Novel therapeutic targets in osteoporosis

Expert Opinion on Therapeutic Targets

Volumn 6, Issue 1, 2002, Pages 41-56

  Tobias, J H ^a,b   Flanagan, A M ^a,c   Scutt, A M ^a,d  

^a UNIVERSITY OF BRISTOL   (United Kingdom)

^b BRISTOL ROYAL INFIRMARY   (United Kingdom)

^c ROYAL FREE AND UNIVERSITY COLLEGE MEDICAL SCHOOL   (United Kingdom)

^d UNIVERSITY OF SHEFFIELD   (United Kingdom)

Author keywords

Androgen; Cathepsin K; Growth factor; Hormone; Integrins; Leptin; Oestrogen; Osteoblast; Osteoclast; Osteoprogenerin; Parathyroid hormone; Prostanoids; TGF ; Wnt proteins

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; ANDROGEN; BISPHOSPHONIC ACID DERIVATIVE; CALCITONIN; CALCITRIOL; CATHEPSIN K INHIBITOR; COLECALCIFEROL; DELTA12 PROSTAGLANDIN J2; ESTROGEN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; IBUTAMOREN; INTEGRIN INHIBITOR; LEPTIN; MECASERMIN RINFABATE; NANDROLONE DECANOATE; PARATHYROID HORMONE DERIVATIVE; PARATHYROID HORMONE[1-34]; PEPTIDE HORMONE; PROSTAGLANDIN; PROSTANOID; PROTEIN INHIBITOR; PROTON PUMP INHIBITOR; RALOXIFENE; ROSIGLITAZONE; SELECTIVE ESTROGEN RECEPTOR MODULATOR; STEROID; TIBOLONE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VITAMIN D DERIVATIVE; VITRONECTIN INHIBITOR; PEPTIDE;

BONE CELL; BONE DISEASE; BONE MARROW TRANSPLANTATION; BONE MASS; CANCER RISK; CELL FUNCTION; CELL PROLIFERATION; CELL SURVIVAL; CLINICAL TRIAL; DRUG MEGADOSE; FRACTURE REDUCTION; GASTROINTESTINAL DISEASE; HORMONE SUBSTITUTION; HUMAN; HYPERCALCEMIA; HYPERCALCIURIA; LIPID METABOLISM; MOLECULAR CLONING; MOLECULAR GENETICS; NONHUMAN; OSSIFICATION; OSTEOBLAST; OSTEOLYSIS; OSTEOPOROSIS; POSTMENOPAUSE OSTEOPOROSIS; PROSTATISM; REVIEW; VIRILIZATION; ANIMAL; BONE; DRUG EFFECT; METABOLISM; PATHOLOGY; PHYSIOLOGY;

ANIMALS; BONE AND BONES; HUMANS; LIPID METABOLISM; OSTEOPOROSIS; PEPTIDES; STEROIDS;

EID: 0036484728     PISSN: 14728222     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728222.6.1.41     Document Type: Review

References (84)

1. WALKER-BONE K, DENNISON E, COOPER C: Epidemiology of Osteoporosis. Rheum. Dis. Clin. North. Am. (2001) 27:1-18. • A comprehensive review of the epidemiology of osteoporosis.
2. JOHANSEN A, STONE M, TORGERSON DJ: The cost of treating osteoporotic fractures in the united kingdom female population. Osteoporos. Int. (2000) 11:551-552.
3. EASTELL R : Pathogenesis of Postmenopausal Osteoporosis. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Favus MJ (Ed.), Lippincott, Williams & Wilkins, Philadelphia, USA (1999):260-262.
4. 3 and calcium to prevent hip fractures in elderly women. N. Engl. J. Med. (1992) 327:1637-1642.
5. COMPSTON J, EASTELL R, FRANCIS R et al.: Osteoporosis: Clinical guidelines for prevention and treatment. Royal College of Physicians of London (2000). •• A summary of the evidence behind currently available therapies for osteoporosis.
6. NEER RM, ARNAUD CD, ZANCHETTA JR et al.: Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N. Engl. J. Med. (2001) 344:1434-1441. •• The first randomised control trial to show a reduction in fracture risk following treatment with an agent designed to stimulate bone formation rather than suppress bone resorption.
7. SIMONET WS, LACEY DL, DUNSTAN CR et al.: Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell (1997) 89:309-319. • This work provided the foundation for discovery of the RANK-RANKL-OPG system for regulating osteoclasts.
8. YASUDA H, SHIMA N, NAKAGAWA N et al.: Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis -inhibitory factor and is identical to TRANCE/RANKL Proc. Natl. Acad. Sci. USA (1998) 95:3597-3602.
9. LI J, YAN X-Q, MORONY S et al.: RANK is the intrinsic hematopoietic cell surface receptor that controls osreoclastogenesis and regulation of bone mass and calcium metabolism. Proc. Natl. Acad. Sci. USA (2000) 97:1566-1571.
10. TOBIAS JH, COMPSTON JE: Does estrogen stimulate osteoblast function in postmenopausal women? Bone (1999) 24:121-124.
11. DUCY P, ZHANG R, GEOFFROY V, RIDALL AL, KARSENTY G: Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell (1997) 89:747-754. • This paper, and those by Otto et al. and Komori et al. below published simultaneously, were the first to demonstrate that Cbfa1 plays a critical role in osteoblast development.
12. OTTO F, THORNELL AP, CROMPTON T et al.: Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell (1997) 89:765-771.
13. KOMORI T, YAGI H, NOMURA S et al.: Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell (1997) 89:755-764.
14. YAMAGUCHI A, KOMORI T, SUDA T: Regulation of osteoblast differentiation mediated by bone morphogenetic proteins, hedgehogs and Cbfa1. Endocr. Rev. (2000) 21:393-411. • This is a comprehensive review of the mechanism of action of bone morphogenetic proteins and Cbfa1, two of the most important regulators of osteoblast differentiation.
15. NUTTALL ME, GIMBLE JM: Is there a therapeutic opportunity to either prevent or treat osteopenic disorder by inhibiting marrow adipogenesis? Bone (2000) 27:177-184.
16. WEINSTEIN RS, MANOLAGAS SC: Apoptosis and osteoporosis. Am. J. Med. (2000) 108:153-64.
17. KOUSTENI S, BELLIDO T, PLOTKIN LI et al.: Nongenotropic, sex-nonspecific signaling through estrogen or androgen receptors: dissociation from transcriptional activity. Cell (2001) 104:719-730. • This paper suggests that non-genotropic actions play a significant role in regulating osteoblast survival.
18. WEINSTEIN RS, JILKA RL, PARFITT AM, MANOLAGAS SC: Inhibition of osteohistogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. J. Clin. Invest. (1998) 102:274-282.
19. NOBLE B, REEVE J: Osteocyte function, osteocyte death and bone fracture resistance. Mol. Cell. Endocrinol. (2000) 159:7-13.
20. HUGHES AE, RALSTON SH, MARKEN J et al.: Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat. Genet. (2000) 24:45-48.
21. KORNAK U, KASPER D, BOSL MR et al.: Loss of the CLC-7 chloride channel leads to osteopeterosis in mice and men. Cell (2001) 104:205-215.
22. FRATTINI A, ORCHARD PJ, SOBACCHI C et al.: Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat. Genet. (2000) 25(3):343-346.
23. MUNDLOS S, OTTO F, MUNDLOS C et al.: Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell (1997) 89(5):773-779.
24. GONG Y, SLEE RB, FUKAI N et al.: LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell (2001) 107:513-523. • This paper demonstrates the importance of the LRP5-Wnt signalling pathway in bone formation.
25. 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. Gen. (2001) 68:577-589. • This paper illustrates how loss of function of a naturally occurring bone morphogenetic protein inhibitor leads to increased bone formation.
26. VAN BEZOOIJEN RL, KARPERIEN M, VISSER A et al.: BMP-antagonist sclerostin is expressed in mineralised bone and blocks BMP-induced bone formation in vitro. J. Bone Miner. Res. (2001) 16(Suppl. 1):S163.
27. ETTINGER B, BLACK DM, MITLAK BH et al.: Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. JAMA (1999) 282:637-645.
28. PAIGE LA, CHRISTENSEN DJ, GRON H et al.: Estrogen receptor (ER) modulators each induce distinct conformational changes in ER alpha and ER beta. Proc. Natl. Acad. Sci. USA (1999) 96:3999-4004. • This paper suggests that the tissue - selective effects of SERMs reflects their ability to induce different conformational changes in the ER compared to conventional agonists like 17β-oestradiol.
29. TOBIAS JH: The effects of SERMs on the skeleton. J. Endo. Invest. (1999) 22:604-608.
30. VEDI S, PURDIE DW, BALLARD P et al.: Bone remodeling and structure in postmenopausal women treated with long-term, high-dose estrogen therapy. Osteoporos. Int. (1999) 28:52-58.
31. KHASTGIR G, STUDD J, HOLLAND N et al.: Anabolic effect of estrogen replacement on bone in postmenopausal women with osteoporosis: histomorphometric evidence in a longitudinal study. J. Clin. Endocrinol. Metab. (2001) 86:289-295. • This is the first prospective study to demonstrate that oestrogen exerts its protective effect on the skeleton by stimulating bone formation as well as suppressing bone resorption.
32. KUIPER GGJM, ENMARK E, PELTO-HUIKKO M, NILSSON S, GUSTAFSSON J-A: Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc. Natl. Acad. Sci. USA (1996) 93:5925-5930
33. WINDAHL SH, NORGARD M, KUIPER GGJM, GUSTAFSSON J-A, ANDERSSON G: Cellular distribution of estrogen receptor b in neonatal rat bone. Bone (2000) 26:117-121.
34. WEATHERMAN RV, CLEGG NJ, SCANLAN TS: Differential SERM activation of the estrogen receptors (ER alpha and ER beta) at AP-1 sites. Chem. Biol. (2001) 8:427-436.
35. MCDOUGALL KE, PERRY MJ, TOBIAS JH: Distinct effects of deletion of ERalpha and ERbeta on responsiveness of the skeleton to exogenous estrogen in male mice. J. Bone Miner. Res. (2001) 16(Suppl. 1):S550.
36. SIMONCINI T, HAFEZI-MOGHADAM A, BRAZIL DP et al.: Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature (2000) 407:538-541.
37. NEMERE I, FARACH-CARSON MC: Membrane receptors for steroid hormones: a case for specific cell surface binding sites for vitamin D metabolites and estrogens. Biochem. Biophys. Res. Comm. (1998) 248:443-449.
38. BENTEN WPM, STEPHAN C, LIEBERHERR M, WUNDERLICH F: Estradiol signaling via sequestrable surface receptors. Endocrinology (2001) 142:1669-1677.
39. COLLINS P, WEBB C: Estrogen hits the surface. Nat. Med. (1999) 5:1130-1131.
40. BAUSS F, ESSWEIN A, REIFF K, SPONER G, MULLER-BECKMANN B: Effect of 17beta-estradiol-bisphophonate conjugates, potential bone-seeking estrogen pro-drugs, on 17beta-estradiol serum kinetics and bone mass in rats. Calcif. Tiss. Int. (1996) 59:168-173.
41. YOKOGAWA K, MIYA K, SEKIDO T et al.: Selective delivery of estradiol to bone by aspartic acid oligopeptide and its effects on ovariectomised mice. Endocrinology (2001) 142:1228-1233.
42. CENCI S, WEITAMANN MN, ROGGIA C et al.: Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. J. Clin. Invest. (2000) 106:1229-1237.
43. ARRON JR, CHOI Y: Osteoimmunology: bone versus immune system. Nature (2000) 408:535-536.
44. FRANCIS R: The effects of testosterone on osteoporosis in men. Clin. Endocrinol. (1999) 50:411-414.
45. REID IR, WATTLE DJ, EVANS MC, STAPLETON JP: Testosterone therapy in glucocorticoid-treated men. Arch. Intern. Med. (1996) 156:1173-1177.
46. TOBIAS JH, GALLAGHER A, CHAMBERS TJ: 5 alpha-dihydrotestosterone partially restores cancellous bone volume in osteopenic ovariecromised rats. Am. J. Physiol. (1994) 267:E853-E859.
47. LEA CK, FLANAGAN AM: Physiological plasma levels of androgens reduce bone loss in the ovariectomised rat. Am. J. Physiol. (1998) 274:E328-E335.
48. GALLAGHER AC, CHAMBERS TJ, TOBIAS JH: Androgens contribute to the stimulation of cancellous bone formation by ovarian hormones in female rats. Am. J. Physiol. (1996) 270(3 Pt 1):E407-E412.
49. GADELETA SJ, BOSKEY AL, PASCHALIS E et al.: A physical, chemical and mechanical study of lumbar vertebrae from normal, ovariectomised and nadrolone decanoate-treated cynomolgus monkeys. Bone (2000) 27:541-550.
50. GENNARI C, AGNUSDEI D, GONNELLI S, NARDI P: Effects of nandrolone decanoate therapy on bone mass and calcium metabolism in women with established postmenopausal osteoporosis: a double-blind placebo-controled study. Maturitas (1989) 3:187-197.
51. FURUYA K, YAMAMOTO N, NEJISHIMA H et al.: Novel, non-steroidal selective androgen receptor modulators (SARMs) increase bone mass and reduce androgenic virilising effects in adult osteoporotic rats. J. Bone Miner. Res. (2001) 16(Suppl. 1):S148.
52. RYMER J, ROBINSON J, FOGELMAN I: Effects of 8 years treatment with tibolone 2.5mg daily on postmenopausal bone loss. Osteoporos. Int. (2001) 12:478-483.
53. SUDA T, SINKI T, TAKAHASHI N: The role of vitamin D in bone and intestinal cell differentiation. Ann. Rev. Nutr. (1990) 10:195-211.
54. TILYARD MW, SPEARS GFS, THOMSON J, DOVEY S: Treatment of postmenopausal osteoporosis with calcitriol or calcium. N. Engl. J. Med. (1992) 326:357-362.
55. DREZNER M, NESBITT T: Role of calcitriol in prevention of osteoporosis: Part I. Metabolism (1990) 39S:18-23.
56. FAUGERE M, OKAMOT S, DELUCA H, MALLUCHE H: Calcitriol corrects bone loss induced by oophorectomy in rats. Am. J. Physiol. (1986) 250:E35-E38.
57. TSURUKAMI H, NAKAMURA T, SUZUKI K et al.: A novel synthetic vitamin D analogue, ED-71, increases bone mass by stimulating the bone formation in normal and ovariectomised rats. Calcif. Tiss. Int. (1994).
58. GRAM J, JUNKER P, NIELSEN H, BOLLERSLEV J: Dose-response effect of short-term calcitriol treatment on bone and mineral metabolism in normal males. Bone (1996) 18:539-544.
59. HIRATA M, KATSUMATA K, MASAKI T et al.: 22-oxacalcitriol ameliorates high-turnover bone and marked osteitis fibrosa in rats with slowly progressive nephritis. Kidney Int. (1999) 56:2040-2047.
60. 3 and calcium in osteopenic ovariectomised rats: evidence for a direct anabolic effect on bone. Endocrinology (1998) 139:4319-4328.
61. ERBEN RG, KOLLENKIRCHEN U, BRAUTIGAM M, HABEREY M: Cyclical treatment with high dose calcitriol increases bone mass in normal and osteopenic rats. J. Bone Miner. Res. (1994) 9(Suppl. 1):S196.
62. GOWEN M, STROUP GB, DODDS RA et al.: Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats. J. Clin. Invest. (2000) 105:1595-1605.
63. CHAMBERS TJ, MAGNUS CJ: Calcitonin alters behaviour of isolated osteoclasts. J. Pathol. (1982) 136:27-39.
64. KANIS JA, MCCLOSKEY EV: Effect of calcitonin on vertebral and other fractures. Q. J. Med. (1999) 92:143-149.
65. SILVERMAN SL, CHESNUT C, BAYLINK D et al.: Salmon calcitonin nasal spray is effective and safe in older osteoporotic women-results from the PROOF study. J. Bone Miner. Res. (2001) 16(Suppl. 1):S530.
66. GOWEN M, EMERY JG, KUMAR S: Emerging therapies for osteoporosis. Emerg. Drugs (2000) 5:1-43. •• A comprehensive review of recently developed drugs for osteoporosis.
67. WADA S, UDAGAWA N, NAGATA N, MARTIN TJ, FINDLAY DM: Calcitonin receptor down-regulation relates to calcitonin resistance in mature mouse osteoclasts. Endocrinology (1996) 137:1042-1048.
68. BOUILLON R: Growth hormone and bone. Horm. Res. (1991) 36:49-55.
69. MARCUS R, BUTTERFIELD G, HOOLOWAY L et al.: Effects of short term administration of recombinant human growth hormone to elderly people. J. Clin. Endocrinol. Metab. (1990) 70:519-527.
70. BRIXEN K, NIELSEN HK, MOSEKILDE L, FLYVBJERG A: A short course of recombinant growth hormone treatment stimulates osteoblasts and activates bone remodeling in normal human volunteers. J. Bone Min. Res. (1990) 5:609-618.
71. MURPHY MG, WEISS S, MCCLUNG M et al.: Effect of alendronate and MK-677, individually and in combination, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women. J. Clin. Endocrinol. Metab. (2001) 86:1116-1125.
72. ROSEN CJ, BILEZIKIAN JP: Clinical review 123: anabolic therapy for osteoporosis. J. Clin. Endocrinol. Metab. (2001) 86:957-964.
73. ZHAO G, MONIER-FAUGERE M-C, LANGUB MC et al.: Targeted overexpression of insulin-like growth Factor I to osteoblasts of transgenic mice: increased trabecular bone volume without increased osteoblast proliferation. Endocrinology (2000) 141:2674-2682.
74. FRIEDLANDER AL, BUTTERFIELD GE, MOYNIHAN S et al.: One year of insulin-like growrh Factor I treatment does not effect bone density, body composition or psychological measures in postmenopausal women. J. Clin. Endocrinol. Metab. (2001) 86:1496-1503.
75. BAGI C, VAN DER MEULEN M, BROMMAGE R, ROSEN D, SOMMER A: The effect of systemically administered rhIGF-I/IGFBP-3 complex on cortical bone strength and structure in ovariectomised rats. Bone (1995) 16:559-565.
76. OWEN ME: Marrow stromal stem cells. J. Cell Sci. (1988) 10(Suppl):63-76.
77. FRIDENSTEIN AJ: Osteogenic stem cells in the bone marrow. In: Bone and Mineral Research (Volume 7). Heersche JNM, Kanis JA (Eds.), Elsevier, Amsterdam (1990):243-272.
78. MEUNIER PJ, AARON J, EDOUARD C, VIGNON G: Osteoporosis and the replacement of cell populations of the marrow by adipose tissue. Clin. Orthop. Rel. Res. (1971) 80:147-154.
79. LOLLMAN B, GRUNINGER S, STRICKER-KRONGRAD A, CHIESI M: Detection and quantification of the leptin receptor splice variants Ob-Ra, b, and e in different mouse tissues. Biochem. Biophys. Res. Commun. (1997) 238:648-652.
80. THOMAS T, GORI F, KHOSLA S et al.: Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes. Endocrinology (1999) 140:1630-1638.
81. RESELAND JE, SYVERSEN U, BAKKE I et al.: Leptin is expressed in and secreted from primary cultures of human osteoblasts and promotes bone mineralisation. J. Bone Miner. Res. (2001) 16:1426-1433.
82. STEPPAN CM, CRAWFORD DT, CHIDSEY-FRINK KL, KE H, SWICK AG: Leptin is a potent stimulator of bone growth in ob/ob mice. Regul. Pept. (2000) 92:73-78.
83. BURGUERA B, HOFBAUER LC, THOMAS T et al.: Leptin reduces ovariectomy-induced bone loss in rats. Endocrinology (2001) 142:3546-3553.
84. TAKEDA S, KARSENTY G: Central control of bone formation. J. Bone Miner. Metab. (2001) 19:195-198.