osteoporosis management: what does the data support? osteoporosis definition 2001: compromised bone...
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Osteoporosis Management:What Does the Data Support?
Osteoporosis Definition 2001Osteoporosis Definition 2001: :
Compromised bone strength Compromised bone strength
predisposing to increased risk predisposing to increased risk
of fragility fracturesof fragility fractures
Osteoporosis - DiagnosisFragility Fractures
Spine ~ 700,000/year in USSpine ~ 700,000/year in US
Hip ~ 300,000/year in USHip ~ 300,000/year in US
Wrist ~ 250,000/year in USWrist ~ 250,000/year in US
Normal Normal T-score > -1.0T-score > -1.0
Osteopenia Osteopenia T-score = -1.0 to -2.5T-score = -1.0 to -2.5
Osteoporosis Osteoporosis T-score < -2.5T-score < -2.5
Established in Postmenopausal Women
Osteoporosis - DiagnosisBone Densitometry Criteria
Bone Densitometry Report
-4.5-4
-3.5-3
-2.5-2
-1.5-1
-0.50
20 30 40 50 60 70 80 90 100Age (years)
SD
(T
-sco
re)
x
T-score
T-score = -3.0
T-score predicts fracture risk
Who to Treat?
All Patients With Existing Osteoporotic Fractures (Hip, Spine, Wrist) or . . .
National Osteoporosis Foundation. Washington, DC. 1998.
Who to Treat?
Therapy Decision
High Risk
Treat
Moderate Risk
Treat if other risk factors
Low Risk
Check again in 1-2 years
T-Score*
Below -2.0
-1.5 to -2.0
Above -1.5
National Osteoporosis Foundation. Washington, DC. 1998.
* Based on measurements from central DXA.
Case Presentation
A 56 year old woman inquires about her A 56 year old woman inquires about her osteoporosis risk. No prior fractures.osteoporosis risk. No prior fractures.PMH: negative PMH: negative Family Hx: mother - osteoporosisFamily Hx: mother - osteoporosisDietary calcium: 600 mg/dayDietary calcium: 600 mg/dayMeds: calcium 600 mg/day, vitaminsMeds: calcium 600 mg/day, vitaminsPE: Ht 5’7’’ 128 lb. no kyphosisPE: Ht 5’7’’ 128 lb. no kyphosis
BMD:BMD: T-scoreT-score Z-scoreZ-scoreSpine (L2-L4) -1.91Spine (L2-L4) -1.91 -1.31 -1.31Femoral NeckFemoral Neck -1.68 -1.68 -1.08 -1.08
What does the data support?
Therapy Decision
High Risk
Treat
Moderate RiskTreat if other risk factors
Low Risk
Check again in 1-2 years
T-Score*
Below -2.0
-1.5 to -2.0
Above -1.5
National Osteoporosis Foundation. Washington, DC. 1998.
* Based on measurements from central DXA.
0
0.5
1
T-Score <= -2.5 T-Score > -2.5
Ev
en
ts p
er
10
0 P
YR Placebo
Alendronate
Black et al, ASBMR M352 2002
37% Reduction
P=0.044
60% Reduction
P=0.005
Treatment of Patients with OsteopeniaClinical Fracture Prevention - Alendronate
Osteoporosis Osteopenia
Case Presentation
A 75 year old woman with 2 past vertebral A 75 year old woman with 2 past vertebral fractures. No back pain at present.fractures. No back pain at present.PMH: HTN, DJDPMH: HTN, DJD Fam Hx: no osteoporosisFam Hx: no osteoporosisDietary calcium: 300 mg/day Dietary calcium: 300 mg/day Meds: lisinopril, calcium 500 mg/day, Meds: lisinopril, calcium 500 mg/day, vitamins vitamins PE: Ht 5’4’’ 116 lb. dorsal kyphosisPE: Ht 5’4’’ 116 lb. dorsal kyphosis
BMD:BMD: T-scoreT-score Z-scoreZ-scoreSpine (L2-L4) -3.69Spine (L2-L4) -3.69 -1.42 -1.42Femoral NeckFemoral Neck -2.98 -2.98 -1.01 -1.01
Therapy Decision
High RiskTreat
Moderate Risk
Treat if other risk factors
Low Risk
Check again in 1-2 years
T-Score*
Below -2.0
-1.5 to -2.0
Above -1.5
National Osteoporosis Foundation. Washington, DC. 1998.
* Based on measurements from central DXA.
What does the data support?
OsteoporosisNon-Pharmacological Measures
Calcium: 1500 mg/dayCalcium: 1500 mg/day Vitamin D: 400-800 units/dayVitamin D: 400-800 units/day ExerciseExercise
AerobicAerobic ResistanceResistance
Hip ProtectorsHip Protectors Fall Prevention Fall Prevention Habit Alteration (cigarettes, alcohol)Habit Alteration (cigarettes, alcohol)
OsteoporosisNon-Pharmacological Measures
Calcium: 1500 mg/dayCalcium: 1500 mg/day Vitamin D: 400-800 units/dayVitamin D: 400-800 units/day ExerciseExercise
AerobicAerobic ResistanceResistance
Hip ProtectorsHip Protectors Fall Prevention Fall Prevention Habit Alteration (cigarettes, alcohol)Habit Alteration (cigarettes, alcohol)
Dietary Calcium Intake Estimate
300 mg calcium in general diet300 mg calcium in general diet 300 mg calcium in every dairy serving300 mg calcium in every dairy serving
1 cup of milk1 cup of milk1 oz. of cheese1 oz. of cheese1 cup of yogurt1 cup of yogurt1 cup of calcium fortified citrus drink1 cup of calcium fortified citrus drink
Calcium SupplementsSolubility and Absorption
Heaney R, Calc Tissue Int 1990; 46:300-304
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%
352 calcium absorption studies in normal subjectsDouble isotope (45Ca, 47Ca) or single isotope (45Ca)
0
10
20
30
40
50
60
Previous Fracture No Previous Fracture
PlaceboCalcium
Osteoporosis TreatmentCalcium Supplementation
RCT: 197 healthy women (mean age: 73.5 yr.)(< 1 gm Ca/day) Previous fracture (n=94); No previous fracture (n=103) Calcium carbonate (1,200 mg/d) vs. Placebo x 4 years
Recker R, J Bone Min Res 1996; 11:1961-6
% WhoFractured
P=.023
P=.435
42% reduction
No reduction
OsteoporosisNon-Pharmacological Measures
Calcium: 1500 mg/dayCalcium: 1500 mg/day Vitamin D: 400-800 units/dayVitamin D: 400-800 units/day ExerciseExercise
AerobicAerobic ResistanceResistance
Hip ProtectorsHip Protectors Fall Prevention Fall Prevention Habit Alteration (cigarettes, alcohol)Habit Alteration (cigarettes, alcohol)
0
2
4
6
8
10
12
14
Nonvertebral Fracture
PlaceboCalcium + Vitamin D
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
Dawson-Hughes, NEJM 1997; 337:670-6
% WhoFractured
P=.02
55% reduction
0
20
40
60
80
100
120
Hip Fracture NonvertebralFracture
ControlCalcium + Vitamin D
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
Chapuy M, NEJM 1992; 327:1637-42
Numberof
Fractures
P=.043
P=.015
43% reduction
32% reduction
OsteoporosisNon-Pharmacological Measures
Calcium: 1500 mg/dayCalcium: 1500 mg/day Vitamin D: 400-800 units/dayVitamin D: 400-800 units/day ExerciseExercise
AerobicAerobic ResistanceResistance
Hip ProtectorsHip Protectors Fall Prevention Fall Prevention Habit Alteration (cigarettes, alcohol)Habit Alteration (cigarettes, alcohol)
Osteoporosis TreatmentExercise
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Nelson M, JAMA 1994; 272:1909-14
Control Exercise
P=.03
RCT: 39 women, sedentary, no estrogen (Age: 50-70 yr.) Strength training (n=20) vs. Controls (n=19) for 1 year
-3
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
1.5
FemoralNeckLumbarSpine
Mu
scle
Mas
s C
han
ge (
Kg)
BM
D C
han
ge (
%)
Control Exercise
P=.02P=.04
OsteoporosisNon-Pharmacological Measures
Calcium: 1500 mg/dayCalcium: 1500 mg/day Vitamin D: 400-800 units/dayVitamin D: 400-800 units/day ExerciseExercise
AerobicAerobic ResistanceResistance
Hip ProtectorsHip Protectors Fall Prevention Fall Prevention Habit Alteration (cigarettes, alcohol)Habit Alteration (cigarettes, alcohol)
Osteoporosis TreatmentHip Protectors
05
10152025
3035404550
Control Hip Protector
Hip Fracturesper 1000patient years
Kannus P, NEJM 2000; 343:1506-13
P = .008
60% reduction
RCT: 1801 elderly adults (mean age: 82 yr.) (1409 F, 392 M) Hip protector group (n=653) vs. Control group (n=1148)
OsteoporosisNon-Pharmacological Measures
Calcium: 1500 mg/dayCalcium: 1500 mg/day Vitamin D: 400-800 units/dayVitamin D: 400-800 units/day ExerciseExercise
AerobicAerobic ResistanceResistance
Hip ProtectorsHip Protectors Fall PreventionFall Prevention Habit Alteration (cigarettes, alcohol)Habit Alteration (cigarettes, alcohol)
Osteoporosis TreatmentFall Prevention
0
10
20
30
40
50
60
Control Intervention
Jensen J, Ann Intern Med 2002; 136:733-41
0
1
2
3
4
5
6
7
Control Intervention
% Who Fell % Who Fractured Hip
22% reduction 77% reduction
RCT: 402 Nursing home residents (age > 65 yr.; median 83 yr.)Multiple Risk Factor Intervention (n=194) vs. Control (n=208)
OCOB
OB
OBOldBone
NewBone
Ca P04
Bone Remodeling
OCOB
OB
OBOldBone
NewBone
Ca P04
Osteoporosis TreatmentAnti-Resorptive AgentsBisphosphonatesRaloxifeneCalcitoninEstrogens
Anabolic AgentsParathyroid hormoneGrowth hormoneTestosteroneFluoride
OCOB
OB
OBOldBone
NewBone
Ca P04
Osteoporosis TreatmentAnti-Resorptive AgentsBisphosphonatesRaloxifeneCalcitoninEstrogens
Anabolic AgentsParathyroid hormoneGrowth hormoneTestosteroneFluoride
Women’s Health Initiative - HRTVertebral Fracture Prevention
RCT: 16,608 postmenopausal women treated with Premarin + Provera for 5.2 years – RCT: 16,608 postmenopausal women treated with Premarin + Provera for 5.2 years – baseline bone status unknownbaseline bone status unknown
0
0.25
0.50
0.75
PlaceboHRT
N=60 N=41
% Women
With New Vertebral Fracture
1.0
34%*
Nominal 95% CI:0.44-0.98
Adjusted 95% CI:0.32-1.34
Writing Group. JAMA. 2002;288(3):321–333.
Women’s Health Initiative - HRTHip Fracture Prevention
RCT: 16,608 postmenopausal women treated with Premarin + Provera for 5.2 years – RCT: 16,608 postmenopausal women treated with Premarin + Provera for 5.2 years – baseline bone status unknownbaseline bone status unknown
Nominal 95% CI:0.45-0.98
Adjusted 95% CI:0.33-1.33
Writing Group. JAMA. 2002;288(3):321–333.
0
0.25
0.50
0.75
PlaceboHRT
N=62 N=44
1.0
34%*%
Women With New
HipFracture
OCOB
OB
OBOldBone
NewBone
Ca P04
Osteoporosis TreatmentAnti-Resorptive AgentsBisphosphonatesRaloxifeneCalcitoninEstrogens
Anabolic AgentsParathyroid hormoneGrowth hormoneTestosteroneFluoride
0
10
20
30
40 Placebo
100 IU/day
200 IU/day
400 IU/day
RCT: 1255 women with PMO and vertebral fracture treated for 5 yearsRCT: 1255 women with PMO and vertebral fracture treated for 5 years
Calcitonin: PROOF Study Vertebral Fracture Prevention
* Relative risk reduction, P=0.03 vs placebo. N = number of women with new fracture.
Chesnut CH, Am J Med. 2000;109:267-276
33%*%
Women With 1 New VertebralFracture
N=70 N=51N=59 N=61
OCOB
OB
OBOldBone
NewBone
Ca P04
Osteoporosis TreatmentAnti-Resorptive AgentsBisphosphonatesRaloxifeneCalcitoninEstrogens
Anabolic AgentsParathyroid hormoneGrowth hormoneTestosteroneFluoride
0
5
10
15
20
25Placebo
Raloxifene (60 mg/day)
Raloxifene: MORE Study Vertebral Fracture PreventionRCT: 7705 women with PMO, with and without vertebral RCT: 7705 women with PMO, with and without vertebral fracture, treated for 3 yearsfracture, treated for 3 years
30%*% Women
With New VertebralFracture
Preexisting Fractures*P<0.05. N = number of women with new fracture.
Ettinger B, JAMA. 1999;282:637-645
N=163
50%*N=113 N=68 N=35
No Preexisting Fractures
OCOB
OB
OBOldBone
NewBone
Ca P04
Osteoporosis TreatmentAnti-Resorptive AgentsBisphosphonatesRaloxifeneCalcitoninEstrogens
Anabolic AgentsParathyroid hormoneGrowth hormoneTestosteroneFluoride
0
10
20Placebo Risedronate (5 mg/day)
RCT: 2458 women with PMO and vertebral fracture treated for 3 yearsRCT: 2458 women with PMO and vertebral fracture treated for 3 years
* Relative risk reduction, P=0.003 vs placebo. N = number of women with new fracture.
Harris ST, JAMA. 1999;282:1344-1352
Risedronate: VERT NA Trial Vertebral Fracture Reduction
% Women
With New Vertebral Fracture
41%*
N=93 N=61
Vertebral Fx
0.69
Non-Vertebral Fx
Harris0.64
Pooled Estimate0.64 (0.54 - 0.77) (n=2604)
0.60
0.70
0.64 Harris
Clemensen
Fogelman
Reginster
0.73 (0.61 - 0.87) (n=12958)
1.52
0.76 0.620.710.71
ClemensenMcClungFogelmanReginsterMcClung
Risedronate Treatment Meta-analysisRisedronate Treatment Meta-analysis Fracture PreventionFracture Prevention
Cranney A, Endocrine Reviews 2002; 23:495-578
36% 27%
Low BMD Group
70-79 years oldOsteoporosis
Femoral Neck T-Score < -4or
Femoral Neck T-Score < -3plus 1 Risk Factor
Clinical Risk Factor(s) Group
80 years oldNo BMD Requirement
1 Risk Factor or
Femoral Neck T-Score < -4Femoral Neck T-Score < -3
and Hip Axis 11.1 cm
RCT: 9331 women with PMO and/or non-skeletal risk factors treated for 3 years
McClung MR, N Engl J Med. 2001;344:333-340.
Risedronate: Hip Study Hip Fracture Reduction
0
2
4
6Placebo
Risedronate (2.5 and 5 mg/day)
Relative risk reduction: * P=0.02 vs placebo; ** P=0.009 vs placebo.N = number of women with new fracture.
McClung MR, N Engl J Med. 2001;344:333-340.
Overall Low BMD Clinical Risk Factor(s)
30%*40%**
% Women
With Hip Fracture
N=95 N=137 N=46 N=55 N=49 N=82
RCT: 9331 women with PMO and/or non-skeletal risk factors treated for 3 years
Risedronate: Hip Study Hip Fracture Reduction
0
10
20Placebo
Alendronate (5 mg/day [2 years] + 10 mg/day [1 year])
Alendronate: FIT Trial Vertebral Fracture Prevention
% Women
With New Vertebral Fracture
* Relative risk reduction, P<0.001.N = number of women with new fracture.
Black DM, Lancet. 1996;348:1535-1541
RCT: 2027 women with PMO and vertebral fracture treated for 3 yearsRCT: 2027 women with PMO and vertebral fracture treated for 3 years
47%*
N=145 N=78
Alendronate Treatment Meta-analysisAlendronate Treatment Meta-analysis Fracture PreventionFracture Prevention
0.36
Vertebral Fx Non-Vertebral Fx
Cranney A, Endocrine Reviews 2002; 23:495-578
0.51
0.510.530.520.520.250.68
0.53 (0.43 - 0.65) (n=8005)
Pooled Estimate
ChesnutBone
Liberman (USA)Liberman (INT)
Adami
Black
0.55
0.49 (0.36-0.67) (n=3456)
0.43
0.650.470.35 Rosen
AdamiChesnut
Liberman (USA)
Liberman (INT)
PolsCummings
(25.47)
47% 51%
0
1
2
3Placebo
Alendronate (5 mg/day [2 years] +10 mg/day [1 year])
51%*
% Women
With HipFracture
* Relative risk reduction, P=0.047 vs placebo. N = number of women with new fracture.
Black DM, Lancet. 1996;348:1535-1541
N=22 N=11
Alendronate: FIT Trial Hip Fracture Prevention
RCT: 2027 women with PMO and vertebral fracture treated for 3 yearsRCT: 2027 women with PMO and vertebral fracture treated for 3 years
0
1
2
3
4
5
Lumbar Spine Femoral Neck (Hip)
Risedronate (5 mg/day)
Risedronate (35 mg/week)
Risedronate: Weekly vs DailySpine and Hip BMD No Fracture Data
% Increasein BMD
Lindsay R, November 2001. Abstract.
1456 women with PMO and an existing vertebral fracture treated for 1 year
N = number of women with BMD measurement.
N=480 N=485 N=485N=480
0
1
2
3
4
5
6
Spine Femoral Neck (Hip)
Alendronate (10 mg/day)
Alendronate (70 mg/week)
Alendronate: Weekly vs Daily Spine and Hip BMD No Fracture Data
% Change
From Baselinein BMD
N = number of women with
BMD measurement. Schnitzer T, Aging Clin Exp Res. 2000;12:1-12
1258 women with PMO and vertebral fracture treated for 1 year1258 women with PMO and vertebral fracture treated for 1 year
N=370 N=519 N=519N=370
Intravenous BisphosphonatesVertebral BMD Change
8%
6%
4%
2%
0%PamidronateNa Fluoride
Pamidronate 30 mg (250-500 cc NS) IV over 2 hours every 3 months
Thiebaud D, Osteoporosis Int 4:76-83, 1994
8%
6%
4%
2%
0%Placebo
Zoledronate Intravenously
Reid IR, NEJM 346:653-61, 2002
1 mg q 3mos
2 mg q 6mos
4 mg q year
Spine
Hip
Intravenous BisphosphonatesBMD Change
Osteoporosis TreatmentAlendronate added to ongoing HRT
4%
2%
0%
BMD Change
Lindsay R, JCEM 84:3076-81, 1999
HRT +Placebo
HRT +Alend
Spine Hip
OCOB
OB
OBOldBone
NewBone
Ca P04
Osteoporosis TreatmentAnti-Resorptive AgentsBisphosphonatesRaloxifeneCalcitoninEstrogens
Anabolic AgentsParathyroid hormoneGrowth hormoneTestosteroneFluoride
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 1997;138:4607-4612
RCT: 1637 postmenopausal women with previous vertebral fracturesPTH (n=1093) vs placebo (n=544)
BMDChange
PTH 1-34 Therapy 18 Month BMD Data
Neer R, NEJM 344:1434, 2001
15%
0%
+14%
HipSpine
+10%
+5%+3%
HipSpine
PTH 20 ug/d PTH 40 ug/d
RCT: 1637 postmenopausal women with previous vertebral fracturesPTH (n=1093) vs placebo (n=544)
FractureReduction
PTH 1-34 Therapy 18 Month Fracture Data
Neer R, NEJM 344:1434, 2001
0%
-75% -69%
Non-spineSpine
-65%-40%-35%
PTH 20 ug/d PTH 40 ug/d
Non-spineSpine
BMD Monitoring on Treatment
Response Patterns
Anti-resorptive Agent Anabolic Agent
Least Significant Change*
2.7% in Spine5.7% in Hip *must be established
for each instrument
Risk BenefitStroke
Coronary Artery DiseaseBreast Cancer
Plan to Study Until 2005
Additional Benefits:• Osteoporosis• Colon Cancer• Overall Mortality
Additional Risks:• VTE
Writing Group. JAMA. 2002;288:321-333.
Women’s Health InitiativeHormone Replacement Hypotheses
Women’s Health InitiativeHormone Replacement Design
Hysterectomy
Premarin0.625 mg/d
Placebo Premarin/Provera0.625/2.5 mg/d
YESN=10,739
NON=16,608
Placebo
(Age: 50-79; mean 63 yr.)
Study Duration8.5 years with interim analysis at 5.2 years
Writing Group, JAMA 2002; 288:321-333
26% Increase Breast Cancer
WHI HRT Study5.2 Year Findings in Premarin/Provera Group
211% increase VTE
37% Colon Cancer reduction 34% Fracture reduction
Early STOP=Clear Harm
29% Increase Coronary Artery
Disease41% Increase Stroke
Risk Benefit
Writing Group. JAMA. 2002;288:321-333.
Women’s Health InitiativeInterim Analysis at 5.2 Years
Hysterectomy
Premarin0.625 mg/d
Placebo Premarin/Provera0.625/2.5 mg/d
YESN=10,739
NON=16,608
Placebo
ERT ArmContinued
Writing Group, JAMA 2002; 288:321-333
HRT ArmStopped
Coronary Heart DiseaseCoronary Heart Disease 7 more cases 7 more cases Breast CancerBreast Cancer 8 more cases8 more cases VTEVTE 8 more cases8 more cases StrokeStroke 8 more cases8 more cases Colon CancerColon Cancer 6 fewer cases6 fewer cases Hip FractureHip Fracture 5 fewer cases5 fewer cases
Women’s Health InitiativeAttributable Risk of HRT – 5.2 Year Analysis
10,000 patient years (2000 patients treated for 5 years)
Writing Group. JAMA. 2002;288(3):321–333.
These results do not address:These results do not address:
Premarin alone (data analysis in 2005)Premarin alone (data analysis in 2005)
Oral estradiol +/- progesterone/norethindroneOral estradiol +/- progesterone/norethindrone
Patch estradiol +/- progesterone/norethindronePatch estradiol +/- progesterone/norethindrone
Women under age 50Women under age 50
Quality of LifeQuality of Life
Women’s Health InitiativeCaveats – 5.2 Year Analysis
Vertebral Fracture Reduction RCTs in Women with PMO and Vertebral Fractures
0%-10%-20%-30%-40%-50%
Calcitonin Raloxifene Estrogen Risedronate Alendronate
PROOF MORE WHI VERT-NA FIT
Chesnut C, AM J Med 2000, 109:267 Harris S, JAMA 1999, 282:1344Ettinger B, JAMA 1999, 282:637 Black D, Lancet 1996, 348:1535Writing Group, JAMA 2002, 288:321
33% 30%34%
41%47%
Hip Fracture Reduction RCTs in Women with PMO
0%-10%-20%-30%-40%-50%
Calcitonin Raloxifene Estrogen Risedronate Alendronate
WHI HIP FIT
Writing Group, JAMA 2002, 288:321 McClung M, NEJM 2001, 344:333 Black D, Lancet 1996, 348:1535
34%40%
51%