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