osteoporosis - prostate cancer

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

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