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ESTROGEN ACTION, BONE CELL FUNCTION, AND OSTEOPOROSIS

ESTROGEN ACTION, BONE CELL FUNCTION, AND OSTEOPOROSIS. ESTROGEN ACTION, BONE AND OSTEOPOROSIS New and Emerging Paradigms. As of 1995, there were five pillars of belief about E-action that were widely accepted by almost everyone

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ESTROGEN ACTION, BONE CELL FUNCTION, AND OSTEOPOROSIS

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  1. ESTROGEN ACTION, BONE CELL FUNCTION, AND OSTEOPOROSIS 2342

  2. ESTROGEN ACTION, BONE AND OSTEOPOROSISNew and Emerging Paradigms • As of 1995, there were five pillars of belief about E-action that were widely accepted by almost everyone • Since then, these have been swept away by a sea change in conventional wisdom • New paradigms are emerging to replace these traditional concepts 2227

  3. ESTROGEN ACTION, BONE AND OSTEOPOROSIS Areas of Paradigm Shifts • Molecular bases of E-action • E-effects on skeletal growth and maturation • E-deficiency and bone loss in elderly women • E-interaction with biomechanical strain • E-deficiency and bone loss in elderly men 2341

  4. ESTROGEN ACTION, BONE AND OSTEOPOROSISPrevailing Paradigms (~1995) • 1. E-action on the skeleton • a) is transduced through a single ER in bone cells • b) is gender-specific for its receptor • c) is mediated by a single, or only a few, paracrine cytokines 2105.1aP1

  5. ESTROGEN ACTION, BONE AND OSTEOPOROSISPrevailing Paradigms (~1995) • 1. E-action on the skeleton • a) is transduced through a single ER in bone cells • b) is gender-specific for its receptor • c) is mediated by a single, or only a few, paracrine cytokines 2105.1aP2

  6. ESTROGEN RECEPTORS (ERs) IN BONE CELLSRecent Advances • Discovery and cloning of 2nd ER (PNAS 93:5925, 1996) • ER is always a transcriptional activator whereas ER is sometimes inhibitory (Endocrinology 140:5566, 1999) • ER predominates in cancellous bone whereas ER predominates in cortical bone (JCEM 86:2309, 2001) • ER KO mice are protected against age-related loss of cancellous bone (JBMR 165:160, 2001) • ER/ER ratio may be a key determinate of E-action on bone 2114c

  7. ESTROGEN ACTION, BONE AND OSTEOPOROSISPrevailing Paradigms (~1995) • 1. E-action on the skeleton • a) is transduced through a single ER in bone cells • b) is gender-specific for its receptor • c) is mediated by a single, or only a few, paracrine cytokines 2105.1aP3

  8. GENDER NON-SPECIFICITY IN SEX STEROID SIGNALING Recent Advances i. Sex steroids have non-genomic, gender non-specific effects on decr. apoptosis in OB cells and incr. apoptosis in OC cells • These effects occur via either E or DHT, act througheither ER or AR and can be blocked with either ICI or flutamide (Kousteni et al. Cell 104:719, 2001) • A synthetic ligand (4-estren-3a,7b-diol) reproduces the non-genotrophic effects of sex steroids without affecting classical transcription and was as effective as either E2 or DHT in increasing bone mass in gonadectomized mice(Kousteni et al. Science, in press) 2340

  9. GENDER NON-SPECIFICITY IN SEX STEROID SIGNALING Recent Advances (cont’d) ii. At least in the prostate and aorta (and possibly in bone and other target tissues), the androgen metabolite, 5a-androstane-3b,17b-diol (3bAdiol) activates signaling via ERb(Weihua et al. PNAS 98:6330, 2001) 2340.1

  10. ESTROGEN ACTION, BONE AND OSTEOPOROSISPrevailing Paradigms (~1995) • 1. E-action on the skeleton • a) is transduced through a single ER in bone cells • b) is gender-specific for its receptor • c) is mediated by a single, or only a few, paracrine cytokines 2105.1aP4

  11. REGULATION OF BONE RESORPTION Role of Paracrine Cytokines REGULATION OF OC FORMATION AND FUNCTION Model T CELLS MONOCYTES Stimulatory Factors Inhibitory Factors TNFa IL-1 TNFa TNFa OC APOPTOSIS ACTIVE OC OC PRECURSORS Differentiation and activation OPG M-CSF RANKL RANKL IL-6 PGE2 GM-CSF TGFb TGFb STROMAL CELLS/ OSTEOBLASTS 2288P1

  12. MEDIATORS OF ESTROGEN ACTIONCandidates “Upstream” regulatorsIL-1(Pacifici 1993),TNF(Kimble 1997), IL-6 (Jilka 1992),PGE2(Kitazawa 1994),IL1ra(Pacifici 1993) “Downstream” regulatorsM-CSF(Kimble 1996),OPG(Hofbauer 1999, Saika 2001),TGF(Oursler 1991) Responsiveness of osteoclasts to RANKLcJUN, NF-B, JNK1(Shevde 2000, Srivastava 2000) 2225b

  13. RANKL EXPRESSION IN VARIOUS CELL TYPESEffect of Estrogen Deficiency Premenopausal N = 12 Untreated Postmenopausal N = 12 Postmenopausal + ERT N = 12 * Vs PostM E(+) ** Vs PreM ** * P<0.001 P<0.001 P=0.003 P<0.001 90 ** * ** * ** * 60 Normalized Fluorescence Intensity for OPG-Fc-FITC 30 0 B - Cells T - Cells Total Marrow stromal cells 2293.2

  14. RANKL EXPRESSION PER CELLCORRELATES WITH BONE RESORPTION IN WOMEN Urine NTx Serum CTx 0.48, P=0.002 0.36, P=0.02 0.48, P=0.002 0.36, P=0.02 MSC T-Cells B-cells Total 0.42, P=0.009 0.34, P=0.03 0.48, P=0.002 0.43, P=0.007 2364

  15. REGULATION OF BONE RESORPTION Sites of Estrogen Regulation T CELLS MONOCYTES Stimulatory Factors Inhibitory Factors TNFa IL-1 TNFa TNFa E(-) OC APOPTOSIS E(-) E(-) ACTIVE OC OC PRECURSORS Differentiation and activation OPG E(+) E(+) M-CSF E(+) RANKL RANKL TGFb IL-6 PGE2 GM-CSF TGFb E(-) E(-) E(-) E(-) STROMAL CELLS/ OSTEOBLASTS 2288P2

  16. ESTROGEN ACTION, BONE AND OSTEOPOROSISPrevailing Paradigms (~1995) 1. E-action on the skeleton a) is transduced through a single ER in bone cells; b) is gender-specific for its receptor; and c) is mediated by a single, or only a few, paracrine cytokines 2. Pubertal skeletal growth and maturation is regulated by E in females and by T in males 2105.2a

  17. E IS REQUIRED FOR MALES TO ACHIEVENORMAL BMD AND TO CLOSE EPIPHYSESResults of Human Experiments of Nature • Young adult male with ER gene mutation (Smith 1994)and two young adult males with aromatase gene mutations had low BMD, despite T-sufficiency (Carani 1997, Morishima 1997) • All three mutants had open epiphyseal growth plates and failed to undergo pubertal growth spurt (Grumbach 1999) 1170c

  18. EFFECT OF E TREATMENT ON LINEAR GROWTH AND BMD IN ERa AND AROMATASE MUTANT MALES 20 Aromatase mutant ERa mutant Lumbar Spine Normal males (adjusted to pubarche) 10 220 0 Estrogen 200 20 Femoral Neck Aromatase mutant D from baseline, % 10 180 Stature, cm 0 160 20 Radius 10 140 0 120 0 12 24 36 8 10 12 14 16 18 20 22 24 26 28 Age, yrs Duration of ERT (mo) Smith et al. NEJM 331: 1056, 1994 Bilezikian et al. NEJM 339: 599, 1998 2294

  19. SEXUAL DIMORPHISM IS ACHIEVED DURING PUBERTY BY DIFFERENTIAL CHANGES ON BONE SURFACES PREPUBERTAL CHILD (8 yr) YOUNG ADULT (18 yr) Gained FEMALE Lost C.A. = 24 mm2 C.A. = 43 mm2 MALE C.A. = 26 mm2 C.A. = 58 mm2 Garn 1970, Seeman 1999 2290P1

  20. E AND T HAVE BOTH DIVERGENT AND COMPLIMENTARY EFFECTS ON BONE Histomorphometry in 3 mo. old rats 21 days of treatment Iliac biopsy of PMO women 3 months of treatment ESTROGEN TREATMENT ANDROGEN TREATMENT OVX FEMALES ORX MALES 140 0 120 ESTROGEN TREATMENT -20 P<0.05 D, % from placebo D, % resorption surfaces 100 TESTOSTERONE TREATMENT -40 80 -60 P<0.001 60 PERIOSTEAL FORMATION BONE RESORPTION Turner et al. Endocrinology 122:1146, 1988 Turner et al. J. Orthop. Res. 8:612, 1990 Riggs et al. JCI 51:1659, 1972 2286

  21. ESTROGEN ACTION, BONE AND OSTEOPOROSISPrevailing Paradigms (~1995) 1. E-action on the skeleton a) is transduced through a single ER in bone cells; b) is gender-specific for its receptor; and c) is mediated by a single, or only a few, paracrine cytokines 2. Pubertal skeletal growth and maturation is regulated by E in females and by T in males 3. In postmenopausal women, E deficiency causes the early, rapid phase of bone loss, whereas age-related factors cause the late slow phase 2105.3a

  22. PATTERN OF INVOLUTIONAL BONE LOSS Cortical Bone Cancellous Bone Women Men Menopause 100 100 90 90 80 80 % of initial BMD 70 % of initial BMD 70 60 60 50 50 0 0 50 60 70 80 90 50 60 70 80 90 Age, yrs Age, yrs glw227sla

  23. PATTERN OF INVOLUTIONAL BONE LOSS Cortical Bone Cancellous Bone Women Men Menopause 100 100 90 90 80 80 % of initial BMD 70 % of initial BMD 70 60 60 50 50 Cortical Loss - 6% Cancellous Loss - 25% 0 0 50 60 70 80 90 50 60 70 80 90 Age, yrs Age, yrs glw227slaP1

  24. PATTERN OF INVOLUTIONAL BONE LOSS Cortical Bone Cancellous Bone Women Men Menopause 100 100 Cortical Loss - 25% Cancellous Loss - 25% 90 90 80 80 % of initial BMD 70 % of initial BMD 70 60 60 50 50 Cortical Loss - 6% Cancellous Loss - 25% 0 0 50 60 70 80 90 50 60 70 80 90 Age, yrs Age, yrs glw227slaP2

  25. PATTERN OF INVOLUTIONAL BONE LOSS Cortical Bone Cancellous Bone Women Men Menopause 100 100 Cortical Loss - 25% Cancellous Loss - 25% 90 90 80 80 % of initial BMD 70 % of initial BMD 70 Cortical Loss - 25% Cancellous Loss - 25% 60 60 50 50 Cortical Loss - 6% Cancellous Loss - 25% 0 0 50 60 70 80 90 50 60 70 80 90 Age, yrs Age, yrs glw227slaP3

  26. RAPID TRANSIENT PHASE OF BONE LOSSIS INITIATED BY MENOPAUSE • Characterized by high bone turnover (BR > BF), predominantly cancellous bone loss and duration of 4 - 8 yr • Outpouring of Ca from bone partially suppresses PTH secretion • Caused by loss of restraining effects of E on bone turnover acting directly through ER in OBs and OCs 2279a

  27. Young Normal Postmenopausal Osteoporosis PERFORATIVE RESORPTION OF TRABECULAE IN RAPID PHASE DISRUPTS BONE MICROARCHITECTURE Micro CT images of vertebral biopsy samples are courtesy of Ralph Mueller, Ph.D. 1220.1

  28. THE SUBSEQUENT SLOW PHASE OF BONE LOSS CONTINUES INDEFINITELY Thought to be mainly due to age-related abnormalities rather than E-deficiency because • Pattern of bone loss differs from that of early postmenopausal bone loss • Similar pattern occurs in aging men • Driven mainly by 2O hyperparathyroidism associated with age-related impairment of external Ca homeostasis 2280a

  29. AGING IS ASSOCIATED WITH 2O HPT AND HIGH BONE TURNOVER IN BOTH SEXES Women Men D 64% r=0.30, P<0.001 D 84% r=0.30, P<0.001 Men Women D 30% r=0.30, P<0.001 D 62% r=0.25, P<0.001 D 77% r=0.37, P<0.001 D 93% r=0.25, P<0.001 Khosla et al JCEM 83: 2266, 1998 2295

  30. EFFECT OF Ca SUPPLEMENTATION OR ERT IN ELDERLY POSTMENOPAUSAL WOMEN N=88 (ages 68-78 yrs) Untreated 1.5 g Ca ERT 60 60 Serum PTH Urine free DPD 40 40 D%, young adult values D%, young adult values 20 20 P<0.005 0 0 P<0.005 P<0.005 -20 -20 P<0.005 McKane et al JCEM 81: 169, 1996 McKane et al Proc Assoc Am Phys 109: 174, 1997 2287

  31. POSTMENOPAUSAL BONE LOSSQuestions • How can E-deficiency both suppress PTH secretion (during the early, rapid phase) and increase it (during the slow, late phase)? • How can both estrogen (a hormone) and calcium (a nutrient) both normalize the increased bone resorption and 2º hyperparathyroidism in elderly women? The answer lies in the emerging concept of extraskeletal actions of E on peripheral calcium metabolism 2226

  32. ESTROGEN ENHANCES CALCITRIOL-STIMULATED INTESTINAL Ca ABSORPTION Perimenopausal women undergoing OVX were treated with HRT (N=7) or PL (N=7) for 6 mo. 0.3 Placebo HRT 0.2 P=0.004 ANOVA P<0.001 Fractional Ca Abs 0.1 1 mg/d x7 d Calcitriol 0 BSL 6 months after OVX Gennari et al. JCEM 71:1288, 1990 NGPP070slB.1

  33. ESTROGEN ENHANCES RENAL Ca CONSERVATION INDEPENDENTLY OF PTH 18 early postmenopausal women before and after 6 mo. of ERT 100 *# * 99 * TRCa, % 98 97 * p < 0.001 vs bsl # p < 0.001 for ERT vs PTH 3 Urine Ca excretion, µmol/dL GF * * 2 *# 1 0 ERT - + - + PTH - - + + McKane et al JCEM 80: 3458, 1995 1261A.1

  34. ESTROGEN AND BONE FORMATIONBackground • E increases IGF-I and procollagen production by osteoblasts in vitro (Ernst 1989, Kassem 1997) • E increases OB differentiation in vitro but effects on proliferation are less established (Harris 1997, Okazaki 2002) • E increases osteoblast life-span by opposing apoptosis (Manolagas 2000) • In elderly women, long-term (6-14 yr), high dose estradiol implants increased TBV and WT of trabecular packets (P < 0.001) (Vedi 1994, Khastigir 2001) 1280e

  35. INVOLUTIONAL BONE LOSS IN WOMEN Model ? Dietary calcium Indirect effects Estrogen deficiency (rapid onset) Decreased bone formation Secondary hyperparathyroidism Direct effects Remodelingimbalance Increased bone resorption BONE LOSS CA732660-01C

  36. ESTROGEN ACTION, BONE AND OSTEOPOROSISPrevailing Paradigms (~1995) 4. The two major regulators of bone mass -- sex steroids and biomechanical strain -- have independent actions 2106.1

  37. ACTIONS OF E AND MECHANICAL STRAINON BONE CELL FUNCTION ARE RELATED • Frost (1992) hypothesized that bone contains a cybernetic system (“the mechanostat”) that adjusts bone mass commensurate with mechanical strain • Because histological changes following immobilization and E-deficiency are similar, Frost (1999) suggested that E deficiency impairs mechanostat sensing • Osteocytes can sense mechanical strain (Lanyon 1993) and contain ER (Tompkinson 1998) 2282a

  38. ACTION OF E AND MECHANICAL STRAIN ON BONE CELL FUNCTION ARE RELATED (Cont’d) • Loading studies in E-deficient or E-replete rats before and during orbital space flight (Westerlind 1997) suggest that E and mechanical strain share a common signal transduction pathway(s) • Effects of mechanical strain on OB proliferation in vitro are blocked by ER antagonists and both E and strain utilize MAP kinase and ERK-1 signaling pathways (The Lanyon Group 1996-2001) 2283a

  39. MODEL FOR E AND STRAIN INTERACTIONS Bone loss E(+) Bone Mass - Strain signal PREMENOPAUSE (Steady State) 0 + Strain generator Bone gain Mechanostat Bone loss Bone Mass E(-) - Strain signal POSTMENOPAUSE (Non-Steady State) 0 Strain generator + Bone gain Mechanostat Bone loss E(-) - Bone Mass Strain signal POSTMENOPAUSE (Steady State) 0 Strain generator + Bone gain Mechanostat 2289

  40. ESTROGEN ACTION, BONE AND OSTEOPOROSISPrevailing Paradigms (~1995) 4. The two major regulators of bone mass -- sex steroids and biomechanical strain -- have independent actions 5. Sex steroid deficiency plays only a minor role in the etiology of osteoporosis in men 2106.2

  41. AGE-RELATED BONE LOSS IN MEN Background • Men lose 1/2 as much bone with aging as women and have 1/3 the number of fractures • Both sexes have similar patterns of late bone loss and 2ºhyperparathyroidism • Serum total sex steroids decrease only slightly with aging 2319

  42. CHANGES IN SEX STEROIDS OVER LIFE Gender Differences Men (N=350) % change -27** -47** -64** +124** +285** +505** Women (N=350) % change -45** -83** -28* -1 +731** +1805** Lateral spine BMD Serum: Bio E Bio T SHBG LH FSH *P<0.05, **P<0.005 Khosla, et al. JCEM 83:2266-2274, 1998 1172

  43. MECHANISMS OF SEX STEROID DEFICIENCYDifferences Between Genders Males Gradual and progressive ++ ++++ +++ a) Increased binding by SHBGb) Reduced secretory capacity for GH and T Females Begins acutely atmenopause ++++ ++ 0 Ovarian failure Onset E-deficiency T-deficiency , SHBG Mechanism 1199b

  44. RELATIONSHIP OF SERUM E TO BMDResults of Observational Studies Ten population-based observational studies have now shown that in aging men serum E is more closely related to BMD than is serum T  Slemenda et al. JCI 100:1755, 1997 Greendale et al. JBMR 12:1833, 1997 Khosla et al. JCEM 83:2266, 1998  Center et al. JBMR 15:1405, 2000 Annewieke et al. JCEM 85:3276, 2000 Amin et al. Ann Intern Med 133:951, 2000 Szulc et al. JCEM 86:192, 2001 Goemaere et al. IOF, 2002  Gennari et al. IOF, 2002 Kaufman IMS, 2002 1518d

  45. EVIDENCE FOR A THRESHOLD FOR BONE LOSS DUE TO E-DEFICIENCY IN ELDERLY MEN Rate of change in BMD Urine NTx 2 8 r = -0.12 r = -0.43 P = 0.347 P = 0.0004 0 6 Mid-Radius, %/yr -2 4 nmol/LGF -4 2 r = 0.05 r = 0.36 P = 0.702 P = 0.003 -6 0 30 0 10 20 30 0 10 20 Bioavailable E2, pg/mL Bioavailable E2, pg/mL Khosla et al. JCEM 86: 3555, 2001 1409.2

  46. E RATHER THAN T IS THE MAJOR REGULATOR OF BONE RESORPTION IN ELDERLY MEN ANOVA E effect P=0.005; T effect P=0.232 ANOVA E effect P=0.0002; T effect P=0.085 Urinary Dpd *** 40 Urinary NTx ** 30 * For change from baseline *P<0.05 **P<0.01 ***P<0.001 ** % change 20 * 10 0 (-T, -E) (-T, +E) (+T, -E) (+T, +E) Falahati-Nini et al. JCI 106: 1553, 2000 2026A.2

  47. INVOLUTIONAL BONE LOSS IN MEN Model Testosterone deficiency Dietary calcium Indirect effects ? Estrogen deficiency (slow onset) Decreased bone formation Secondary hyperparathyroidism Direct effects Remodelingimbalance Increased bone resorption BONE LOSS CA732660-02F

  48. ESTROGEN ACTION, BONE AND OSTEOPOROSISNew and Emerging Paradigms (2002) 1. E action on the skeleton a. Is determined in part by ERa/ERb ratio b. Includes cross-talk between E and T signal transduction pathways c. Involves multiple paracrine mediators but, in humans, the RANKL/OPG ratio (and possibly the TNFa level) in the bone marrow microenvironment are particularly important 2107c

  49. ESTROGEN ACTION, BONE AND OSTEOPOROSISNew and Emerging Paradigms (2002) 2. E is the major sex steroid regulating skeletal growth and maturation in both sexes a. E is an absolute requirement for the pubertal growth spurt and for epiphyseal plate closure b. E contributes substantially to attainment of peak BMD in both sexes c. Males have larger bones mainly because of divergent actions of T and E on periosteal bone apposition 2108a

  50. ESTROGEN ACTION, BONE AND OSTEOPOROSISNew and Emerging Paradigms (2002) 3. E deficiency is the major cause of both phases of postmenopausal bone loss a. Early, rapid phase is caused by loss of direct effects of E on bone cells b. Late, slow phase is mainly caused by secondary hyperparathyroidism induced by loss of E effect on peripheral calcium metabolism 2109a

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