Risk of Fractures

Rebecca D. Jackson, M.D.Associate Professor of Internal MedicineDivision of Endocrinology, Diabetes and

MetabolismThe Ohio State University

Vice-Chair, WHI Steering Committee

• A condition of skeletal fragility characterized by reduced bone mass and microarchitectural deterioration

WHO, Guidelines for Preclinical Evaluation and Clinical Trials in Osteoporosis,1998

Normal Bone Osteoporosis

Definition of Osteoporosis

Epidemiology of Osteoporosis

• Major public health threat for 44 million Americans– 10 million women and men already have osteoporosis– 34 million have low bone mass

• One in every two women will have an osteoporosis-related fracture in their lifetime

• Responsible for more than 1.5 million fractures annually– 300,000 hip fractures– 700,000 vertebral fractures– 250,000 wrist fractures– ~300,000 other fractures

• Estimated direct expenditures for osteoporosis and fractures is $14 billion each year

Survival Rates After FracturesSurvival Rates After Fractures

Adapted from Cooper C et al. Am J Epidemiol. 1993;137:1001-1005

%Survival

Time After Fracture (Years)

ExpectedObserved

100

80

60

40

20

01 2 3 4 5

Vertebral Fracture(Relative Survival = 0.81)

100

80

60

40

20

01 2 3 4 5

Hip Fracture(Relative Survival = 0.82)

00

10001000

20002000

30003000

40004000

35–3935–39 85+85+AgeAge

Fra

ctur

e In

cide

nce

Fra

ctur

e In

cide

nce

per

100,

000

Per

son-

Yea

rspe

r 10

0,00

0 P

erso

n-Y

ears

Riggs BL, Melton LJ. N Engl J Med. 1986;314:1676–1686.Riggs BL, Melton LJ. N Engl J Med. 1986;314:1676–1686.Faulkner, KG. J Clin Densitometry. 1998;1:279–285.Faulkner, KG. J Clin Densitometry. 1998;1:279–285.

60%60%

70%70%

80%80%

90%90%

100%100%

3030 4040 5050 6060 7070 8080 9090AgeAge

Rel

ativ

e B

MD

Rel

ativ

e B

MD

ForearmForearm Hip and HeelHip and Heel SpineSpine WristWristVertebraeVertebrae HipHip

Bone Density and Bone StrengthDecreases in BMD and Increases in

Fractures as a Function of Age in Women

CEE: conjugated equine estrogen; MPA: medroxyprogesterone acetate; MP: micronized progesterone;cyc: cyclic admin. (days 1–12 of each month); and con: continuous admin. (daily throughout the month)

Writing Group for the PEPI Trial. JAMA, 1996;276:1389–96.

–6

–4

–2

0

2

4

6

Perc

en

t C

han

ge f

rom

Baselin

e

Baseline 12 mo 36 mo

Spine Hip

–6

–4

–2

0

2

4

6

Baseline 12 mo 36 mo

PlaceboCEE OnlyCEE-MPA (cyc)

CEE-MPA (cont)CEE-MPCEE-MPA (cont)CEE-MP

Estrogen and Progestin Effect on BMD The PEPI Trial

Prior Positive Fracture PreventionTrials with Hormones

• Nachtigall LE et al, Ob& Gyn 1979;53:277-81– Ten years in 84 pairs of women, 7 FX vs 0

• Lindsay R et al, Lancet 1980;2:1151-53. – 100 oophorectomized women, mestranol, 9 yr f/u, significantly

reduced the incidence of vertebral compression.• Lufkin EG et al, . Ann Intern Med 1992;117:1-9

– Transderm estrogen, 75 women, 40% reduction in radiographic vertebral fracture rate

• Komulainen MH et al, Maturitas 1998;31:45-54– 5 yrs, Finland, 47 to 56 yrs old, reduced the risk of non-

vertebral fractures by about 60%

Metanalysis of the Effect of Hormone Therapy on Non-vertebral Fracture Rates

Hazard Ratio 95% CI

All Trials 0.73 0.56-0.94

Women < 60 y.o. 0.67 0.46-0.98

Women > 60 y.o. 0.88 0.71-1.08

JAMA 2001; 285: 2891-2897

Baseline Characteristics of Women In the WHI E+P Trial

Characteristic E+P Placebo P value

Age at screening (%)

50-59 33.4 33.1

60-69 45.3 45.1 .80

70-79 21.3 21.7

BMI (kg/m2) < 25 30.4 30.8 .89

Current Smoking 10.5 10.5 .85

Nulliparity 10.1 10.3 .67

No Prior Hormone Use

73.9 74.4 .49

>1 Fall in last 12 mo 33.8 32.5 .18

Fracture at > 55 13.5 13.6 .87

Prevalence of Osteoporosis at the Total Hip among E+P Participants* by Age

Age

Pe

rce

nt

* BMD subset of E+P cohort (n= 1025)

Clinical Fracture Outcomes as Annualized Percentage

60 41

788650

# of FX

62 44

An

nu

aliz

ed P

erce

nt

701

**

* All comparisons are significant

* *

579

Kaplan-Meier Estimates of Cumulative Hazards for Hip Fracture

0.0

0.01

0.02

0.03

0.04

0.05

0 1 2 3 4 5 6 7

Time (years)

E+PPlacebo

E+P 8506 8382 8299 8190 7073 4305 2116 826

Placebo 8102 8009 7915 7807 6659 3958 1763 525

HR 0.66 CI (0.45, 0.98)

Number of women at risk

Kaplan-Meier Estimates of Cumulative Hazards for Total Fractures

0.0

0.05

0.10

0.15

0 1 2 3 4 5 6 7

Time (years)

E+PPlacebo

E+P 8506 8236 8042 7827 6676 3991 1943 745

Placebo 8102 7856 7627 7361 6163 3593 1574 448

HR 0.76

CI (0.69, 0.85)

Number of women at risk

Hip Fracture Rate/1,000 women yearsAs a Function of Age Group

19 15

4027

# of FX

3 2

P >0.5

(33%) (45%) (22%)

(age distribution)

All Fracture Rate/1,000 women years As a Function of Age Group

*

**p<0.01

**

189171

372295

227184

# of FX

(33%) (45%) (22%)

(age distribution)

*p<0.05

Hip Fracture Rate/1,000 women yearsAs a Function of BMI

**p<0.05

BMI kg/m2

2916

2314

1014

# of FX

All Fracture Rate/1,000 women years As a Function of BMI

* *p<0.01

*

BMI kg/m2

272215

275208

235222

# of FX

Overall Efficacy of E+P on Risk for Osteoporotic Fracture

• Estrogen +progestin reduces the rate of hip and clinical vertebral fractures by approximately one-third

• There was also an approximate one-fourth reduction for other osteoporotic fractures and total fractures

• There was a trend toward a larger treatment effect in older women but this was only significant for total fractures

• There is a stronger treatment effect in women with lower BMI for both hip and total fractures

Prevention and Treatment Options for Osteoporosis

Ca Balance Antiresorptive Anabolic

Calcium Hormone Therapy GH

Ergocalciferol Raloxifene PTH

Calcitriol Alendronate IGF-1

Thiazides Risedronate Fluoride

Calcitonin Statins (?)

Etidronate

Pamidronate

Conclusion

Although estrogen and progestin are effective for the prevention and treatment of osteoporosis, the substantial risks for CVD and breast cancer must be weighed against the benefit for fracture reduction in selecting from among the therapeutic agents that can prevent and treat osteoporosis