bone tissue serves as a repository for vital minerals, including calcium phosphate,8 and various biologically active molecules, such as growth factors.9 The release of calcium from the bone can play a role in maintaining its homeostasis within the body.8
The cells responsible for building new bone tissue are known as osteoblasts.3 Osteoblasts are thought to be derived from cells found to be associated with blood vessels.10 Once active, they start to produce the organic component of bone osteoid, which is predominantly made of collagen.3
Minerals start to crystallize around the collagen scaffold to form hydroxyapatite, the major inorganic constituent of bone, which contains calcium phosphate.2,11 Bone mineral density (or BMD) can be used to estimate the strength of bone and to assess the risk of fracture.12
As osteoblasts form new bone tissue, many become embedded within the matrix and differentiate into osteocytes.3
The structure, composition and cellular processes that occur within bone allow it to simultaneously serve as a calcium reservoir,8 while providing structural support for the vital organs and for locomotion.1
1. Watkins J. The Skeleton. In: Watkins J. Structure and Function of the Musculoskeletal System. Human Kinetics Publishers, Inc;2010:21-58.
2. Nather A, Ong HJC, Aziz Z. Structure of Bone. In: Nather A. Bone Grafts and Bone Substitutes: Basic Science and Clinical Applications. World Scientific Publishing.
3. Raggatt LJ, Partridge NC. Cellular and molecular mechanisms of bone remodeling. J Biol Chem. 2010;285:25103-25108.
4. Vashishth D, Verborgt O, Divine G, et al. Decline in osteocyte lacunar density in human cortical bone is associated with accumulation of microcracks with age. Bone. 2000;26:375-380.
5. Adachi T, Kameo Y, Hojo M. Trabecular bone remodelling simulation considering osteocytic response to fluid-induced shear stress. Phil Trans R Soc A. 2010;368:2669-2682.
6. Wilkins BS. Histology of normal haemopoiesis: bone marrow histology I. J Clin Pathol. 1992;45:645-649.
7. Tinkler SMB, Linder JE, Williams DM, et al. Formation of osteoclasts from blood monocytes during 1 alpha-OH Vit D-stimulated bone resorption in mice. J Anat. 1981;133:389-396.
8. Komarova SV. Mathematical model of paracrine interactions between osteoclasts and osteoblasts predicts anabolic action of parathyroid hormone on bone. Endocrinology. 2005;146:3589-3595.
9. Yin JJ, Pollock CB, Kelly K. Mechanisms of cancer metastasis to the bone. Cell Res. 2005;15:57-62.
10. Doherty MJ, Ashton BA, Walsh S, et al. Vascular pericytes express osteogenic potential in vitro and in vivo. J Bone Miner Res. 1998;13:828-838.
11. Simão AMS, Yadav MC, Ciancaglini P, et al. Proteoliposomes as matrix vesicles' biomimetics to study the initiation of skeletal mineralization. Braz J Med Biol Res. 2010;43:234-241.
12. Hanssens L, Reginster JY. Relevance of bone mineral density, bone quality and falls in reduction of vertebral and non-vertebral fractures. J Musculoskelet Neuron Interact. 2003;3:189-193.
The skeleton changes across the human life span. This is characterized predominantly by bone formation and growth throughout childhood, followed by a gradual loss of bone density that begins in early adulthood that can accelerate significantly in older adults.1,2
The density of bone is modulated by a group of cells including osteoclasts, which are multinucleated cells that resorb bone, and osteoblasts, which refill the resorption cavities created by osteoclasts.3
Osteoclasts anchor themselves to the surface of bone.3 This creates a microenvironment underneath the cell, which is referred to as the “sealed zone”.
Within this zone, the osteoclasts create an acidic environment that dissolves the bone’s mineral content.3 Once the mineral content of the bone has been dissolved, enzymes released from osteoclasts remove the remaining collagenous bone matrix to complete the process of resorption.3,4
Following resorption, osteoblasts move into the resorption space and start to produce and deposit organic matrix called osteoid. Osteoid, a substance made predominantly of collagen, forms a scaffold in which minerals, including calcium and phosphate, begin to crystallize.3,5,6 Some active osteoblasts become trapped within the matrix they secrete, and thereby become osteocytes.3
Other osteoblasts will undergo apoptosis or will revert back to lining cells which cover the surface of bone.3
This cycle of bone resorption and formation is referred to as remodeling. There is also a process where bone formation by osteoblasts occurs without prior bone resorption by osteoclasts; this results in an increase in bone mass and is referred to as bone modeling.7 Bone modeling promotes the growth of bones and is important for maintaining bone strength.7
Remodeling also plays an important role during bone growth by optimizing the growing structure.7
After the age of 30, most people experience a gradual loss in bone mass due to a relative decrease in the activity of osteoblasts compared with osteoclasts.1 However, there are many factors that impact the process of bone remodeling and influence the degree of bone loss we experience as we age. For example, medications, such as glucocorticoids, which can promote osteoclast activity and also reduce bone formation.8-10
Proper nutrition and physical activity can help strengthen bone.8,9 It is also believed that osteocytes form a complex network in bone that can sense any increased work load on the bone and respond by triggering the differentiation and activity of osteoblasts to increase bone density.9,11
Conversely, when bone experiences reduced loading conditions, such as during long term bed rest, resorption and remodeling increase to eliminate underloaded bone.9,11,12
Loss of bone mass reduces its strength and increases the risk of fracture.1 This highlights the importance of staying active, maintaining good nutrition throughout life, and being aware of personal risk factors associated with low bone density.8,9
1. van der Linden JC, Homminga J, Verhaar JAN, et al. Mechanical consequences of bone loss in cancellous bone. J Bone Miner Res. 2001;16:457-465.
2. U.S. Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services, Office of the Surgeon General, 2004.
3. Raggatt LJ, Partridge NC. Cellular and molecular mechanisms of bone remodeling. J Biol Chem. 2010;285:25103-25108.
4. Saftig P, Hunziker E, Wehmeyer O, et al. Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc Natl Acad Sci U S A. 1998;95:13453-13458.
5. Nather A, Ong HJC, Aziz Z. Structure of Bone. In: Nather A. Bone Grafts and Bone Substitutes: Basic Science and Clinical Applications. World Scientific Publishing Company; 2005:3-18
6. Simão AMS, Yadav MC, Ciancaglini P, et al. Proteoliposomes as matrix vesicles' biomimetics to study the initiation of skeletal mineralization. Braz J Med Biol Res. 2010;43:234-241.
7. Seeman E. Osteocytes--martyrs for integrity of bone strength. Osteoporos Int. 2006;17:1443-1448.
8. Prentice A, Schoenmakers I, Laskey MA, et al. Nutrition and bone growth and development. Proc Nutr Soc. 2006;65:348-360.
9. Bergmann P, Body JJ, Boonen S, et al. Loading and skeletal development and maintenance. J Osteoporos. 2010;2011:786752.
10. Jia D, O'Brien CA, Stewart SA, et al. Glucocorticoids act directly on osteoclasts to increase their life span and reduce bone density. Endocrinology. 2006;147:5592-5599.
11. Moester MJC, Papapoulos SE, Löwik CWGM, et al. Sclerostin: current knowledge and future perspectives. Calcif Tissue Int. 2007;87:99-107.
12. Zerwekh JE, Ruml LA, Gottschalk F, et al. The effects of twelve weeks of bed rest on bone histology, biochemical markers of bone turnover, and calcium homeostasis in eleven normal subjects. J Bone Miner Res. 1998;13:1594-1601.