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Androgen Deprivation Therapy and Bone Loss in Men With Prostate Cancer. William K. Oh, MD Associate Professor of Medicine Harvard Medical School Clinical Director, Lank Center for GU Oncology Dana-Farber Cancer Institute Boston, Massachusetts. Osteoporosis. - PowerPoint PPT Presentation
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Androgen Deprivation Therapy and Bone Loss in Men With Prostate Cancer
William K. Oh, MDAssociate Professor of Medicine
Harvard Medical School
Clinical Director, Lank Center for GU Oncology
Dana-Farber Cancer Institute
Boston, Massachusetts
Osteoporosis
National Institutes of Health Consensus Definition
“Osteoporosis is defined as a skeletal
disorder characterized by compromised bone
strength predisposing to an increased risk of
fracture.”
Osteoporosis Prevention, Diagnosis, and Therapy. NIH ConsensusStatement Online. 2000 March 27-29;17[27-29;17:1-36].
Osteoporosis in Men in the United States
2 million men with osteoporosis
8 million men with osteopenia
1 in 4 lifetime fracture risk for men over
the age of 50 years
Disease Statistics: Fast Facts. Washington, DC: NationalOsteoporosis Foundation.
Diagnosis of Bone Loss
Bone mineral density (BMD) testing
- DEXA (dual-energy x-ray absorptiometry) scan
- Quantitative CT (computed tomography) scan or
ultrasound
WHO-defined T-score (SD below normal)
- Normal: +1 < T ≤ -1
- Osteopenia: -1 < T < -2.5
- Osteoporosis: T ≤ -2.5
Older age Smoking Alcohol abuse Inactive lifestyle Chronic glucocorticoid therapy Hypogonadism
- Low testosterone and estrogen
Disease Statistics: Fast Facts. Washington, DC: NationalOsteoporosis Foundation.
Causes of Acquired Osteoporosis in Men
Increasing Androgen Deprivation Therapy (ADT) Use
Barry MJ, et al. BJU Int. 2006;98:973-978.
ADT Toxicity Is Significant
Hot flashes
Loss of libido
Weight gain
Decreased muscle mass
Accelerated osteoporosis
Increased bone fractures
Decreased cognitive
function
Increased diabetes mellitus
Altered lipid profile
Increased cardiovascular risk
-5
-4
-3
-2
-1
0
1
2
Control
LHRH Agonist
LumbarSpine
TotalHip
P < .001 for each comparison
% C
han
ge
in
Bo
ne
Min
eral
Den
sity
LHRH Agonists Decrease BMD in Men With Prostate Cancer
12-month data
Mittan D, et al. J Clin Endocrinol Metab. 2002;87:3656-3661.
Relationship Between BMD and Rates of Vertebral Fracture
Eastell R. N Engl J Med. 1998;338:736-746.
Proportion of Men With Fractures1-5 Years After Cancer Diagnosis
0
3
6
9
12
15
18
Any Fracture Fracture Resulting in Hospitalization
Fre
qu
en
cy (
%)
+2.8%; P < .001
+6.8%; P < .001
ADT (n = 6650)
No ADT (n = 20,035)
12.6
21
5.2
19.4
2.4
Shahinian VB, et al. N Engl J Med. 2005;352:154-164.
Years After Diagnosis
Un
adju
sted
Fra
ctu
re-F
ree
Su
rviv
al (
%)
No androgen deprivation (n = 32,931)
LHRH agonist, 1-4 doses (n = 3763)
LHRH agonist,≥ 9 doses(n = 5061)
Orchiectomy(n = 3399)
LHRH agonist,5-8 doses(n = 2171)
100
40
60
80
50
70
90
1 2 3 4 5 6 7 8 9 10
Fracture-Free Survival Decreases With Cumulative ADT Exposure
Shahinian VB, et al. N Engl J Med. 2005;352:154-164.
Overall Survival
Months
Cu
mu
lati
ve P
rop
ort
ion
Su
rviv
ing
History of fractureNo history of fracture (P = .04, log rank)
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 20 40 60 80 100 120 140 160 180 200
Fractures and Increased Mortality in Patients With Prostate Cancer
N = 195
Oefelein MG, et al. J Urol. 2002;168:1005-1007.
Prevention of Bone Loss in Patients Receiving ADT
Men on ADT should take calcium 1200-1500 mg/day and vitamin D 800-1000 IU/day
A series of trials have shown that bisphosphonates can prevent bone loss associated with ADT use
- Pamidronate
- Zoledronic acid every 3 months and annually
- Alendronate
Pamidronate Prevents Bone Loss During LHRH Agonist Therapy
-5
-4
-3
-2
-1
0
1
2
BM
D P
erce
nt C
hang
e
No pamidronatePamidronate
LumbarSpine
Total Hip
P < .005 for each comparison
12-month data
N = 47
Smith MR, et al. N Engl J Med. 2001;345:948-955.
Quarterly Zoledronic Acid Increases BMD During LHRH Agonist Therapy
-4
-2
0
2
4
6
8
BM
D P
erc
ent Change
PlaceboZoledronic acid
Lumbarspine
Total hip
P < .001 for each comparison
12-month data
N = 106
Smith MR, et al. J Urol. 2003;169:2008-2012.
Annual Zoledronic Acid Increases BMD During LHRH Agonist Therapy
-6
-4
-2
0
2
4
6
BM
D P
erc
ent Change
PlaceboZoledronic acid
Lumbarspine
Total hip
P < .005 for each comparison
12-month data
N = 40
Michaelson MD, et al. J Clin Oncol. 2006;25:1038-1042.
Alendronate to Prevent Bone Loss During LHRH Agonist Therapy
-3-2-101
23456
BM
D P
erc
ent Change
PlaceboAlendronate
Lumbarspine
Total hip
P < .05 for each comparison
12-month data
N = 112
LHRH = luteinizing hormone-releasing hormoneGreenspan SL, et al. Ann Intern Med. 2008;146:416-424.
Risks of Bisphosphonates
Flu-like symptoms (myalgias, fever)
Nausea
Fatigue
Renal toxicity
Osteonecrosis of the jaw
Estrogens Regulate BMD
ADT causes severe estrogen deficiency
Lower estrogen levels lead to decreased BMD
Selective estrogen receptor modulators (SERMs) activate ER-alpha in bone and increase BMD in castrated men
-4
-3
-2
-1
0
1
2
3
BM
D P
erc
ent Change
No raloxifene
Raloxifene
Lumbarspine
Total hip
P = .07 P < .001
12-month data
Raloxifene Increases BMD During LHRH Agonist Therapy
N = 48
Smith MR, et al. J Clin Endocrinol Metab. 2004;89:3841-3846.
Toremifene Fracture Prevention Study
RANDOMI ZE
Toremifene daily
for 2 yearsCurrent androgen deprivation therapy for
prostate cancer;Age > 70 or low BMD
(n = 1382)Placebo daily
for 2 years
Primary Endpoint: Incident vertebral fractures
Secondary Endpoints: BMD, lipids, breast symptoms, hot flashes
Toremifene 80 mg Increases Bone Mineral Density
-3
-2
-1
0
1
2
3
BM
D P
erc
ent Change
PlaceboToremifene
Lumbar spine
Total hip
P < .001 P = .001
12-month data
Smith MR, et al. J Urol. 2008;179:152-155.
Toremifene Decreases Risk for New Vertebral Fractures
0
1
2
3
4
5
6
Pe
rce
nt
(%)
PlaceboToremifene
Relative risk 0.46(95% CI 0.22, 0.95)P = .032
Smith MR, et al. Proceedings of the 99th Annual Meeting of the AACR. Abstract LB-241.
Events Toremifene Placebo
Total 17 7
First year 13 4
Second year 4 3
In subjects with major risk factors (high risk) 12 4
In subjects with no major risk factors, and < 2 minor risk factors (low risk)
3 2
Major risk factors include: > 80 years of age, history of VTE, recent surgery, recent bone fracture, and immobilization. Minor risk factors include: megestrol acetate use, metastatic disease, hypertension, hypercholesterolemia, cigarette smoking, obesity, diabetes.
Increased Risk for Venous Thromboembolic Events (VTE)
Summary
ADT predisposes to loss of bone mineral density and fractures
Treatment with bisphosphonates and SERMs is effective in preventing bone loss and, in some studies, fractures
Optimal timing of therapy remains uncertain and requires taking into account baseline BMD, underlying risks, and planned duration of ADT
Suggestions
Baseline DEXA in men initiating ADT
Calcium/vitamin D supplements
Exercise; alcohol and smoking cessation
Treat osteoporosis with bisphosphonates
Consider treating osteopenia if starting long-term ADT with fracture risks
Monitor BMD every 1-2 years
Saad F, et al. J Clin Oncol. 2008;26:5465-5476.
1. Assess risk factors for osteoporosis and fractures:
Major Risk Factors-Prior fragility fracture (> 40 years of age)*
-Age (> 65 years)*
-Low bone mineral density (T-score < -2.5)*
-Family history of osteoporotic fracture*
-Vertebral compression fracture
-Osteopenia apparent on X-ray film
-Hypogonadism
-Early menopause (before age 45)
Minor Risk Factors-Rheumatoid arthritis
-Low dietary calcium intake
-Smoker
-Excessive alcohol intake
-Excessive caffeine intake (> 4 cup/day)
-Weight (< 57 kg)
-Weight loss > 10% of weight at age 25
*Key Fracture Risk Factors
2. Dual energy x-ray absorptiometry (DEXA) scans at baseline.
3. Thoracic and lumbar spine x-rays to rule out vertebral fracture in patients with kyphosis, historic height loss ≥ 6 cm, acute incapacitating back pain syndrome, and in patients 65 years and older.
4. “Bone hygiene” measures: lifestyle modification that promotes bone health, such as:
-Calcium
-Vitamin D (1000 IU/day)
-Smoking cessation
-Modest alcohol (< 2 units per day)
-Increase exercise activity
5. Consider bisphosphonate therapy if T-score ≤ -2.5, or higher but risk factors for fracture present.
6. DXA scans every 1-2 years.
Management of Bone Health in Patients on ADT
Recommended