Osteoporosis Management:

1
Osteoporosis Management What Does the Data
Support?
Osteoporosis Definition 2001 Compromised bone
strength predisposing to increased risk of
fragility fractures
2
Osteoporosis - DiagnosisFragility Fractures

• Spine 700,000/year in US
• Hip 300,000/year in US
• Wrist 250,000/year in US

3
Osteoporosis - DiagnosisBone Densitometry
Criteria

• Normal T-score gt -1.0
• Osteopenia T-score -1.0 to -2.5
• Osteoporosis T-score lt -2.5

Established in Postmenopausal Women
4
Bone Densitometry Report
T-score
Age (years)
20
30
40
50
60
70
80
90
100
SD (T-score)
T-score -3.0
x
T-score predicts fracture risk
5
Who to Treat?
All Patients With Existing Osteoporotic Fractures
(Hip, Spine, Wrist) or . . .
National Osteoporosis Foundation. Washington, DC.
1998.
6
Who to Treat?
T-Score Below -2.0 -1.5 to -2.0 Above -1.5
Therapy Decision High Risk Treat Moderate
Risk Treat if other risk factors Low Risk Check
again in 1-2 years
Based on measurements from central DXA.
National Osteoporosis Foundation. Washington, DC.
1998.
7
Case Presentation
A 56 year old woman inquires about her
osteoporosis risk. No prior fractures. PMH
negative Family Hx mother - osteoporosis Dietary
calcium 600 mg/day Meds calcium 600 mg/day,
vitamins PE Ht 57 128 lb. no
kyphosis BMD T-score Z-score Spine
(L2-L4) -1.91 -1.31 Femoral Neck -1.68
-1.08
8
What does the data support?
T-Score Below -2.0 -1.5 to -2.0 Above -1.5
Therapy Decision High Risk Treat Moderate
Risk Treat if other risk factors Low Risk Check
again in 1-2 years
Based on measurements from central DXA.
National Osteoporosis Foundation. Washington, DC.
1998.
9
Treatment of Patients with OsteopeniaClinical
Fracture Prevention - Alendronate
37 Reduction
P0.044
60 Reduction
P0.005
Osteoporosis
Osteopenia
Black et al, ASBMR M352 2002
10
Case Presentation
A 75 year old woman with 2 past vertebral
fractures. No back pain at present. PMH HTN,
DJD Fam Hx no osteoporosis Dietary calcium 300
mg/day Meds lisinopril, calcium 500 mg/day,
vitamins PE Ht 54 116 lb. dorsal
kyphosis BMD T-score Z-score Spine
(L2-L4) -3.69 -1.42 Femoral Neck -2.98
-1.01
11
What does the data support?
T-Score Below -2.0 -1.5 to -2.0 Above -1.5
Therapy Decision High Risk Treat Moderate
Risk Treat if other risk factors Low Risk Check
again in 1-2 years
Based on measurements from central DXA.
National Osteoporosis Foundation. Washington, DC.
1998.
12
OsteoporosisNon-Pharmacological Measures

• Calcium 1500 mg/day
• Vitamin D 400-800 units/day
• Exercise
• Aerobic
• Resistance
• Hip Protectors
• Fall Prevention
• Habit Alteration (cigarettes, alcohol)

13
OsteoporosisNon-Pharmacological Measures

• Calcium 1500 mg/day
• Vitamin D 400-800 units/day
• Exercise
• Aerobic
• Resistance
• Hip Protectors
• Fall Prevention
• Habit Alteration (cigarettes, alcohol)

14
Dietary Calcium Intake Estimate

• 300 mg calcium in general diet
• 300 mg calcium in every dairy serving
• 1 cup of milk
• 1 oz. of cheese
• 1 cup of yogurt
• 1 cup of calcium fortified citrus drink

15
Calcium SupplementsSolubility and Absorption
352 calcium absorption studies in normal
subjects Double isotope (45Ca, 47Ca) or single
isotope (45Ca)
Fractional Fractional Solubility
Absorption Absorption Preparation
(mM/liter) w Meal w/o Meal Calcium
carbonate 0.14 30
24 Tricalcium phosphate 0.97
25 Calcium citrate 7.3
24 Calcium citrate malate 80 36
Heaney R, Calc Tissue Int 1990 46300-304
16
Osteoporosis TreatmentCalcium Supplementation
RCT 197 healthy women (mean age 73.5 yr.)(lt 1
gm Ca/day) Previous fracture (n94) No
previous fracture (n103) Calcium carbonate
(1,200 mg/d) vs. Placebo x 4 years
42 reduction
Who Fractured
P.023
No reduction
P.435
Recker R, J Bone Min Res 1996 111961-6
17
OsteoporosisNon-Pharmacological Measures

• Calcium 1500 mg/day
• Vitamin D 400-800 units/day
• Exercise
• Aerobic
• Resistance
• Hip Protectors
• Fall Prevention
• Habit Alteration (cigarettes, alcohol)

18
Osteoporosis TreatmentVitamin D Supplementation
RCT 389 ambulatory subjects (mean age 71 yr
213 F, 176 M) Vitamin D (700 U/d) Calcium (500
mg/d) vs. Placebo
Who Fractured
55 reduction
P.02
Dawson-Hughes, NEJM 1997 337670-6
19
Osteoporosis TreatmentCalcium and Vitamin D
RCT 3270 healthy elderly women (mean age 84
yr.) Calcium (1,200 mg/d) Vitamin D (800
U/d) vs. Control
32 reduction
Number of Fractures
P.015
43 reduction
P.043
Chapuy M, NEJM 1992 3271637-42
20
OsteoporosisNon-Pharmacological Measures

• Calcium 1500 mg/day
• Vitamin D 400-800 units/day
• Exercise
• Aerobic
• Resistance
• Hip Protectors
• Fall Prevention
• Habit Alteration (cigarettes, alcohol)

21
Osteoporosis TreatmentExercise
RCT 39 women, sedentary, no estrogen (Age 50-70
yr.) Strength training (n20) vs. Controls
(n19) for 1 year
P.04
P.03
P.02
BMD Change ()
Muscle Mass Change (Kg)
Control
Exercise
Control
Exercise
Nelson M, JAMA 1994 2721909-14
22
OsteoporosisNon-Pharmacological Measures

• Calcium 1500 mg/day
• Vitamin D 400-800 units/day
• Exercise
• Aerobic
• Resistance
• Hip Protectors
• Fall Prevention
• Habit Alteration (cigarettes, alcohol)

23
Osteoporosis TreatmentHip Protectors
RCT 1801 elderly adults (mean age 82 yr.) (1409
F, 392 M) Hip protector group (n653) vs.
Control group (n1148)
Hip Fractures per 1000 patient years
60 reduction
P .008
Kannus P, NEJM 2000 3431506-13
24
OsteoporosisNon-Pharmacological Measures

• Calcium 1500 mg/day
• Vitamin D 400-800 units/day
• Exercise
• Aerobic
• Resistance
• Hip Protectors
• Fall Prevention
• Habit Alteration (cigarettes, alcohol)

25
Osteoporosis TreatmentFall Prevention
RCT 402 Nursing home residents (age gt 65 yr.
median 83 yr.) Multiple Risk Factor Intervention
(n194) vs. Control (n208)
Who Fell
Who Fractured Hip
22 reduction
77 reduction
Jensen J, Ann Intern Med 2002 136733-41
26
Bone Remodeling
27
Osteoporosis Treatment
Anti-Resorptive Agents Bisphosphonates Raloxifene
Calcitonin Estrogens
Anabolic Agents Parathyroid hormone Growth
hormone Testosterone Fluoride
28
Osteoporosis Treatment
Anti-Resorptive Agents Bisphosphonates Raloxifene
Calcitonin Estrogens
Anabolic Agents Parathyroid hormone Growth
hormone Testosterone Fluoride
29
Womens Health Initiative - HRTVertebral
Fracture Prevention
RCT 16,608 postmenopausal women treated with
Premarin Provera for 5.2 years baseline bone
status unknown
Placebo
1.0
HRT
Women With New Vertebral Fracture
Nominal 95 CI 0.44-0.98 Adjusted 95
CI 0.32-1.34
0.75
34
0.50
0.25
N60
N41
0
Writing Group. JAMA. 2002288(3)321333.
30
Womens Health Initiative - HRTHip Fracture
Prevention
RCT 16,608 postmenopausal women treated with
Premarin Provera for 5.2 years baseline bone
status unknown
Placebo
1.0
HRT
Women With New Hip Fracture
Nominal 95 CI 0.45-0.98 Adjusted 95
CI 0.33-1.33
34
0.75
0.50
0.25
N62
N44
0
Writing Group. JAMA. 2002288(3)321333.
31
Osteoporosis Treatment
Anti-Resorptive Agents Bisphosphonates Raloxifene
Calcitonin Estrogens
Anabolic Agents Parathyroid hormone Growth
hormone Testosterone Fluoride
32
Calcitonin PROOF Study Vertebral Fracture
Prevention
RCT 1255 women with PMO and vertebral fracture
treated for 5 years
Placebo
40
100 IU/day
200 IU/day
Women With? 1 New VertebralFracture
30
400 IU/day
33
20
10
N70
N51
N59
N61
0
Relative risk reduction, P0.03 vs placebo. N
number of women with new fracture.
Chesnut CH, Am J Med.
2000109267-276
33
Osteoporosis Treatment
Anti-Resorptive Agents Bisphosphonates Raloxifene
Calcitonin Estrogens
Anabolic Agents Parathyroid hormone Growth
hormone Testosterone Fluoride
34
Raloxifene MORE Study Vertebral Fracture
Prevention

• RCT 7705 women with PMO, with and without
  vertebral fracture, treated for 3 years

30
Women With New VertebralFracture
50
N163
N113
N68
N35
Preexisting Fractures
No Preexisting Fractures
Plt0.05. N number of women with
new fracture. Ettinger B,
JAMA. 1999282637-645
35
Osteoporosis Treatment
Anti-Resorptive Agents Bisphosphonates Raloxifene
Calcitonin Estrogens
Anabolic Agents Parathyroid hormone Growth
hormone Testosterone Fluoride
36
Risedronate VERT NA Trial Vertebral Fracture
Reduction
RCT 2458 women with PMO and vertebral fracture
treated for 3 years
41
Women With New Vertebral Fracture
N93
N61
Relative risk reduction, P0.003 vs placebo.
N number of women with new fracture.
Harris ST, JAMA.
19992821344-1352
37
Risedronate Treatment Meta-analysis Fracture
Prevention
Vertebral Fx
Non-Vertebral Fx
0.64
?
Harris
?
0.64
Harris
?
1.52
Clemensen
?
0.70
0.76
?
Clemensen
McClung
?
0.62
Fogelman
?
0.69
Fogelman
?
0.71
Reginster
?
0.60
?
0.71
Reginster
McClung
?
?
Pooled Estimate
0.64 (0.54 - 0.77) (n2604)
0.73 (0.61 - 0.87) (n12958)
Cranney A, Endocrine Reviews 2002 23495-578
38
Risedronate Hip Study Hip Fracture Reduction
RCT 9331 women with PMO and/or non-skeletal risk
factors treated for 3 years
Low BMD Group 70-79 years old Osteoporosis Femora
l Neck T-Score lt -4 or Femoral Neck T-Score lt
-3 plus ?1 Risk Factor
Clinical Risk Factor(s) Group ?80 years old No
BMD Requirement ?1 Risk Factor or Femoral Neck
T-Score lt -4 Femoral Neck T-Score lt -3and Hip
Axis ?11.1 cm
McClung MR, N Engl J Med. 2001344333-340.
39
Risedronate Hip Study Hip Fracture Reduction
RCT 9331 women with PMO and/or non-skeletal risk
factors treated for 3 years
Women With Hip Fracture
30
40
N95 N137 N46 N55 N49 N82
Overall Low BMD Clinical Risk Factor(s)
Relative risk reduction P0.02 vs placebo
P0.009 vs placebo.N number of women with new
fracture. McClung MR, N Engl J Med.
2001344333-340.
40
Alendronate FIT Trial Vertebral Fracture
Prevention
RCT 2027 women with PMO and vertebral fracture
treated for 3 years
Women With New Vertebral Fracture
47
N145
N78
Relative risk reduction, Plt0.001. N number
of women with new fracture.
Black DM, Lancet. 19963481535-1541
41
Alendronate Treatment Meta-analysis Fracture
Prevention
Vertebral Fx
Non-Vertebral Fx
0.36
Adami
?
?
0.68
Bone
?
0.43
Chesnut
?
0.25
Chesnut
0.55
?
Liberman (USA)
?
0.52
Liberman (USA)
0.65
?
0.52
Liberman (INT)
?
Liberman (INT)
0.47
?
0.53
Black
?
Pols
0.35
?
0.51
Cummings
?
Rosen

?
0.51
Adami
(25.47)
?
0.53 (0.43 - 0.65) (n8005)
Pooled Estimate
?
0.49 (0.36-0.67) (n3456)
Cranney A, Endocrine Reviews 2002 23495-578
42
Alendronate FIT Trial Hip Fracture Prevention
RCT 2027 women with PMO and vertebral fracture
treated for 3 years
Women With HipFracture
51
N11
N22
Relative risk reduction, P0.047 vs placebo.
N number of women with new
fracture.
Black DM, Lancet. 19963481535-1541
43
Risedronate Weekly vs DailySpine and Hip BMD
No Fracture Data
1456 women with PMO and an existing vertebral
fracture treated for 1 year
Increasein BMD
N480
N485
N485
N480
N number of women with BMD measurement.
Lindsay R, November 2001. Abstract.
44
Alendronate Weekly vs Daily Spine and Hip BMD
No Fracture Data
1258 women with PMO and vertebral fracture
treated for 1 year
ChangeFrom Baselinein BMD
N370
N519
N519
N370
N number of women with BMD measurement.
Schnitzer T, Aging Clin Exp Res. 2000121-12

45
Intravenous BisphosphonatesVertebral BMD Change
Pamidronate 30 mg (250-500 cc NS) IV over 2
hours every 3 months
8
6
4
2
0
Pamidronate
Na Fluoride
Thiebaud D, Osteoporosis Int 476-83, 1994
46
Intravenous BisphosphonatesBMD Change
Zoledronate Intravenously
Spine
8
Hip
6
4
2
0
1 mg q 3mos
2 mg q 6mos
4 mg q year
Placebo
Reid IR, NEJM 346653-61, 2002
47
Osteoporosis TreatmentAlendronate added to
ongoing HRT
BMD Change
4
HRT Placebo
HRT Alend
2
0
Spine
Hip
Lindsay R, JCEM 843076-81, 1999
48
Osteoporosis Treatment
Anti-Resorptive Agents Bisphosphonates Raloxifene
Calcitonin Estrogens
Anabolic Agents Parathyroid hormone Growth
hormone Testosterone Fluoride
49
PTH Mode of Delivery Determines Bone Activity
Continuous exposure results in increased
osteoclastic bone resorption Intermittent
exposure results in increased osteoblast number
and bone formation.
Dobnig Turner. Endocrinology 19971384607-4612
50
PTH 1-34 Therapy 18 Month BMD Data
RCT 1637 postmenopausal women with previous
vertebral fractures PTH (n1093) vs placebo
(n544)
PTH 20 ug/d
PTH 40 ug/d
14
15 0
10
BMD Change
5
3
Spine
Spine
Hip
Hip
Neer R, NEJM 3441434, 2001
51
PTH 1-34 Therapy 18 Month Fracture Data
RCT 1637 postmenopausal women with previous
vertebral fractures PTH (n1093) vs placebo
(n544)
PTH 20 ug/d
PTH 40 ug/d
0 -75
Fracture Reduction
-35
-40
-65
-69
Spine
Spine
Non-spine
Non-spine
Neer R, NEJM 3441434, 2001
52
BMD Monitoring on Treatment
Response Patterns
Anti-resorptive Agent
Anabolic Agent
Least Significant Change
2.7 in Spine 5.7 in Hip
must be established for each instrument
53
Womens Health InitiativeHormone Replacement
Hypotheses
Risk
Benefit

• Additional Benefits
• Osteoporosis
• Colon Cancer
• Overall Mortality

• Additional Risks
• VTE

Writing Group. JAMA. 2002288321-333.
54
Womens Health InitiativeHormone Replacement
Design
(Age 50-79 mean 63 yr.)
Hysterectomy
YES N10,739
NO N16,608
Premarin0.625 mg/d
Placebo
Premarin/Provera 0.625/2.5 mg/d
Placebo
Study Duration 8.5 years with interim analysis at
5.2 years
Writing Group, JAMA 2002 288321-333
55
WHI HRT Study5.2 Year Findings in
Premarin/Provera Group
Risk
Benefit
29 Increase Coronary Artery Disease
41 Increase Stroke
26 Increase Breast Cancer
37 Colon Cancer reduction 34 Fracture
reduction
211 increase VTE
Early STOPClear Harm
Writing Group. JAMA. 2002288321-333.
56
Womens Health InitiativeInterim Analysis at 5.2
Years
Hysterectomy
YES N10,739
NO N16,608
Premarin0.625 mg/d
Placebo
Premarin/Provera 0.625/2.5 mg/d
Placebo
ERT Arm Continued
HRT Arm Stopped
Writing Group, JAMA 2002 288321-333
57
Womens Health InitiativeAttributable Risk of
HRT 5.2 Year Analysis
10,000 patient years (2000 patients treated for 5
years)

• Coronary Heart Disease 7 more cases
• Breast Cancer 8 more cases
• VTE 8 more cases
• Stroke 8 more cases
• Colon Cancer 6 fewer cases
• Hip Fracture 5 fewer cases

Writing Group. JAMA. 2002288(3)321333.
58
Womens Health InitiativeCaveats 5.2 Year
Analysis

• These results do not address
• Premarin alone (data analysis in 2005)
• Oral estradiol /- progesterone/norethindrone
• Patch estradiol /- progesterone/norethindrone
• Women under age 50
• Quality of Life

59
Vertebral Fracture Reduction RCTs in Women with
PMO and Vertebral Fractures
Raloxifene
Calcitonin
Estrogen
Risedronate
Alendronate
0
-10
-20
-30
30
33
-40
34
41
-50
47
PROOF
MORE
WHI
VERT-NA
FIT
Chesnut C, AM J Med 2000, 109267 Harris S,
JAMA 1999, 2821344 Ettinger B, JAMA 1999,
282637 Black D, Lancet 1996,
3481535 Writing Group, JAMA 2002, 288321
60
Hip Fracture Reduction RCTs in Women with PMO
Raloxifene
Calcitonin
Estrogen
Risedronate
Alendronate
0
-10
-20
-30
-40
34
40
-50
51
WHI
HIP
FIT
Writing Group, JAMA 2002, 288321 McClung M,
NEJM 2001, 344333 Black D, Lancet 1996,
3481535