osteoporosis - prostate cancer
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Michael A. Carducci, MDAEGON Professor in Prostate Cancer ResearchJohns Hopkins Kimmel Cancer CenterBaltimore, Maryland
Preventing Osteoporotic Fractures in Men With Early-Stage Prostate Cancer
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Disclosure
Michael A. Carducci, MD, has disclosed that he has received consulting fees from Amgen, Bristol-Myers Squibb, and Novartis.
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Case 1
68-yr-old retired truck driver
High blood pressure; diabetes, noninsulin requiring
BMI: 32 (obese); nonsmoker; alcohol intake: 2-3 beers/day
Presents with PSA 50
DRE clinical stage T3b
TRUS: biopsies with Gleason 4 + 3 in 9 of 12 cores
No detectable metastases by bone scan and CT
After discussing options, patient decides on external beam radiation therapy + 3 yrs of ADT
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Would you recommend additional therapy to prevent bone loss/fractures?A. No, since I did not get a baseline BMD
B. Yes, regardless of baseline BMD
C. Yes, but only if he is osteoporotic
D. Yes, if he is osteopenic or osteoporotic
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ADT-Associated Bone Loss
Healthy men[1]
Early menopausal women[1]
Late menopausal women[1]
AI therapy in postmenopausal women[2]
Androgen deprivation therapy[4]
AI therapy + GnRH agonist[5]
Ovarian failure secondary to chemotherapy[6]
Bone marrow transplant[3]
0Lumbar Spine BMD Loss at 1 Yr (%)
2 4 6 8
0.5%
1.0%
2.0%
2.6%
3.3%
4.6%
7.0%
7.7%
1. Kanis JA. Osteoporosis. Blackwell Healthcare Communications Ltd; 1997. 2. Eastell R, et al. J Bone Mineral Res. 2002;17(suppl 2). Abstract 1170. 3. Lee WY, et al. J Clin Endocrinol Metab. 2002;87:329-335. 4. Maillefert JF, et al. J Urol. 1999;161:1219-1222. 5. Gnant M. Breast Cancer Res Treat. 2002; 76(suppl 1):S31. Abstract 12. 6. Shapiro CL, et al. J Clin Oncol. 2001;19:3306-3311.
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Proportion of Patients With Fractures1-5 Yrs After Cancer Diagnosis
0
3
6
9
12
15
18
Any Fracture Fracture Resulting in Hospitalization
Fre
qu
ency
(%
)
+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.
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Fractures Impact Mortality and Life Expectancy Hip fracture
– Affects life expectancy dramatically[1,2]
– Aged 60-69 yrs: 11.5 yrs of decreased life expectancy
– Aged 0-79 yrs: 5.0 yrs of decreased life expectancy
Vertebral facture
– Prevalence in men is high (20%)[3]
– Clinical consequences: pain, kyphosis, loss of height, respiratory problems [4,5]
– 4 x increased risk of subsequent fracture[6]
– Predict increased mortality in men with a 10-yr HR of 2.4 (95% CI: 1.6-3.9)[6,7]
1. Cree M, et al. J Am Geriatr Soc. 2000;48:283-288. 2. Center JR, et al. Lancet. 1999;353:878-882. 3. O’Neill TW, et al. J Bone Miner Res. 1996;11:1010-1018. 4. Matthis C, et al. Osteoporosis Int. 1998;8: 364-372. 5. Francis RM, et al. QJM. 2004;97:63-74. 6. Johnell O, et al. Osteoporos Int. 2004;15:175-179. 7. Lau E, et al. J Bone Joint Surg Am. 2008;90:1479-1486. 8. Hasserius R, et al. Osteoporos Int. 2003;14:61-68.
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Screening for Bone Loss in Men: Who Is at Risk?Demographic Factors 65 yrs of age or older
History Family history of osteoporotic fractureFragility fracture after 40 yrs of ageSignificant height loss
Lifestyle and Dietary Factors SmokingExcessive intake of alcohol or caffeine (> 4 cups/day)Inadequate dietary calcium intakeWeight < 57 kg (or loss of > 10% of weight at 25 yrs of age)
Physical Findings Vertebral deformity (eg, kyphosis) or osteopenia evident on x-ray
Diseases Associated With Bone Loss Prostate cancerCOPDMalabsorption syndromeHyperparathyroidismHyperthyroidismHypogonadismRheumatoid arthritisRenal insufficiencyVitamin D deficiency
Treatments Associated With Bone Loss ADTAnticonvulsantsHeparinSystemic glucocorticoids (duration > 3 mos)
Brown JP, et al. CMAJ. 2002;167:S1-S34. Greenspan SL. J Clin Endocrinol Metab. 2008;93:2-7.
Entries in bold are considered major risk factors.
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The FRAX® Index: Assessing Fracture Risk
Available at: http://www.sheffield.ac.uk/FRAX/. Image used with permission of the WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield. FRAX® is registered to Professor JA Kanis, University of Sheffield.
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Case 2
80-yr-old male with biochemically recurrent, nonmetastatic prostate cancer starting ADT for a PSA of 15
5′9″ (175.3 cm), 158 lbs (72.1 kg)
DEXA scan at baseline reveals T-score of -0.9 at the femoral neck of the left hip and -0.2 at the spine
Patient also has Crohn’s disease and frequently receives steroid treatment
Drinks 4 glasses of wine/day and is a 60 pack-yr cigarette smoker
No previous history of fracture
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In addition to lifestyle modification, would you also recommend bone-targeted therapy for this patient?
A. No
B. Yes, alendronate 70 mg/wk PO
C. Yes, denosumab 60 mg SC q6m
D. Yes, zoledronic acid 5 mg IV annually
E. Yes, zoledronic acid 4 mg IV annually
F. Yes, zoledronic acid 4 mg IV quarterly
Treatment Options
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Alendronate Increases BMD During GnRH Agonist Therapy
Greenspan SL, et al. Ann Intern Med. 2007;146:416-424.
-3
-2
-1
0
1
2
3
4
5
BM
D P
erce
nt
Ch
ang
e
AlendronatePlacebo
LumbarSpine
TotalHip
12-Mo Data
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Annual Zoledronic Acid Increases BMD During GnRH Agonist Therapy
Michaelson MD, et al. J Clin Oncol. 2007;25:1038-1042.
-6
-4
-2
0
2
4
6P < .005 for each comparison
Zoledronic acid 4 mg/yr IV Placebo
LumbarSpine
Final 12-Mo Data
BM
D P
erce
nt
Ch
ang
e
TotalHip
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Quarterly Zoledronic Acid Increases BMD During GnRH Agonist Therapy
LumbarSpine
TotalHip
Smith MR, et al. J Urol. 2003;169:2008-2012.
-4
-2
0
2
4
6
8P < .001 for each comparison
Final 12-Mo Data
Zoledronic acidPlacebo
BM
D P
erce
nt
Ch
ang
e
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Denosumab Increased BMD at All Skeletal Sites
1086420
-2-4-6
01 3 6 12 24 36Mos
Ch
an
ge
in
BM
D
Fro
m B
as
eli
ne
(%
)
C. Femoral Neck
Denosumab
Placebo
Difference at 24 mos,3.9 percentage points
1086420
-2-4-6
01 3 6 12 24 36Mos
Ch
an
ge
in
BM
D
Fro
m B
as
eli
ne
(%
) 86420
-2-4-6
01 3 6 12 24 36Mos
Ch
an
ge
in
BM
D
Fro
m B
as
eli
ne
(%
)
A. Lumbar Spine
Denosumab
Placebo
Difference at 24 mos,6.7 percentage points
Denosumab
Placebo
Difference at 24 mos,4.8 percentage points
B. Total Hip
86420
-2-4-6
01 3 6 12 24 36Mos
Ch
an
ge
in
BM
D
Fro
m B
as
eli
ne
(%
)
Placebo
Difference at 24 mos,5.5 percentage points
D. Distal Third of Radius
Smith MR, et al. N Engl J Med. 2009;361:745-755.
Denosumab
10
10
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Denosumab for Fracture Prevention
12Mos
24 36
P = .004 P = .004 P = .006
1.9
0.3
3.3
1.0
3.9
1.5
0
2
4
6
8
10
New
Ver
teb
ral
Fra
ctu
re (
%) Placebo
Denosumab
13 2 22 7 26 10Patientsat Risk, n
Smith MR, et al. N Engl J Med. 2009;361:745-755.
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Conclusions
Osteoporosis and fractures are an important health problem in older men
ADT for prostate cancer increases risks for osteoporosis and fractures
Some but not all men require drug therapy to prevent fractures during ADT
Effective therapies are available
– Bisphosphonates increase BMD
– Denosumab increases BMD and decreases vertebral fractures
Go Online for More Education on Bone Health
Interactive Decision Support Tools: Experts make treatment recommendations for patients with prostate or breast cancer
Optimizing Bone Health in Patients With Cancer: Proceedings of an Independent Expert Panel
Downloadable slides
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