Prevention of Osteoporosis in early menopause

Dr. Santiago PalaciosAntonio Acuña, 9

28009 MadridPhone: +34 91 578 05 17

E-mail: [email protected]

Prevention of osteoporosis in early menopause

www.institutopalacios.com

Diapositivas/Slides

http://www.institutopalacios.com/

• CONCEPT• EFFECT OF ESTROGEN DEFICIENCY ON

BONE LOSS• BONE LOSS AFTER NATURAL

MENOPAUSE• EFFECT OF EARLY MENOPAUSE ON BMD• EARLY MENOPAUSE AND FRACTURES• PREVENTION• CONCLUSIONS

EARLY MENOPAUSE

Bilateral oophorectomyBilateral oophorectomy

Acute hypoestrogenismand hypoandrogenism

Acute hypoestrogenismand hypoandrogenism

ET may be higherET may be higher

Premature ovarian failurePremature ovarian failure

The transition issimilar to natural

menopause

The transition issimilar to natural

menopause

BILATERAL OOPHORECTOMY

Ovarian, endometrial or fallopian tubecancersSevere endometriosisBilateral tubo-ovarian abscessFamilial breast-ovarian cancer syndromeSevere premenstrual syndrome

Surgical Menopause in USA

• Chen WY Manson JE 2006 JNCI

• “Premature Ovarian Failure in Cancer Survivors: New Insights, Looming Concerns”

• 598 000 hysterectomies 1994-1999 in women below 40 (1/3 with BSO) i.e. 100 000 pa!

• ie. Every year in US 33 000 left menopausal and 66 000 left with increased risk of POF.

PREMATURE OVARIAN FAILURE

Is the development of amenorrhea with concomitant sex hormone deficiency and elevated serum gonadotropin levels before age of 40 years?

Is the development of amenorrhea with concomitant sex hormone deficiency and elevated serum gonadotropin levels before age of 40 years?

Clinical Definitions• Abnormal Menses: a history of at least 3

consecutive months of oligomenorrhea or abnormal uterine bleeding.

• Evidence of Reduced Fecundity: the development of fewer than 5 follicles (>15 mm) after appropriate gonadotropin stimulation (300 IU/day) or no pregnancy after one year of unprotected intercourse.

• Elevated FSH: above the normal limit (95% CI) for the early follicular phase (days 2 to 5) as defined by the assay employed.

PREMATURE OVARIAN FAILURESTUDY OF WOMEN ACROSS THE NATION (SWAN)

CAUCASIAN 1.0%

AFRICAN – AMERICAN 1.4%

LATIN 1.4%

CHINESE 0.5%

JAPANESE 0.1%

~ 70.000 women in Spain who have experienced premature ovarian failure

Coulam CB et al. Obstet Gynecol. 1986 Apr;67(4):604-6

Aetiology of POF

42% 43%

13%

2%

0%5%

10%15%20%25%30%35%40%45%50%

Idiopathic Cancer Benign Genetic

% o

f pat

ient

s




Influence of Estrogens on the development of physiologic bone geometry and bone architecture

Age

Bon

e M

ass

(g/m

2 )

„normal“

menopausepeak bone mass

menarche

SD

mean

1,2

1,1

1,0

0,9

0,8

00 10 20 30 40 50 60 70 80

I I I I I I I I

-

-

-

-

-

fracture threshold

Influence of Estrogens on Bone Remodeling Sequence Influence of Estrogens on Bone Remodeling Sequence EstrogenEstrogen

Neg.

Neg.

EstrogenEstrogenNeg.Neg

.

Neg.




Influence of age on Spine-BMD

Age

Bon

e M

ass

(g/m

2 )

„normal“

menopausepeak bone mass

SD

mean

1,2

1,1

1,0

0,9

0,8

00 10 20 30 40 50 60 70 80

I I I I I I I I

-

-

-

-

-

fracture threshold

Age-adjusted RR for Spine and Hip-Fracturein Relation to endogenous Serum E2-Levels

1.0 1.0

0.4 0.40.3 0.3

0.5 0.5

Cummings et al. (1998); NEJM Vol 339 No 11, 733-740

0,00

0,25

0,50

0,75

1,00

Rel

ativ

e R

isk

< 5 5-6 7-9 > 9Endogenous Serum Estradiol Level [pg/ml]

Hip-Fracture Spine-Fracture

Independent of BMDIndependent of BMD




SD

Age0 10 20 30 40 50 60 70 80

Peak bone mass

Mean

1,2

1,1

1,0

0,9

0,8

0

-

-

-

-

-

Lum

ber S

pine

BM

D (g

/m2 )

fracture threshold

Increased bone loss

Effect of estrogen deficiency on BMD in premenopausal women

Hadji et al. Frauenarzt 46, 10: 890-897 (2005)

T – SCORES vs Z-SCORES

The Z-score compares bone mass density with that of someone of similar age, sex, weight and ethnic/racial origin.

So a Z-score of -0.5 indicates a bone density one-half of a standard deviation less than the norm.

Peak bone mass reaches its maximum between ages 20 to 29 yearsUp to 60% of adult total bone mineral is acquired during adolescenceThere are no normative tables for women <25 years

PREMATURE OVARIAN FAILURE

(A) Normal bone (B) Osteoporotic bone

is WHO criteria appropriate for diagnosis of

osteopaenia/osteoporosisin POF ?

Current T scores are invalid diagnostic markers of bone density in young POF patients POF patients require their own group specific baseline BMD valuesThe rising incidence of premature ovarian failure in an increasingly younger age group warrants re-evaluation of our diagnostic criteria to facilitate management of reduced bone mass in this vulnerable patient group.

ALTERNATIVES:Quantitative computed tomography (QCT)

- evaluate bone in 3 dimensions, ‘gold standard’, primarily for researchQuantitative ultrasound

- no radiation exposure, inexpensive, lack adequate normative databases Magnetic resonance imaging

- radiation-free, evaluate bone geometry AND quality, lack normative databases




EARLY MENOPAUSE AS PREDICTOR OF FRACTURES

AUTHOR % INCREASED

Gardsel et al. 1991 50

Mallmin et al. 1994 100 (Colles fractures)

Vega et al. 1994 300 (hip fractures)

Tuppurainen et al. 1995 300

Van Der Voort et al. 2003 40

Van Der Klift et al 2004 247 (vertebral fractures)

OOPHORECTOMY AS PREDICTOR OF FRACTURE

(1) Women younger than age 45 years Fracture %

Oophorectomy 39

Histerectomy (non oop.) 24

Natural menopause 21

(2) Oophorectomy after menopause

Equal than natural menopause

(1) Johansson C et al. Maturitas 1993;17:39-50(2) Antoniucci DM et al. J Bone Miner Res 2005;20:741-47




PROPHYLACTIC OOPHORECTOMYRoutine prophylactic oophorectomy concumitantly with hysterectomyRoutine prophylactic oophorectomy concumitantly with hysterectomy

The familiar cancer syndromesThe familiar cancer syndromes

After chilbearingAfter chilbearing •Prevention of ovarian cancer 1.000 cases prevented 300.000 oophorectomies performed

•Reoperations for ovarian pathology 4-5 % of women who have had a previous hysterectomy

•Prevention of ovarian cancer 1.000 cases prevented 300.000 oophorectomies performed

•Reoperations for ovarian pathology 4-5 % of women who have had a previous hysterectomy

>40 years old>40 years old

Piver MS et al. Cancer. 1993 May 1;71(9):2751-5.

Christ JE, Lotze EC. Obstet Gynecol. 1975 Nov;46(5):551-6.

Principles of Hormone Replacement in early menopause

Estrogen replacement is first line treatment

1)Pre pubertal : To induce development of secondary sexual characteristics

2)To relieve the immediate sequelae of menopause i.e. symptom relief and quality of life

3)To prevent the long term sequelae of the menopause

4)To create an environment conducive to the successful replacement of donated embryos

Early menopauseTherapeutic Options

• Route / Type HRT

• Choice of oestrogen route of administration must be made on individual basis

• No controlled studies regarding the ideal hormone replacement strategy for women with premature ovarian failure

In principle, non oral E2 / progesterone preparations can be better monitored but what is ideal E2 level?

HRT preparations in Early menopause

• Progestogenic opposition if uterus present– Even after radiotherapy

• Aim for minimum effective oral dose or local opposition with Mirena / Crinone / Cyclogest

• ?Aim for natural progesterone replacement

Timing of HRT Usage• Management

– Liaise with gynae oncologists / medical oncologists / haematologists re time to start

– Immediately if curative procedure (after hist diagn)

– Delay (1 year disease free interval) if oestrogen sensitive tumour e.g. endometrial carcinoma

– Treat at least until average age of menopause

– HRT “holidays” to test ovarian function

Hormonal Replacement Therapy

• Hormonal therapy would seem warranted for women – to eliminate symptoms and prevent bone loss; data from the WHI do not apply.

• Abundant data indicate that E/P in any form does not prevent ovulation and pregnancy – for unclear reasons. Thus, barrier contraception may be warranted.

• Young women without ovarian function may require more estrogen than older women to alleviate symptoms of estrogen deficiency.

• There are virtually no data regarding the safety and efficacy ofE/P in women with POF.

17th Nov 200533 West London

Menopause & PMS Centre

Premature Ovarian FailureTherapeutic Options

• Combined oral contraceptive pill

– “Use of ethinylestradiol has been driven by practicalities rather than science”

» Conway et al (1996)

Guttman et al Clin Endocrinol 2001 West London Menopause & PMS Centre

Premature Ovarian FailureTherapeutic Options

• Combined Pill v HRT– 0.625mg v 30mcg EE in 17 adult women with Turner’s

Syndrome

– 6 month cross over study :Hormones, Lipids, Bone Turnover etc

– FSH most suppressed by EE, BUT HRT was superior at minimising hyperinsulinaemia & bone turnover

Questions for Gynecologists, ACOG 2003-5: Would you give a woman with idiopathic POF hormone

therapy (HT)?

• Yes – 94%• No – 6%

Questions for Gynecologists, ACOG 2003-5: What form of HT would you administer to women with

POF?

• Combination oral contraceptives 60%• Continuous combined HT 16%• Sequential HT 22%• No therapy 1%

Questions for Gynecologists, ACOG 2003-5: How long should a woman with POF be treated?

• Until the expected age of menopause 67%• For the remainder of her life 11%• For 1 to 5 years 11%• Uncertain 11%

Questions for Gynecologists, ACOG 2003-5: Is a woman with POF at increased risk of side effects from

estrogen?

• Yes 25%• No 38%• Uncertain 37%

Additional Treatment in POF

• Addition of exogenous androgen?• Recommendations to prevent osteoporosis are

warranted:– Calcium 1200-1500 mg/day– Daily weight bearing exercise– Daily vitamin D

Fertility Options in women at risk of POF

• Surgery– Ovarian transposition

– Ovarian Tissue Cryopreservation• Transplantation – e.g. (Donnez 2004, Chaim Sheba Medical

Centre Israel 2005, Oktay 2006)

• IVF– Own Embryo Cryopreservation– Own Oocyte Cryopreservation (1st pregnancy 2001)




FUTURE RESEARCH IN WOMEN UNDERGOINGPREMATURE MENOPAUSE

1. Is premature menopause a deficiency diseaserequiring physiologic replacement?

2. Should be treated with exogenous E with or withoutprogestin?

3. What form of HT is most appropiate?4. For how long should HT be administrated?5. How safe is HT in women with premature versus

natural menopause?

Hendrix SL. Am J Med. 2005 Dec 19;118(12 Suppl 2):131-5.

Future Objectives:

• Need to merge data over the long term to look at quality of life / fertility outcomes / osteoporosis / CV disease

• POF patients should therefore remain under long term follow up

Health & Medicine

Prevention of Osteoporosis in early menopause