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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

2342


Estrogen action bone and osteoporosis new and emerging paradigms
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


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


Estrogen action bone and osteoporosis prevailing paradigms 1995
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


Estrogen action bone and osteoporosis prevailing paradigms 19951
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


Estrogen receptors ers in bone cells recent advances
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


Estrogen action bone and osteoporosis prevailing paradigms 19952
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


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


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


Estrogen action bone and osteoporosis prevailing paradigms 19953
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


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


Mediators of estrogen action candidates
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


Rankl expression in various cell types effect of estrogen deficiency
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


Rankl expression per cell correlates with bone resorption in women
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


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


Estrogen action bone and osteoporosis prevailing paradigms 19954
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


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


Effect of e treatment on linear growth and bmd in er a and aromatase mutant males
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


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


E and t have both divergent and complimentary effects on bone
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


Estrogen action bone and osteoporosis prevailing paradigms 19955
ESTROGEN ACTION, BONE AND OSTEOPOROSIS BONEPrevailing 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


PATTERN OF INVOLUTIONAL BONE LOSS BONE

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


PATTERN OF INVOLUTIONAL BONE LOSS BONE

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


PATTERN OF INVOLUTIONAL BONE LOSS BONE

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


PATTERN OF INVOLUTIONAL BONE LOSS BONE

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


Rapid transient phase of bone loss is initiated by menopause
RAPID TRANSIENT PHASE OF BONE LOSS BONEIS 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


Perforative resorption of trabeculae in rapid phase disrupts bone microarchitecture

Young Normal BONE

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


The subsequent slow phase of bone loss continues indefinitely
THE SUBSEQUENT SLOW PHASE OF BONE BONELOSS 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


AGING IS ASSOCIATED WITH 2 BONEO 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


Effect of ca supplementation or ert in elderly postmenopausal women
EFFECT OF Ca SUPPLEMENTATION OR ERT IN BONEELDERLY 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


Postmenopausal bone loss questions
POSTMENOPAUSAL BONE LOSS BONEQuestions

  • 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


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


ESTROGEN ENHANCES RENAL Ca CONSERVATION INDEPENDENTLY OF PTH ABSORPTION

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


Estrogen and bone formation background
ESTROGEN AND BONE FORMATION ABSORPTIONBackground

  • 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


INVOLUTIONAL BONE LOSS IN WOMEN ABSORPTION

Model

?

Dietary

calcium

Indirect effects

Estrogen

deficiency

(rapid onset)

Decreased bone formation

Secondary

hyperparathyroidism

Direct effects

Remodelingimbalance

Increased bone resorption

BONE LOSS

CA732660-01C


Estrogen action bone and osteoporosis prevailing paradigms 19956
ESTROGEN ACTION, BONE AND OSTEOPOROSIS ABSORPTIONPrevailing Paradigms (~1995)

4. The two major regulators of bone mass -- sex steroids and biomechanical strain -- have independent actions

2106.1


Actions of e and mechanical strain on bone cell function are related
ACTIONS OF E AND MECHANICAL STRAIN ABSORPTIONON 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


Action of e and mechanical strain on bone cell function are related cont d
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


MODEL FOR E AND STRAIN INTERACTIONS RELATED (Cont’d)

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


Estrogen action bone and osteoporosis prevailing paradigms 19957
ESTROGEN ACTION, BONE AND OSTEOPOROSIS RELATED (Cont’d)Prevailing 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


AGE-RELATED BONE LOSS IN MEN RELATED (Cont’d)

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


Changes in sex steroids over life gender differences
CHANGES IN SEX STEROIDS OVER LIFE RELATED (Cont’d)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


Mechanisms of sex steroid deficiency differences between genders
MECHANISMS OF SEX STEROID DEFICIENCY RELATED (Cont’d)Differences 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


Relationship of serum e to bmd results of observational studies
RELATIONSHIP OF SERUM E TO BMD RELATED (Cont’d)Results 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


Evidence for a threshold for bone loss due to e deficiency in elderly men
EVIDENCE FOR A THRESHOLD FOR BONE LOSS RELATED (Cont’d)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


E rather than t is the major regulator of bone resorption in elderly men
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


INVOLUTIONAL BONE LOSS IN MEN ELDERLY 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


Estrogen action bone and osteoporosis new and emerging paradigms 2002
ESTROGEN ACTION, BONE AND OSTEOPOROSIS ELDERLY MENNew 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


Estrogen action bone and osteoporosis new and emerging paradigms 20021
ESTROGEN ACTION, BONE AND OSTEOPOROSIS ELDERLY MENNew 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


Estrogen action bone and osteoporosis new and emerging paradigms 20022
ESTROGEN ACTION, BONE AND OSTEOPOROSIS ELDERLY MENNew 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


Estrogen action bone and osteoporosis new and emerging paradigms 20023
ESTROGEN ACTION, BONE AND OSTEOPOROSIS ELDERLY MENNew and Emerging Paradigms (2002)

4. The direct effects of E and of biomechanical strain on bone are transduced, at least in part, through a common signaling pathway

5. Bone loss in aging men

a. Caused mainly by combined E and T deficiency due to both increased SHBG binding and impaired gonadal secretion

b. BioE is a major predictor but operates only below a critical threshold level

2110b


WHY ARE E EFFECTS ON BONE AND CALCIUM METABOLISM SO COMPLEX? ELDERLY MEN

  • ERa was first steroid nuclear receptor to evolve in vertebrates (PNAS 98:567, 2001)

  • Birds lose ~30-40% of their bone during egg-laying which is then rapidly restored

  • Mammal-like reptiles of Triassic era were oviparous

  • In viviparous mammals, this process was co-opted for mineralization of the fetal skeleton and for lactation

  • Once in place in females, it could be used to regulate bone mass in males

2320a


Overall conclusions
OVERALL CONCLUSIONS ELDERLY MEN

  • E is the most important sex steroid for the formation and maintenance of the adult skeleton

  • Effects of T on bone cells are both complimentary and antagonistic to those of E

  • Actions of E are pervasive and involve multiple cytokines and signaling pathways

  • Sex steroid deficiency is the most important cause of osteoporosis in both sexes

2119a


Acknowledgments
ACKNOWLEDGMENTS ELDERLY MEN

Staff

S. Khosla, M.D.

L.J. Melton, M.D.

T.C. Spelsberg, Ph.D.

Postdoctoral fellows

G.A. Ledger, M.D.

W.R. McKane, M.D.

A. Falahati-Nini, M.D.

G. Eghbali-Fatourechi, M.D.

Staff of Mayo Osteoporosis Research Group and Mayo GCRCN.I.H. Grants PO1 AG04875 and RO1 AR27065

1270b


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