Skeletons dynamically cycle between bone formation and bone resorption through coordinated efforts of osteocytes, osteoclasts, and osteoblastsSeeman—the protein sclerostin plays an important role

Lower levels of sclerostin are associated with increased bone formation2-4

• Sclerostin is a negative regulator of bone formation and limits the accumulation of bone mass5,6

• With more exercise or increased levels of estrogen, osteocytes secrete less sclerostin, and bone formation increases7-10

Higher levels of sclerostin are also associated with reduced bone formation11

• With less exercise and lower levels of estrogen, more secretion of sclerostin by osteocytes indirectly results in reduced bone formation7-10

Higher levels of sclerostin are also associated with increased bone resorption12

• Higher levels of sclerostin decrease the expression of osteoprotegerin (OPG) and increase the expression of RANKL, indirectly resulting in an increased amount of bone resorbed by osteoclasts12

See the Effect of Sclerostin Levels on Bone Formation

HEALTHY BONE STRUCTURE

COMPROMISED BONE STRUCTURE

OSTEOPOROTIC BONE

Skeletons dynamically cycle between bone formation and bone resorption through coordinated efforts of osteocytes, osteoclasts, and osteoblasts1—the protein sclerostin plays an important role

Amgen is committed to deepening our understanding about the role of sclerostin in bone formation.

Learn more about the role of sclerostin in bone formation at www.notjustafracture.com.

• Natural genetic deficiencies of sclerostin (known as sclerosteosis) are associated with higher bone mass and stronger, more fracture-resistant bone13,14

• Sclerostin also indirectly affects bone resorption12

Bone Formation

Sclerostin

Sclerostin

Reduced sclerostin is associated with

increased bone formation.

Increased sclerostin is associated with

decreased bone formation.

Bone Formation

Sclerostin plays a key role in bone formation

References1. Seeman E, Delmas PD. Bone quality—the material and structural basis of bone strength

and fragility. N Engl J Med. 2006;354:2250-2261.

2. Ryan ZC, Ketha H, McNulty MS, et al. Sclerostin alters serum vitamin D metabolite and fibroblast growth factor 23 concentrations and the urinary excretion of calcium. Proc Natl Acad Sci U S A. 2013;110:6199-6204.

3. Li X, Ominsky M, Niu QT, et al. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res. 2008;23:860-869.

4. Gardner JC, van Bezooijen RL, Mervis B, et al. Bone mineral density in sclerosteosis; affected individuals and gene carriers. J Clin Endocrinol Metab. 2005;90:6392-6395.

5. Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med. 2013;19:179-192.

6. 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;199:805-814.

7. 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;24:1651-1661.

8. 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;95:1991-1997.

9. 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;25:2743-2754.

10. Robling AG, Niziolek PJ, Baldridge LA, et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem. 2008;283:5866-5875.

11. Winkler DG, Sutherland MK, Geoghegan JC, et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. 2003;22:6267-6276.

12. 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:e25900.

13. van Lierop AH, Hamdy NA, van Egmond ME, Bakker E, Dikkers FG, Papapoulos SE. Van Buchem disease: clinical, biochemical, and densitometric features of patients and disease carriers. J Bone Miner Res. 2013;28:848-854.

14. Hamersma H, Gardner J, Beighton P. The natural history of sclerosteosis. Clin Genet. 2003;63:192-197.

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