Sklerostin des Osteozyten – von der Expression zur klinischen Anwendung

Zusammenfassung

Sklerostin ist ein sezerniertes Glykoprotein und ein Produkt des SOST-Gens, welches im Knochen vorranging von Osteozyten exprimiert wird und zu einer Inhibition der Osteoblasten-induzierten Knochenformation und damit zu einer reduzierten Knochenmasse führen kann. Im Gegensatz dazu induziert eine Funktionsdeletion des SOST-Gens einen High-bone-mass-Knochenphänotyp. Darüber hinaus wirkt Sklerostin auf den Osteozyten selbst, wodurch der Osteoklasten-gesteuerte Knochenabbau gefördert werden kann und die osteozytäre Osteolyse unterstützt wird. Die Sklerostin-Expression kann durch verschiedene Mechanismen beeinflusst werden und bildet aufgrund der anabolen Rolle in der Knochenformation einen potenziellen Behandlungsansatz. Der Sklerostin-Antikörper Romosozumab ist seit Anfang 2019 in Japan und den USA zugelassen, und es zeigen sich erste positive Ergebnisse bei der Behandlung postmenopausaler Osteoporose. Andere Studien präsentieren Daten zu Sklerostin-Serumwerten in Relation zu Frakturraten oder Erkrankungen wie Diabetes mellitus Typ 2, lassen jedoch die Frage offen, ob sich Sklerostin als Biomarker in der Frakturrisikodiagnostik eignet.

Abstract

Sclerostin is a secreted glycoprotein and a product of the SOST gene, which is primarily expressed in osteocytes. Expression of sclerostin leads to inhibition of osteoblast-induced bone formation and therefore to reduced bone mass. In contrast, the loss-of-function deletion of the SOST gene induces a high bone mass bone phenotype. Furthermore, sclerostin may act on the osteocyte itself which leads to an increased osteoclast-induced bone resorption and supports osteocytic osteolysis. Sclerostin expression can be influenced by different mechanisms and represents a potential treatment option based on the anabolic action in bone formation. The sclerostin antibody Romosozumab is available since the beginning of 2019 in Japan and the US and first studies have shown positive effects on fracture risk and BMD in postmenopausal women. Other studies present data on sclerostin serum values in correlation with fractures and diseases such as diabetes mellitus type 2 which leave the unanswered question whether sclerostin is a possible biomarker for fracture risk diagnostics.

Schlüsselwörter

Sklerostin - Osteozyt - Wnt-Singaltransduktionsweg - Mechanosensation

Keywords

Sclerostin - osteocyte - Wnt-signalling pathway - mechanosensation

Publication History

Received: 11 October 2019

Accepted: 26 November 2019

Article published online:
25 February 2020

• Literatur

• 1 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. Hum Genet 2001; 68: 577-589. DOI: 10.1086/318811.
• 2 Balemans W, Ebeling M, Patel N. et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 2001; 10: 537-543. DOI: 10.1093/hmg/10.5.537.
• 3 Balemans W, Patel N, Ebeling M. et al. Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet 2002; 39: 91-97. DOI: 10.1136/jmg.39.2.91.
• 4 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. J Med Genet 2002; 110: 144-152. DOI: 10.1002/ajmg.10401.
• 5 van Bezooijen RL, Roelen BAJ, 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. DOI: 10.1084/jem.20031454.
• 6 Buenzli PR, Sims NA. Quantifying the osteocyte network in the human skeleton. Bone 2015; 75: 144-150. DOI: 10.1016/j.bone.2015.02.016.
• 7 Kalajzic I, Braut A, Guo D. et al. Dentin matrix protein 1 expression during osteoblastic differentiation, generation of an osteocyte GFP-transgene. Bone 2004; 35: 74-82. DOI: 10.1016/j.bone.2004.03.006.
• 8 Lu Y, Xie Y, Zhang S. et al. DMP1-targeted Cre expression in odontoblasts and osteocytes. J Dent Res 2007; 86: 320-325. DOI: 10.1177/154405910708600404.
• 9 Milovanovic P, Zimmermann EA, Scheidt A. et al. The Formation of Calcified Nano-Pearls during Micropetrosis Represents a Unique Mineralization Mechanism in Aged Human Bone. Small 2017; 13: 1-10
• 10 Kamel-ElSayed SA, Tiede-Lewis LM, Lu Y. et al. Novel approaches for two and three dimensional multiplexed imaging of osteocytes. Bone 2015; 76: 129-140. DOI: 10.1016/j.bone.2015.02.011.
• 11 Stern AR, Stern MM, van Dyke ME. et al. Isolation and culture of primary osteocytes from the long bones of skeletally mature and aged mice. BioTechniques 2012; 52: 361-373. DOI: 10.2144/0000113876.
• 12 Woo SM, Rosser J, Dusevich V. et al. Cell line IDG-SW3 replicates osteoblast-to-late-osteocyte differentiation in vitro and accelerates bone formation in vivo. J Bone Miner Res 2011; 26: 2634-2646. DOI: 10.1002/jbmr.465.
• 13 Kalajzic I, Matthews BG, Torreggiani E. et al. In vitro and in vivo approaches to study osteocyte biology. Bone 2013; 54: 296-306. DOI: 10.1016/j.bone.2012.09.040.
• 14 Dallas SL, Prideaux M, Bonewald LF. The osteocyte: An endocrine cell … and more. Endocr Rev 2013; 34: 658-690. DOI: 10.1210/er.2012-1026.
• 15 Huang J, Romero-Suarez S, Lara N. et al. Crosstalk between MLO-Y4 osteocytes and C2C12 muscle cells is mediated by the Wnt/beta-catenin pathway. JBMR Plus 2017; 1: 86-100. DOI: 10.1002/jbm4.10015.
• 16 Jähn K, Lara-Castillo N, Brotto L. et al. Skeletal muscle secreted factors prevent glucocorticoid-induced osteocyte apoptosis through activation of β-catenin. Eur Cells Mater 2012; 24: 197-210. DOI: vol024a14.
• 17 Sato M, Asada N, Kawano Y. et al. Osteocytes regulate primary lymphoid organs and fat metabolism. Cell Metab 2013; 18: 749-758. DOI: 10.1016/j.cmet.2013.09.014.
• 18 Fulzele K, Krause DS, Panaroni C. et al. Myelopoiesis is regulated by osteocytes through Gsalpha-dependent signaling. Blood 2013; 121: 930-939. DOI: 10.1182/blood-2012-06-437160.
• 19 Dudley HR, Spiro D. The Fine Structure of Bone Cells. Biophys Biochem Cytol 1961; 11: 627-649. DOI: 10.1083/jcb.11.3.627.
• 20 Holtrop ME. Light and Electron Microscopic Structure of Bone-Forming Cells. In: BK H. ed. The Osteoblast and osteocyte. CRC Press, Inc., Boca Raton, Florida, USA; 1990: 1-40.
• 21 Zhang K, Barragan-Adjemian C, Ye L. et al. E11/gp38 selective expression in osteocytes: regulation by mechanical strain and role in dendrite elongation. Mol Cell Biol 2006; 26: 4539-4552.
• 22 Feng JQ, Ward LM, Liu S. et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet 2006; 38: 1310-1315. DOI: 10.1038/nature09421.Oxidative.
• 23 Rowe PS. Regulation of bone-renal mineral and energy metabolism: the PHEX, FGF23, DMP1, MEPE ASARM pathway. Crit Rev Eukaryot Gene Expr 2012; 22: 61-86.
• 24 Touchberry CD, Green TM, Tchikrizov V. et al. FGF23 is a novel regulator of intracellular calcium and cardiac contractility in addition to cardiac hypertrophy. Am J Physiol Endocrinol Metab 2013; 304: E863-873. DOI: 10.1152/ajpendo.00596.2012.
• 25 Poole KE, van Bezooijen RL, Loveridge N. et al. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB 2005; 19: 1842-1844. DOI: 10.1096/fj.05-4221fje.
• 26 Burger EH, Klein-Nulend J, van der Plas A. et al. Function of osteocytes in bone – their role in mechanotransduction. J Nutr 1995; 125: 2020S-2023S.
• 27 Klein-Nulend J, van der Plas A, Semeins CM. et al. Sensitivity of Osteocytes To Biomechanical Stress in Vitro. FASEB 1995; 9: 441-445.
• 28 Klein-Nulend J, Semeins CM, Ajubi NE. et al. Pulsating fluid flow increases nitric oxide (NO) synthesis by osteocytes but not periosteal fibroblasts–correlation with prostaglandin upregulation. Biochem Biophys Res Commun 1995; 217: 640-648. DOI: 10.1006/bbrc.1995.2822.
• 29 Knothe Tate ML. Whither flows the fluid in bone?” An osteocyte’s perspective. J Biomech 2003; 36: 1409-1424. DOI: 10.1016/s0021-9290(03)00123-4.
• 30 Ajubi NE, Klein-Nulend J, Nijweide PJ. et al. Pulsating fluid flow increases prostaglandin production by cultured chicken osteocytes–a cytoskeleton-dependent process. Biochem Biophys Res Commun 1996; 225: 62-68. DOI: 10.1006/bbrc.1996.1131.
• 31 Prideaux M, Findlay DM, Atkins GJ. Osteocytes: The master cells in bone remodelling. Curr Opin Pharmacol 2016; 28: 24-30. DOI: 10.1016/j.coph.2016.02.003.
• 32 Seeman E. Bone modeling and remodeling. J Bone Miner Res 2009; 19: 219-233
• 33 Zhao S, Zhang YK, Harris S. et al. MLO-Y4 osteocyte-like cells support osteoclast formation and activation. J Bone Miner Res 2002; 17: 2068-2079. DOI: 10.1359/jbmr.2002.17.11.2068.
• 34 Nakashima T, Hayashi M, Fukunaga T. et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 2011; 17: 1231-1234. DOI: 10.1038/nm.2452.
• 35 Xiong J, Onal M, Jilka RL. et al. Matrix-embedded cells control osteoclast formation. Nat Med 2011; 17: 1235-1241
• 36 van Bezooijen RL, Svensson JP, Eefting D. et al. Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation. J Bone Miner Res 2007; 22: 19-28. DOI: 10.1359/jbmr.061002.
• 37 Kato Y, Windle JJ, Koop BA. et al. Establishment of an osteocyte-like cell line, MLO-Y4. J Bone Miner Res 1997; 12: 2014-2023
• 38 Wijenayaka AR, Kogawa M, Lim HP. et al. Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway. PLoS One 2011; 6: e25900. DOI: 10.1371/journal.pone.0025900.
• 39 Kogawa M, Wijenayaka AR, Ormsby RT. et al. Sclerostin regulates release of bone mineral by osteocytes by induction of carbonic anhydrase 2. J Bone Miner Res 2013; 28: 2436-2448. DOI: 10.1002/jbmr.2119.
• 40 Qing H, Ardeshirpour L, Divieti Pajevic P. et al. Demonstration of Osteocytic Perilacunar/Canalicular Remodeling in Mice during Lactation. J Bone Miner Res 2012; 27: 1018-1029. DOI: 10.1002/jbmr.1567.Demonstration.
• 41 Jähn K, Kelkar S, Zhao H. et al. Osteocytes Acidify Their Microenvironment in Response to PTHrP In Vitro and in Lactating Mice In Vivo. J Bone Miner Res 2017; 32: 1761-1772. DOI: 10.1002/jbmr.3167.
• 42 Tsourdi E, Jähn K, Rauner M. et al. Physiological and pathological osteocytic osteolysis. J Musculoskelet Neuronal Interact 2018; 18: 292-303
• 43 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. DOI: 10.1093/emboj/cdg599.
• 44 Li X, Zhang Y, Kang H. et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 2005; 280: 19883-19887. DOI: 10.1074/jbc.M413274200.
• 45 Leupin O, Piters E, Halleux C. et al. Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function. J Biol Chem 2011; 286: 19489-19500. DOI: 10.1074/jbc.M110.190330.
• 46 Atkins GJ, Rowe PS, Lim HP. et al. Sclerostin is a locally acting regulator of late-osteoblast/preosteocyte differentiation and regulates mineralization through a MEPE-ASARM-dependent mechanism. J Bone Miner Res 2011; 26: 1425-1436. DOI: 10.1002/jbmr.345.
• 47 Moustafa A, Sugiyama T, Prasad J. et al. Mechanical loading-related changes in osteocyte sclerostin expression in mice are more closely associated with the subsequent osteogenic response than the peak strains engendered. Osteoporosis Int 2012; 23: 1225-1234. DOI: 10.1007/s00198-011-1656-4.
• 48 Li X, Ominsky MS, 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. DOI: 10.1359/jbmr.080216.
• 49 Little RD, Carulli JP, Del Mastro RG. et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Hum Genet 2002; 70: 11-19. DOI: 10.1086/338450.
• 50 Van Wesenbeeck L, Cleiren E, Gram J. et al. Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Hum Genet 2003; 72: 763-771. DOI: 10.1086/368277.
• 51 Joeng KS, Lee YC, Lim J. et al. Osteocyte-specific WNT1 regulates osteoblast function during bone homeostasis. J Clin Invest 2017; 127: 2678-2688. DOI: 10.1172/JCI92617.
• 52 Luther J, Yorgan TA, Rolvien T. et al. Wnt1 is an Lrp5-independent bone-anabolic Wnt ligand. Sci Transl Med 2018; 10. DOI: 10.1126/scitranslmed.aau7137.
• 53 Glass DA, 2nd, Bialek P, Ahn JD. et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 2005; 8: 751-764. DOI: 10.1016/j.devcel.2005.02.017.
• 54 Holmen SL, Zylstra CR, Mukherjee A. et al. Essential role of beta-catenin in postnatal bone acquisition. J Biol Chem 2005; 280: 21162-21168. DOI: 10.1074/jbc.M501900200.
• 55 Jia M, Chen S, Zhang B. et al. Effects of constitutive beta-catenin activation on vertebral bone growth and remodeling at different postnatal stages in mice. PLoS One 2013; 8: e74093. DOI: 10.1371/journal.pone.0074093.
• 56 Tu X, Delgado-Calle J, Condon KW. et al. Osteocytes mediate the anabolic actions of canonical Wnt/beta-catenin signaling in bone. PNAS 2015; 112: E478-486. DOI: 10.1073/pnas.1409857112.
• 57 Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 2013; 19: 179-192. DOI: 10.1038/nm.3074.
• 58 Ota K, Quint P, Ruan M. et al. Sclerostin is expressed in osteoclasts from aged mice and reduces osteoclast-mediated stimulation of mineralization. J Cell Biochem 2013; 114: 1901-1907. DOI: 10.1002/jcb.24537.
• 59 Weivoda MM, Youssef SJ, Oursler MJ. Sclerostin expression and functions beyond the osteocyte. Bone 2017; 96: 45-50. DOI: 10.1016/j.bone.2016.11.024.
• 60 Brunetti G, Oranger A, Mori G. et al. Sclerostin is overexpressed by plasma cells from multiple myeloma patients. Ann N Y Acad Sci 2011; 1237: 19-23. DOI: 10.1111/j.1749-6632.2011.06196.x.
• 61 Zhu D, Mackenzie NC, Millan JL. et al. The appearance and modulation of osteocyte marker expression during calcification of vascular smooth muscle cells. PLoS One 2011; 6: e19595. DOI: 10.1371/journal.pone.0019595.
• 62 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. DOI: 10.1074/jbc.M705092200.
• 63 Robling AG, Bellido T, Turner CH. Mechanical stimulation in vivo reduces osteocyte expression of sclerostin. J Musculoskelet Neuronal Interact 2006; 6: 354
• 64 Tu X, Rhee Y, Condon KW. et al. Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading. Bone 2012; 50: 209-217. DOI: 10.1016/j.bone.2011.10.025.
• 65 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. DOI: 10.1359/jbmr.090411.
• 66 Bonnet N, Garnero P, Ferrari S. Periostin action in bone. Mol Cell Endocrinol 2016; 432: 75-82. DOI: 10.1016/j.mce.2015.12.014.
• 67 Horiuchi K, Amizuka N, Takeshita S. et al. Identification and characterization of a novel protein Periostin, with restricted expression to periosteum and periodontal ligament and increased expression by transforming growth factor ß. J Bone Miner Res 1999; 14: 1239-1249
• 68 Bonnet N, Conway SJ, SL F. Regulation of beta catenin signaling and parathyroid hormone anabolic effects in bone by the matricellular protein periostin. PNAS 2012; 109: 15048-15053
• 69 Keller H, Kneissel M. SOST is a target gene for PTH in bone. Bone 2005; 37: 148-158. DOI: 10.1016/j.bone.2005.03.018.
• 70 Leupin O, Kramer I, Collette NM. et al. Control of the SOST bone enhancer by PTH using MEF2 transcription factors. J Bone Miner Res 2007; 22: 1957-1967. DOI: 10.1359/jbmr.070804.
• 71 Saito H, Gasser A, Bolamperti S. et al. TG-interacting factor 1 (Tgif1)-deficiency attenuates bone remodeling and blunts the anabolic response to parathyroid hormone. Nat Commun 2019; 10: 1354. DOI: 10.1038/s41467-019-08778-x.
• 72 O’Brien CA, Plotkin LI, Galli C. et al. Control of bone mass and remodeling by PTH receptor signaling in osteocytes. PLoS One 2008; 3: e2942. DOI: 10.1371/journal.pone.0002942.
• 73 Robling AG, Kedlaya R, Ellis SN. et al. Anabolic and catabolic regimens of human parathyroid hormone 1-34 elicit bone- and envelope-specific attenuation of skeletal effects in Sost-deficient mice. Endocrinology 2011; 152: 2963-2975. DOI: 10.1210/en.2011-0049.
• 74 Delgado-Calle J, Tu X, Pacheco-Costa R. et al. Control of Bone Anabolism in Response to Mechanical Loading and PTH by Distinct Mechanisms Downstream of the PTH Receptor. J Bone Miner Res 2017; 32: 522-535. DOI: 10.1002/jbmr.3011.
• 75 Delgado-Calle J, Sato AY, Bellido T. Role and mechanism of action of sclerostin in bone. Bone 2017; 96: 29-37. DOI: 10.1016/j.bone.2016.10.007.
• 76 Delgado-Calle J, Sanudo C, Bolado A. et al. DNA methylation contributes to the regulation of sclerostin expression in human osteocytes. J Bone Miner Res 2012; 27: 926-937. DOI: 10.1002/jbmr.1491.
• 77 Cohen-Kfir E, Artsi H, Levin A. et al. Sirt1 is a regulator of bone mass and a repressor of Sost encoding for sclerostin, a bone formation inhibitor. Endocrinology 2011; 152: 4514-4524. DOI: 10.1210/en.2011-1128.
• 78 Baertschi S, Baur N, Lueders-Lefevre V. et al. Class I and IIa histone deacetylases have opposite effects on sclerostin gene regulation. J Biol Chem 2014; 289: 24995-25009. DOI: 10.1074/jbc.M114.564997.
• 79 Gaudio A, Pennisi P, Bratengeier C. et al. Increased sclerostin serum levels associated with bone formation and resorption markers in patients with immobilization-induced bone loss. Clin Endocrinol Metab 2010; 95: 2248-2253. DOI: 10.1210/jc.2010-0067.
• 80 Garcia-Martin A, Rozas-Moreno P, Reyes-Garcia R. et al. Circulating levels of sclerostin are increased in patients with type 2 diabetes mellitus. Clin Endocrinol Metab 2012; 97: 234-241. DOI: 10.1210/jc.2011-2186.
• 81 Gennari L, Merlotti D, Valenti R. et al. Circulating sclerostin levels and bone turnover in type 1 and type 2 diabetes. Clin Endocrinol Metab 2012; 97: 1737-1744. DOI: 10.1210/jc.2011-2958.
• 82 Gaudio A, Privitera F, Battaglia K. et al. Sclerostin levels associated with inhibition of the Wnt/beta-catenin signaling and reduced bone turnover in type 2 diabetes mellitus. J Clin Endocrinol Metab 2012; 97: 3744-3750. DOI: 10.1210/jc.2012-1901.
• 83 Clarke BL, Drake MT. Clinical utility of serum sclerostin measurements. Bonekey Rep 2013; 2: 361. DOI: 10.1038/bonekey.2013.95.
• 84 Heilmeier U, Carpenter DR, Patsch JM. et al. Volumetric femoral BMD, bone geometry, and serum sclerostin levels differ between type 2 diabetic postmenopausal women with and without fragility fractures. Osteoporosis Int 2015; 26: 1283-1293. DOI: 10.1007/s00198-014-2988-7.
• 85 Polyzos SA, Anastasilakis AD, Bratengeier C. et al. Serum sclerostin levels positively correlate with lumbar spinal bone mineral density in postmenopausal women–the six-month effect of risedronate and teriparatide. Osteoporosis Int 2012; 23: 1171-1176. DOI: 10.1007/s00198-010-1525-6.
• 86 Simpson CA, Foer D, Lee GS. et al. Serum levels of sclerostin, Dickkopf-1, and secreted frizzled-related protein-4 are not changed in individuals with high bone mass causing mutations in LRP5. Osteoporosis Int 2014; 25: 2383-2388. DOI: 10.1007/s00198-014-2767-5.
• 87 Frost M, Andersen T, Gossiel F. et al. Levels of serotonin, sclerostin, bone turnover markers as well as bone density and microarchitecture in patients with high-bone-mass phenotype due to a mutation in Lrp5. J Bone Miner Res 2011; 26: 1721-1728. DOI: 10.1002/jbmr.376.
• 88 Cosman F, Crittenden DB, Adachi JD. et al. Romosozumab Treatment in Postmenopausal Women with Osteoporosis. N Engl J Med 2016; 375: 1532-1543. DOI: 10.1056/NEJMoa1607948.
• 89 McClung MR, Brown JP, Diez-Perez A. et al. Effects of 24 Months of Treatment With Romosozumab Followed by 12 Months of Denosumab or Placebo in Postmenopausal Women With Low Bone Mineral Density: A Randomized, Double-Blind, Phase 2, Parallel Group Study. J Bone Miner Res 2018; 33: 1397-1406. DOI: 10.1002/jbmr.3452.
• 90 Lewiecki EM, Blicharski T, Goemaere S. et al. A Phase III Randomized Placebo-Controlled Trial to Evaluate Efficacy and Safety of Romosozumab in Men With Osteoporosis. Clin Endocrinol Metab 2018; 103: 3183-3193. DOI: 10.1210/jc.2017-02163.
• 91 Cosman F, Crittenden DB, Ferrari S. et al. FRAME Study: The Foundation Effect of Building Bone With 1 Year of Romosozumab Leads to Continued Lower Fracture Risk After Transition to Denosumab. J Bone Miner Res 2018; 33: 1219-1226. DOI: 10.1002/jbmr.3427.
• 92 Langdahl BL, Libanati C, Crittenden DB. et al. Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial. Lancet 2017; 390: 1585-1594. DOI: 10.1016/S0140-6736(17)31613-6.
• 93 Chavassieux P, Chapurlat R, Portero-Muzy N. et al. Bone-Forming and Antiresorptive Effects of Romosozumab in Postmenopausal Women With Osteoporosis: Bone Histomorphometry and Microcomputed Tomography Analysis After 2 and 12 Months of Treatment. J Bone Miner Res 2019; 34: 1597-1608. DOI: 10.1002/jbmr.3735.