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Preventing Bone Loss in Early Postmenopausal
WomenA CME Slide Library From the
Council on Hormone Education
Preventing Bone Loss in Early Postmenopausal Women
Section 1: Introduction
Section 2: Mechanisms Underlying Menopause-Related Bone Loss
Section 3: Prevalence and Consequences of Bone Loss
Section 4: Predicting Fracture Risk in Postmenopausal Women
Section 5: Prevention of Bone Loss
Section 6: Osteoporosis Therapies and Fracture Prevention
Section 7: Effect of HT on Fracture Prevention
Section 8: Summary and Conclusions
Section 1:
Introduction
Preventing Bone Loss in Early Postmenopausal Women
10 20 30 40 50 60 70 80
Bone Mass by Age and SexB
on
e M
ass
Age (years)Adapted from Finkelstein JS. Cecil Textbook of Medicine. 21st ed. 1999;1366-73. ©1999 Reprinted with permission from Elsevier.Riggs BL, Melton LJ III. N Engl J Med. 1986;314:1676-86.
Men Women
Menopause-AssociatedBone Loss
Change in Spine and Femoral Neck BMD Versus Years Since Menopause
Pe
rce
nt
per
Ye
ar
Bjarnason NH, et al. Bone. 2002;30:637-42.
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
2 2 to 4 4 to 7 7 to 10 10
Spine Femur
Years Since Menopause
Section 2:
Mechanisms Underlying
Menopause-Related Bone Loss
Preventing Bone Loss in Early Postmenopausal Women
Osteocytes
Osteoclasts
Reversal
Apoptotic Osteoclasts
Lining Cells
Osteocytes
Activation
Osteocytes
Formation
Osteoblasts
Osteocytes
Resorption
Resting Phase
Osteoclasts
Osteoclasts
Bone Remodeling
Osteoid
Lining Cells
Osteocytes
Preosteoblasts
Estrogen Deficiency Increases Bone Resorption
IL = interleukin; TNF = tumor necrosis factor; M-CSF = macrophage colony-stimulating factor; GM-CSF = granulocyte M-CSF; TGF = transforming growth factor ; RANKL = receptor activator of nuclear factor B ligand; OPG = osteoprotegerin.
IncreasedBone
Resorption
MonocytesMonocytes
IL-6IL-6M-CSFM-CSFIL-11IL-11GM-CSFGM-CSFRANKLRANKL
StromalStromalCells/Pre-Cells/Pre-
osteoblastsosteoblasts Active
Osteoclasts IL-1IL-1 TNFTNF
EarlyOsteoclastProgenitors
OPGOPGTGFTGF
= RANK
M-CSFM-CSF IL-6, IL-1 IL-6, IL-1
TNFTNFRANKLRANKL
Estrogen Decreases Bone Resorption
E = estrogen.
IL-1IL-1 TNFTNF
DecreasedBone
Resorption
IL-6IL-6M-CSFM-CSFIL-11IL-11GM-CSFGM-CSFRANKLRANKL
MonocytesMonocytes
StromalStromalCells/Pre-Cells/Pre-
osteoblastsosteoblasts Active
OsteoclastsEarlyOsteoclastProgenitors
OPGOPGTGFTGF E
E= RANK
E M-CSFM-CSF IL-6, IL-1 IL-6, IL-1
TNFTNFRANKLRANKL
Biochemical Markers Predict Early Menopausal Bone Loss
Women with markers of resorption or formation within the premenopausal range
– Bone loss over 4 years, <1%
Women with markers of resorption or formation above the premenopausal range
– Bone loss over 4 years, 1.5% to 2.5%
Garnero P, et al. J Bone Miner Res. 1999;14:1614-21.
4-Y
ear
Ra
te o
f L
oss
(%
)
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
BMD Change: Healthy Postmenopausal Women With Low and High Bone Turnover
BMD = bone mineral density; BAP = bone alkaline phosphatase; PICP = C-terminal propeptide of type I collagen; PINP = N-terminal propeptide of type I collagen; NTX = N-telopeptide breakdown products; CTX = C-telopeptide breakdown products; High turnover = bone marker levels above the upper limit of the premenopausal range .Garnero P, et al. J Bone Miner Res. 1999;14:1614-21. Used with permission.
Low Turnover High Turnover
SerumOsteocalcin
SerumBAP
SerumPICP
SerumPINP
UrinaryNTX
UrinaryCTX
SerumCTX
P = .0016 P = .06 P = .09 P = .01 P = .005 P = .006 P = .0001
Section 3:
Prevalence and Consequences
of Bone Loss
Preventing Bone Loss in Early Postmenopausal Women
Diagnostic Categories for Osteoporosis in Postmenopausal Women (WHO Criteria)
Normal: T-score above –1
Low bone mass (osteopenia): T-score between –1 and –2.5
Osteoporosis: T-score at or below –2.5
WHO = World Health Organization.WHO Study Group. WHO Technical Report Series. 1994;843:5-6.
Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994) for women 50 years of age.Looker AC, et al. J Bone Miner Res. 1997;12:1761-8.
Prevalence of Low Bone Mass and Osteoporosis in Postmenopausal Women
by Ethnicity
Population
Prevalence of Low Bone Mass
(T-score between –1 and –2.5)
Prevalence of Osteoporosis
(T-score –2.5)
Non-Hispanic white
African American
Mexican American
All ethnic groups (total)
42%
28%
37%
40%
17%
8%
12%
16%
Fracture Risk by Ethnicity in US Women
4 out of 10 white women1
2 out of 10 black women2
1Melton LJ III, et al. J Bone Miner Res. 1992;9:1005-10.2Griffin MR, et al. Am J Epidemiol. 1992;136:1378-85.3Melton LJ III. Endocrinol Metab Clin North Am. 2003;32:1-13.
Lifetime Risk for Fracture, After Age 50 Years
Lower risk in Hispanic women compared with non-Hispanic white; greater than in black women3
Risk for vertebral fracture in Asian women similar to non-Hispanic whites; hip fracture risk is lower3
Section 4:
Predicting Fracture Risk in
Postmenopausal Women
Preventing Bone Loss in Early Postmenopausal Women
DXA = dual-energy x-ray absorptiometry; QCT = quantitative computed tomography; pQCT = peripheral quantitative computed tomography; QUS = quantitative ultrasonometry; RA = radiographic absorptiometry.American Association of Clinical Endocrinologists. Endocr Pract. 2003;9:544-64.
Prediction of Fracture Risk
All techniques (DXA, QCT, pQCT, QUS, RA, etc) predict fracture risk
Bone loss can best be monitored using DXA of the spine in early postmenopausal women
Predictive Validity of BMC for Fracture
BMC = bone mineral content; CHD = coronary heart disease.WHO Study Group. WHO Technical Report Series. 1994;843:46; Neaton JD, Wentworth D. Arch Intern Med. 1992;152:56-64.
Re
lati
ve
Ris
k
Increasing Total Cholesterol
Decreasing BMC
0
2
4
6
8
10
12
BMC/Hip Fracture
Total Cholesterol/CHD
Quartile 1 Quartile 4Quartile 2 Quartile 3
Comparison to Predictive Validity of Cholesterol for Heart Disease
2.25 3.37
7.21
4.1
1.56 1.631.72
1.570.71 0.65
0.96 0.73
0
2
4
6
8
10
12
14
16
18
Finger Forearm Heel US Heel SXA
Fra
ctu
re R
ate
per
100
P
atie
nt-
Yea
rs ±
95%
CI
<–2.5
–2.5 to –1.0
>–1.0
NORA: All Devices Studied Predicted Fracture Risk
US = ultrasound; SXA = single-energy x-ray absorptiometry.Fractures during 1-year follow-up in 149,524 postmenopausal Caucasian women. Miller PD, et al. J Bone Miner Res. 2002;17:2222-30. Used with permission.
T-Score
When Measurement of BMD in Women is Inappropriate
Healthy premenopausal women
Healthy children and adolescents
Women initiating HT for menopausal symptom relief
– Other osteoporosis therapies should not be initiated without BMD measurement
When to Measure BMD in Women
All women 65 years and older Postmenopausal women <65 years of age
– If results might influence decisions about intervention
– One or more risk factors
– History of fracture
– Patient requests measurement
American Association of Clinical Endocrinologists. Endocr Pract. 2003;9:544-64.National Osteoporosis Foundation. Washington, DC: National Osteoporosis Foundation; 2003:1-37.
Risk Factors for Osteoporosis-Related Fractures
Non-modifiable Female sex Advanced age Caucasian race History of fracture as
an adult Family history of
osteoporosis Early or premature
menopause
Modifiable Low BMD Low body weight/BMI Smoking Low calcium intake Vitamin D deficiency Inadequate physical
activity Glucocorticosteroid use Estrogen deficiency High risk for falls
American Association of Clinical Endocrinologists. Endocr Pract. 2003;9:544-64.National Osteoporosis Foundation. Washington, DC: National Osteoporosis Foundation; 2003:1-37.
Who Should Be Offered Intervention?
All women with osteoporosis-related fractures irrespective of BMD
All postmenopausal women with a BMD T-score of –2.5 or lower
Who Should Be Considered for Preventive Intervention?
Patients with levels of BMD above –2.5 with other risk factors, including
– Age
– Glucocorticosteroid use
– Low body weight/BMI
– Smoking
– Family history
– Early or premature menopause
Hui SL, et al. J Clin Invest. 1988;81:1804-9.
For a Given BMD, Fracture Risk Increases With Age
0
20
40
60
80
100
120
140
160
>1.0 0.90-0.99 0.80-0.89 0.70-0.79 0.60-0.69 <0.60Fra
ctu
re R
isk
per
10
00 P
erso
n-Y
ear
s
Bone Mass (g/cm)
Age (years)
80+
75-79
70-74
65-69
60-64
55-5950-5445-49<45
NORA: Osteoporotic Fracture Rate by Age
8.1 8.94 9.0911.94
15.28
20.93
27.94
39.24
0
5
10
15
20
25
30
35
40
45
50–54 55–59 60–64 65–69 70–74 75–79 80–84 85+
Age (years)
Fra
ctu
re R
ate
per
100
0 P
erso
n-Y
ears
*
*Corrected for initial BMDDerived from Siris ES, et al. JAMA. 2001;286:2815-22, and Miller PD, et al. J Bone Miner Res. 2002;17:2222-30.
NORA: Factors Associated With Reduced Risk of Osteoporosis
Siris ES, et al. JAMA. 2001;286:2815-22.
FactorOdds Ratio
(95% CI)
BMI 30 kg/m2
Current estrogen use
Alcohol use (14 drinks/week)
Former estrogen use
Regular exercise
0.16 (0.15–0.17)
0.27 (0.25–0.28)
0.62 (0.54–0.71)
0.77 (0.73–0.80)
0.86 (0.82–0.89)
NORA: Inverse Relationship Between BMD and Fracture Rate
BMD T-scores
Fra
ctu
re R
ate
pe
r 10
00
Pe
rso
n-Y
ea
rs
>1.01.0 to 0.5
0.5 to 0.00.0 to –0.5
–0.5 to –1.0–1.0 to –1.5
–1.5 to –2.0–2.0 to –2.5
–2.5 to –3.0–3.0 to –3.5
< –3.5
Adapted from Siris ES, et al. JAMA. 2001;286:2815-22.
Fracture Rate
BMD Distribution
0
10
20
30
40
50
60
# Fractures
NORA: Fracture Rate vs Number of Fractures by T-Score
BMD T-scores
Fra
ctu
re R
ate
pe
r 10
00
Pe
rso
n-Y
ea
rsN
um
be
r of F
ractu
res
>1.01.0 to 0.5
0.5 to 0.00.0 to –0.5
–0.5 to –1.0–1.0 to –1.5
–1.5 to –2.0–2.0 to –2.5
–2.5 to –3.0–3.0 to –3.5
< –3.5
Adapted from Siris ES, et al. JAMA. 2001;286:2815-22.
Fracture Rate
BMD Distribution
0
10
20
30
40
50
60
0
50
100
150
200
250
300
350
400
450
Patient A
Patient B
Gomberg BR, et al. IEEE Trans Med Imaging. 2000;19:166-74.
Bone Quality: Contribution of Bone Micro-Architecture
Two Patients With Similar BMD, Dissimilar Micro-Architecture
Bone Quality: Contribution of Bone Micro-Architecture continued
0
0.2
0.4
0.6
0.8
1
Re
lati
ve
Va
lue
Surface Density Curve Density Surface/Curve Erosion Index
Most plate-like Most rod-like
60-Year-Old Male 68-Year-Old Female 53-Year-Old Female 74-Year-Old Female
Dis
tal R
adiu
s S
pec
imen
s
Gomberg BR, et al. IEEE Trans Med Imaging. 2000;19:166-74.
Section 5:
Prevention of Bone Loss
Preventing Bone Loss in Early Postmenopausal Women
Calcium Supplementation Alone Does Not Prevent Early Postmenopausal Bone Loss
Ch
ang
e in
BM
D A
fter
2 Y
ears
(%
)
-4
-3
-2
-1
0
Placebo(n = 14)
Calcium supplementation = 500 mg/day.*P < .01 vs baseline.Dawson-Hughes B, et al. N Engl J Med. 1990;323:878-83.
CalciumCitrate(n = 25)
CalciumCarbonate
(n = 28)
-4
-3
-2
-1
0
Placebo(n = 11)
CalciumCitrate(n = 24)
CalciumCarbonate
(n = 23)
* **
Spine Femoral Neck
FDA-Approved for the Prevention of Bone Loss
Estrogen
Bisphosphonates
– Alendronate
– Risedronate
Raloxifene
Blue area represents placebo-treated population of oophorectomized women.Lindsay R, et al. Lancet. 1976;1:1038-41.
Met
acar
pal
Bo
ne
Min
eral
Co
nte
nt
(mg
/mm
)
Years
At Oophorectomy
3 Years After Oophorectomy
6 Years After Oophorectomy
44
42
40
38
36
34
0 2 4 6 8 10 12 14 16
Effect of Delayed Initiation of HT on Bone Loss
-4
-3
-2
-1
0
1
2
3
4
Baseline 6 Mo 12 Mo 18 Mo 24 Mo
CEE 0.625/MPA 2.5 mg/dayCEE 0.45/MPA 2.5 mg/dayCEE 0.45/MPA 1.5 mg/dayCEE 0.3/MPA 1.5 mg/dayPlacebo
-4
-3
-2
-1
0
1
2
3
4
Baseline 6 Mo 12 Mo 18 Mo 24 Mo
Me
an
Ch
an
ge
Fro
m B
as
eli
ne
(%
)
CEE 0.625 mg/dayCEE 0.45 mg/day
CEE 0.3 mg/dayPlacebo
CEE CEE/MPA
Changes in Spine BMD With HT
Intent-to-treat population only; Women’s HOPE = Women’s Heart, Osteoporosis, Progestin, Estrogen; CEE = conjugated equine estrogens; MPA = medroxyprogesterone acetate.Lindsay R, et al. JAMA. 2002;287:2668-76. Used with permission.
The Women’s HOPE Study
*Adherent participants only (n = 641, age 45 to 64 years). All active treatment groups significant vs placebo; no significant differences were found among active treatment groups.PEPI = Postmenopausal Estrogen/Progestin Interventions; MP = micronized progesterone.Writing Group for the PEPI Trial. JAMA. 1996;276:1389-96. Used with permission.
Different Progestin Regimens Do Not Modify the Impact of Estrogen on BMD
Ch
an
ge
Fro
m B
ase
line
(%
)*
Baseline 12 Months 36 Months-6
-4
-2
0
2
4
6
Baseline 12 Months 36 Months-6
-4
-2
0
2
4
6
Spine Hip
CEE/MP (cyclic)Placebo
CEE Only
CEE/MPA (cyclic)
CEE/MPA (continuous)
The PEPI Trial
Bone Loss Is UncommonWith HT Use
Among Adherent Women in the PEPI Trial
Only 3% of HT users lost >2% inspinal BMD in the first 12 months vs 41% using placebo
Only 1% of HT users lost >2% in spinal BMD after 12 to 36 months vs 16% using placebo
Greendale GA, et al. Arch Intern Med. 2000;160:3065-71.
Section 6:
Osteoporosis Therapies and
Fracture Prevention
Preventing Bone Loss in Early Postmenopausal Women
FDA-Approved for the Treatment of Osteoporosis
Bisphosphonates
– Alendronate
– Ibandronate*
– Risedronate
Calcitonin
Raloxifene
Teriparatide
*Approved, but not available in the US as of 2/11/04.
Meta-Analysis of Osteoporosis Therapies: Spine BMD
HT (2 year)
Alendronate, 5 mg (2 or 3 year)
Alendronate, 10–40 mg (2–4 year)
Risedronate, 5 mg (1.5–3 year)
Raloxifene, 60 mg (2–3 year)
Calcitonin* (1–5 year)
Calcium (2 year)
*Doses ranged from 250 to 2800 IU per week; predominantly nasal delivery.Cranney A, et al. Endocr Rev. 2002;23:570-8; Endocrine Rev. 2002;23:496-578.
Weighted Mean Difference ± 95% CI (% change in BMD)
0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0
HT (2 year)
Alendronate, 5 mg (2 year)
Alendronate, 10–40 mg (2 year)
Risedronate, 5 mg (1.5–3 year)
Raloxifene, 60 mg (2–3 year)
Calcitonin*
Calcium
-1.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0
Weighted Mean Difference ± 95% CI (% change in BMD)
*Doses ranged from 350 to 800 IU per week; predominantly nasal delivery.Cranney A, et al. Endocr Rev. 2002;23:570-8; Endocrine Rev. 2002;23:496-578.
Meta-Analysis of Osteoporosis Therapies: Total Hip BMD
HT (2 year)
Alendronate, 5 mg (2 year)
Alendronate, 10–40 mg (2–4 year)
Risedronate, 5 mg (1.5 year)
Raloxifene, 60 mg (1 year)
Calcitonin*
Calcium
-1.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0
Weighted Mean Difference ± 95% CI (% change in BMD)
*Doses ranged from 350 to 800 IU per week; predominantly nasal delivery.Cranney A, et al. Endocr Rev. 2002;23:570-8. Endocrine Rev. 2002;23:496-578.
Meta-Analysis of Osteoporosis Therapies: Forearm BMD
-4
-2
0
2
4
6
8
0 12 24 36 48 60
-4
-2
0
2
4
6
8
0 12 24 36 48 60
Effect of Treatment and Discontinuation on BMD in Older Postmenopausal Women
Ch
ang
e F
rom
Bas
elin
e (%
)
*P < .05 compared with baseline measure.†P < .05 compared with placebo group.Gallagher JC, et al. J Clin Endocrinol Metab. 2002;87:4914-23. Copyright 2002, The Endocrine Society.
Spine BMD Femoral Neck BMD
MonthTreatment Follow-up
Ch
ang
e F
rom
Bas
elin
e (%
)
MonthTreatment Follow-up
Placebo HT
*†
*†*†
*
-4
-2
0
2
4
6
8
0 12 24 36
-2
0
2
4
6
8
10
12
0 12 24 36
Effect of Treatment and Discontinuation on BMD in Older Postmenopausal Women
continued
Mea
n C
han
ge
in B
MD
(%
)
Greenspan SL, et al. Ann Intern Med. 2002;137:875-83. Used with permission.
Lumbar Spine Femoral Neck
MonthTreatment Follow-up
Mea
n C
han
ge
in B
MD
(%
)
MonthTreatment Follow-up
Placebo/Placebo CEE/Placebo Alendronate/Placebo
Section 7:
Effect of HT on Fracture
Prevention
Preventing Bone Loss in Early Postmenopausal Women
Years
Fra
ctu
re-F
ree
Su
rviv
al
P < .05; prospective trial of women aged 45 to 58 yrs in which 21 wrist fractures were documented; HT = 2 mg oral estradiol + 10 days of 1 mg norethisterone.Reprinted from Mosekilde L, et al. Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal women—results of the Danish Osteoporosis Prevention Study. Maturitas. 2000;36:181-93. © 2000, with permission from Elsevier Science.
HT(n = 502)
No HT(n = 504)
1.00
0.99
0.98
0.97
0.960 1 2 3 4 5 6
Danish Osteoporosis Prevention Study: Fracture-Free Survival in Early
Postmenopausal WomenWrist Fracture
0.1 1.0 10.0
Meta-Analysis of Osteoporosis Therapies: Nonvertebral Fractures
HT* (n = 20,494)
Alendronate, 5 mg (n = 8603)
Alendronate, 10–40 mg (n = 3723)
Risedronate, 2.5–5 mg (n = 12,958)
Raloxifene, 60 mg (n = 6961)
Calcitonin† (n = 6961)
Calcium (n = 222)
Relative Risk (95% CI)*Includes the Women’s Health Initiative (WHI) trial.†Estimate from the Prevent Recurrence of Osteoporotic Fractures (PROOF) trial.Cranney A, et al. Endocr Rev. 2002;23:570-8. Endocrine Rev. 2002;23:495-578; Rosen C. Presentation for ASBMR at NIH Scientific Workshop: Menopausal Hormone Therapy, October 23-24, 2002. Available at: http://www4.od.nih.gov/orwh/htslides/rosen2.ppt. Accessed 1/18/03.
Women’s Health Initiative (WHI) Trial
WHI: Baseline Prevalence of Osteoporosis (WHO) by DXA Femoral Neck T-scores
Normal(>–1.0)
Low Bone Mass(–1.0 to –2.4)
E+P Placebo
P = .29
Cauley JA. Available at: http://www.fda.gov/ohrms/dockets/ac/cder03.html#EndocrinologicMetabolicDrugs. Accessed 1/7/04.
In 6% of Participants (n = 1024)
32%
58%
10%
35%
53%
12%
Osteoporosis(–2.5 )
-1
0
1
2
3
4
5
6
7
0 1 2 3
-1
0
1
2
3
4
5
6
7
0 1 2 3
PlaceboHT
-1
0
1
2
3
4
5
6
7
0 1 2 3
WHI Results: Mean Change in BMD During 3 Years of E+P
Follow-up (years)
Cauley JA, et al. JAMA. 2003;290:1729-38.
Mea
n C
han
ge
in B
MD
F
rom
Bas
elin
e (%
)
Total Hip Spine
In 6% of Participants (n = 1024)
0.5 1.0 2.0
WHI Results: Fracture Outcomes
Hip
Vertebral
Lower Arm/Wrist
Total
Hazard Ratio
95% nCI
95% aCI
Adjusted confidence interval reported only for hip fracture.Cauley JA, et al. JAMA. 2003;290:1729-38.
0
50
100
150
200
Total Fractures
WHI Results: Effect of E+P in Preventing Fractures
0
20
40
60
80
Hip ClinicalVertebral
Wrist/LowerArm
Nu
mb
er o
f F
ract
ure
s/Y
ear
in 1
0,00
0 W
om
en
Placebo E+P
Number of Fractures/Year in 10,000 Women
Type of FractureCauley JA, et al. JAMA. 2003;290:1729-38.
0.00
0.01
0.02
0.03
0 1 2 3 4 5 6 7
WHI Results: Effect of E+P on Risk of Hip Fracture
Kaplan-Meier Estimate
Time (year)
Cu
mu
lati
ve H
azar
dfo
r H
ip F
ract
ure
HR = 0.6795% nCl = 0.47–0.9695% aCI = 0.41–1.10
Placebo
E+P
Cauley JA, et al. JAMA. 2003;290:1729-38.
0.0
0.1
0.2
0.3
0.4
0.5
0 1 2 3 4 5 6 7
WHI Results: Effect of E+P on Risk of Lower Arm/Wrist Fracture
Adjusted confidence interval not reported.Cauley JA, et al. JAMA. 2003;290:1729-38.
Kaplan-Meier Estimate
Time (year)
Cu
mu
lati
ve H
azar
d f
or
Lo
wer
Arm
/Wri
st F
ract
ure
HR = 0.7195% nCl = 0.59–0.85
Placebo
E+P
0.0
0.1
0.2
0.3
0 1 2 3 4 5 6 7
WHI Results: Effect of E+P on Risk of Vertebral Fracture
Adjusted confidence interval not reported.Cauley JA, et al. JAMA. 2003;290:1729-38.
Kaplan-Meier Estimate
Time (year)
Cu
mu
lati
ve H
azar
d
for
Ver
teb
ral F
ract
ure
HR = 0.6595% nCl = 0.46–0.92
Placebo
E+P
0.00
0.05
0.10
0.15
0 1 2 3 4 5 6 7
Cu
mu
lati
ve H
azar
dfo
r T
ota
l Fra
ctu
re
Time (year)
WHI Results: Effect of E+P on Risk of Total Fracture
Adjusted confidence interval not reported.Cauley JA, et al. JAMA. 2003;290:1729-38.
HR = 0.7695% nCl = 0.69–0.83
Placebo
E+P
Kaplan-Meier Estimate
1Cauley JA, et al. JAMA. 2003;290:1729-38.2Black DM, et al. Osteoporosis Int. 2001;12:519-28.
WHI: Summary Fracture Risk Score
WHI Investigators1 developed a summary fracture risk score guided by the methods used to develop the FRACTURE Index2
Predictive validity of FRACTURE Index has been shown2
Validity of WHI fracture risk score not established
– WHI reported fracture risk score showed moderate predictive strength for hip fracture1
1Cauley JA, et al. JAMA. 2003;290:1729-38.2Black DM, et al. Osteoporosis Int. 2001;12:519-28.
WHI: Summary Fracture Risk Scorecontinued
Differences between FRACTURE Index and WHI risk score1,2
– WHI score includes age, prior fracture after age 55 years, current smoking, and BMI 22.4 kg/m2
– FRACTURE Index includes age, prior fracture after age 50 years, maternal hip fracture after age 50 years, weight 125 lbs, current smoking, use of arms to stand from a chair, and total hip BMD (if available)
HR for Global Index: Stratified by Fracture Risk Scores
Highest
Middle
Lowest
Hazard Ratio (95% nCI)
Fracture Risk*
0.5 1.0 2.0
*Stratified by tertiles of summary fracture risk scores; the WHI Global Index measure and WHI Fracture Risk Score have not been validated.Cauley JA, et al. JAMA. 2003;290:1729-38.
Summary: WHI Results and Considerations
CEE/MPA significantly decreased the risk of hip fractures, vertebral fractures, and all other fractures in a population not specifically selected for being at increased risk of fracture1
This benefit has not been demonstrated in a similarly low-risk population with any other osteoporosis therapy
1Cauley JA, et al. JAMA. 2003;290:1729-38.
Section 8:
Summary and Conclusions
Preventing Bone Loss in Early Postmenopausal Women
Summary:Prevention of Early Bone Loss
Bone loss is most rapid in the years immediately following menopause
Women treated with HT to relieve menopausal symptoms do not need another antiresorptive agent
HT is the only therapy that has been demonstrated to prevent fractures in women whose risk for osteoporosis is unknown