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The silent risk of bone loss
How should we manage patients?
Carlos Rabaça
Serviço Urologia
IPOFG Coimbra
Patients With Prostate Cancer Have Many Factors
That Can Undermine Bone Health
Average
3 - 5 years
Advancing disease
PSA rising again
Average
7 years
Localized disease
New patient; PSA rising
Watchful waiting
Recurrent disease
Restage patient
PSA begins to rise
Consider chemotherapy
ADT usually initiated
Check for
bone metastases
Check for bone mets
Check for CTIBL
Treatment
Check for cancer or age-related
bone loss
Bone health is at risk throughout the disease course
PSA = Prostate-specific antigen; ADT = Androgen-deprivation therapy;
CTIBL = Cancer treatment-induced bone loss.
Adapted from Crawford ED. Eur Urol. 2004;3(suppl):10-15.
High Osteoporosis Incidence in Patients
Diagnosed With Advanced Prostate Cancer
• Prospective study of men with newly diagnosed prostate
cancer requiring hormone treatment (N = 280)
• Patients’ bone health is at risk even before initiation of ADT
Patients with newly
diagnosed advanced PC
Patients, %
50
46%
37%
40
42%
Age-matched controls
37%
27%
30
21%
20
10
0
Normal BMD
Osteopenia
Osteoporosis
BMD Assessmenta
ADT, androgen deprivation therapy; PC, prostate cancer; BMD, bone mineral density; DEXA, dual-energy x-ray absorptiometry.
a BMD measurements were performed by DEXA within 1 week of diagnosis and prior to treatment initiation.
Hussain SA, et al. BJU Int. 2003;92(7):690-694.
Metastatic Hormone-Resistant Prostate Cancer
ADT—bone loss
Metastases
Decreased bone strength
SKELETAL COMPLICATIONS
(SRE)
Almost all patients will experience bone complications!
Bone Loss During Androgen-Deprivation
Therapy in Patients With Prostate Cancer
Natural Distribution of PCa in Pre-PSA Era
Localized
Advanced
20 - 30%
10 - 40%
Radical
therapy
Metastatic
< 30%
Hormone
therapy (HT)
Natural Distribution of PCa in PSA Era
Localized
Advanced
40 - 60%
30 - 40%
Radical
therapy
Metastatic
< 5%
HT
LHRH agonist use
(patients receiving ≥1 dose of LHRH agonist
in first 6 months of diagnosis, %)
Increasing Use of Luteinizing Hormone-Releasing
Hormone (LHRH) Agonists
60
Stage I
Stage II
Stage III
Stage IV
Unknown stage
55
50
45
40
35
30
25
20
15
10
5
0
1991
1992
1993
1994
1995
1996
Year of diagnosis
Adapted from Shahinian VB, et al. Cancer. 2005;103(8):1615-1624.
1997
1998
1999
ADT reduces testosterone and oestrogen levels
Depletion of testosterone and oestrogen accelerates
bone resorption by osteoclasts
Bone Loss Is Accelerated With ADT
Yearly bone loss, %
6
4.6
5
4
3
2
1.0
1
0.5
0
Normal
men1
Postmenopausal
women1
ADT2
1. Kanis JA. Osteoporosis. Blackwell Healthcare Communications Ltd. 1997:22-55.
2. Maillefert JF, et al. J Urol. 1999;161:1219-1222.
Published series consistently show decreased
bone mineral density after one year of ADT
Bone loss is greatest during the first year of ADT
Characteristics of bone mass loss in prostate
cancer patients on ADT
ADT Significantly Increases Fracture Risk Among
Men With Prostate Cancer
Increased risk
1.21
Any fracture
21%
1.76
Hip fracture
76%
1.18
Vertebral fracture
18%
0
0.2
0.4
0.6
0.8
1
1.2 1.4
1.6
1.8
2
2.2
Relative risk
In favor of ADT
N = 3,779 PC patients
treated with GnRH agonist
Smith M, et al. J Urol. 2006;175:136-139.
In favor of no ADT
N = 8,341 PC patients
with no GnRH agonist
2.4
ADT increases risk of fracture
Pathologic Fractures Increase the Risk of Mortality
in Patients With Prostate Cancer
Risk
increase P value
1.29
29%
0
.04
0.2 0.4 0.6 0.8
1
1.2 1.4 1.6 1.8
Hazard ratio (patients)
Decreased mortality
Saad F, et al. Cancer. 2007; Aug 30 [Epub ahead of print].
Increased mortality
2
Fractures increase mortality
Fractures and post-fracture mortality in prostate
cancer patients receiving ADT
Bone loss due to ADT has clinically-significant
consequences
60% of men who survived > 30 days
after hip fracture had impaired mobility
Can Bone Loss Increase the Risk of
Metastasis to Bone?
Reduction in bone resorption prevents
outgrowth of marrow micrometastases???
How should we manage patients?
The Standard of Care for ADTIBL Continues
to Evolve
• The concept of ADTIBL is relatively new outside of the
oncology community
• Routine use of oral BPs is virtually nonexistent
• Calcium and vitamin D supplementation occurs in < 60% of PC
patients receiving ADT
• Since zoledronic acid was introduced for CRPC patients with
bone metastases, it has become easier to convince urologists
to use this therapy and to learn about bone health
• However, there is slow uptake regarding the impact of ADTIBL
on QOL or mortality in the PC population
ADT, androgen deprivation therapy; ADTIBL, androgen deprivation therapy-induced bone loss; BP, bisphosphonate; CRPC, castrate-resistant prostate
cancer; PC, prostate cancer; QOL, quality of life.
Options to help reduce bone loss
Effect of biphosphonates on bone mineral
density in men with prostate cancer
RANK Ligand inhibitor Denosumab
HALT-PC: Denosumab for ADTIBL
Large Phase III Study Powered for Fractures
Early stage prostate cancer
Receiving androgen deprivation
therapy
Not receiving bisphosphonates
Age > 70 or T-score < –1.0
R
Denosumab 60 mg SC q 6 mo
(n = 734)
Placebo
(n = 734)
Randomized, double-blind
N = 1,468
36 months
Primary endpoint: Change from baseline in lumbar spine BMD at 24 mo
Secondary endpoints: Change from baseline in total hip and femoral neck BMD
at 24 mo; change from baseline in lumbar spine, total hip, and femoral neck BMD
at 36 mo; incidence of fractures throughout the study period;
time to first clinical fracture; safety; laboratory values
Study completed
ADTIBL, androgen deprivation therapy-induced bone loss; BMD, bone mineral density; SC, subcutaneous.
Smith MR, et al. N Engl J Med. 2009;361(8):745-755.
Lumbar spinea
10
8
6
Dmab
4
Difference at 24 mo,
6.7 percentage points
2
0
–2
Placebo
–4
–6
01 3
6
12
24
Percentage change in BMD
from baseline
Percentage change in BMD
from baseline
Denosumab Protected Against ADTIBL vs Placebo
at All Sites Evaluated
36
Total hipa
10
8
6
4
Dmab
2
Difference at 24 mo,
4.8 percentage points
0
–2
Placebo
–4
–6
01 3
6
12
8
6
Dmab
2
Difference at 24 mo,
3.9 percentage points
0
–2
Placebo
–4
–6
01 3
6
12
24
Month
ADTIBL, androgen deprivation therapy-induced bone loss.
a P ≤ .001 for all sites.
Smith MR, et al. N Engl J Med. 2009;361(8):745-755.
36
Percentage change in BMD
from baseline
Percentage change in BMD
from baseline
Femoral necka
4
36
Month
Month
10
24
10
Distal 1/3 radiusa
8
6
4
Dmab
2
0
Difference at 24 mo,
–2
5.5 percentage points
Placebo
–4
–6
0
12
24
Month
36
Denosumab Significantly Decreased Vertebral
Fractures vs Placebo
New vertebral fracture, %
• At 36 mo, Dmab produced a statistically significant reduction
in the risk of vertebral fractures and a trend toward reduced risk of any
fractures
Placebo
P = .004
Dmab
P = .004
P = .006
6
3.9
4
2
3.3
1.9
1.5
1.0
0.3
0
12
24
36
Month
No. of patients
For Dmab vs placebo, HR =
13
2
0.15
Smith MR, et al. N Engl J Med. 2009;361(8):745-755.
22
7
0.31
26
10
0.38
The silent risk of bone loss
How should we manage patients?
• Bone loss is not an inevitable consequence of ADT
• Not all men require treatment because of interpatient
variations in1,2
– Peak bone mass
– Rates of treatment-related bone loss
• Guidelines (EAU and independent expert panels)3
–
–
–
–
Evaluate relative risk
Measure baseline BMD
Calcium and vitamin D supplementation
Consider a bisphosphonate for men with low baseline BMD or high
rate of bone loss
ADT, androgen-deprivation therapy; EAU, European Association of Urology; BMD, bone mineral density.
1. Saad F, et al. J Clin Oncol. 2008;26(33):5465-5476; 2. Israeli RS. Rev Urol. 2008;10(2):99-110; 3. Heidenreich A, et al. Eur Urol. 2008;53(1):68-80.
The silent risk of bone loss
How should we manage patients?
• Further clinical trials are necessary to determine the optimal
timing of bone-targeted therapies in this setting
• All patients should have BMD screening before initiating ADT
– Treat osteoporotic patients
– Repeat DEXA at 1 year in other patients
• Consider prophylactic strategies in high-risk patients
– obese, smokers, osteopenic BMD
ADT, androgen-deprivation therapy; BMD, bone mineral density; DEXA, dual-energy X-ray absorptiometry.
The silent risk of bone loss
How should we manage patients?
– Early studies in CTIBL with ADT show that alendronate or
pamidronate can slow or prevent loss of BMD, but does
not increase BMD significantly
• Discontinuation rates for oral BPs are up to 57% in first year
– Zoledronic acid improves BMD loss beyond baseline
during ADT in patients with HSPC
– Denosumab protects against ADTIBL and significantly
decreases vertebral fracture vs placebo during ADT in
patients with HSPC
ADT, androgen-deprivation therapy; BMD, bone mineral density; BP, bisphosphonate; CTIBL, cancer treatment-induced bone loss; HSPC,
hormone-sensitive prostate cancer.