1. The silent risk of bone loss How should we manage patients?
Carlos Rabaça
Serviço Urologia
IPOFG Coimbra

2. Patients With Prostate Cancer Have Many Factors That Can Undermine Bone Health
Localized disease
Recurrent disease
Restage patient
Consider chemotherapy
Check for bone metastases
Advancing disease
PSA rising again
ADT usually initiated
Check for bone mets
Check for CTIBL
Watchful waiting
Treatment
Check for cancer or age-related bone loss
New patient; PSA rising
PSA begins to rise
Average 7 years
Average years
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.

3. 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
21%
37%
46%
42%
27%
BMD Assessmenta
Age-matched controls
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): 3

4. Metastatic Hormone-Resistant Prostate Cancer
ADT—bone loss
Metastases
Decreased bone strength
SKELETAL COMPLICATIONS
(SRE)
Almost all patients will experience bone complications!

5. Bone Loss During Androgen-Deprivation Therapy in Patients With Prostate Cancer

6. Natural Distribution of PCa in Pre-PSA Era
Localized
Advanced
Metastatic % %
< 30%
Radical therapy
Hormone therapy (HT)

7. Natural Distribution of PCa in PSA Era
Localized
Advanced
Metastatic % %
< 5%
Radical therapy HT

8. Increasing Use of Luteinizing Hormone-Releasing Hormone (LHRH) Agonists
Stage I
Stage II
Stage III
Stage IV
Unknown stage 60 55 50 45 40 35
LHRH agonist use (patients receiving ≥1 dose of LHRH agonist in first 6 months of diagnosis, %) 30 25 20 15 10 5
1991
1992
1993
1994
1995
1996
1997
1998
1999
Year of diagnosis
Adapted from Shahinian VB, et al. Cancer. 2005;103(8): 8

9. ADT reduces testosterone and oestrogen levels

10. Depletion of testosterone and oestrogen accelerates bone resorption by osteoclasts

11. Bone Loss Is Accelerated With ADT
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:
References:
1. Pathogenesis of osteoporosis and fracture. In: Kanis JA. Osteoporosis. London, England: Blackwell Healthcare Communications Ltd;1997: Maillefert JF, Sibilia J, Michel F, et al. Bone mineral density in men treated with synthetic gonadotropin-releasing hormone agonists for prostatic carcinoma. J Urol. 1999;161:

12. Published series consistently show decreased bone mineral density after one year of ADT

13. Bone loss is greatest during the first year of ADT

14. Characteristics of bone mass loss in prostate cancer patients on ADT

15. 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%
0.2
0.4
0.6
0.8 1
1.2
1.4
1.6
1.8 2
2.2
2.4
Relative risk
In favor of ADT
In favor of no ADT
N = 3,779 PC patients treated with GnRH agonist
N = 8,341 PC patients with no GnRH agonist
Smith M, et al. J Urol. 2006;175:

16. ADT increases risk of fracture

17. Hazard ratio (patients)
Pathologic Fractures Increase the Risk of Mortality in Patients With Prostate Cancer
Risk increase
P value
1.29
29%
.04
0.2
0.4
0.6
0.8 1
1.2
1.4
1.6
1.8 2
Pathologic Fractures Increase the Risk of Mortality
Evidence from several clinical studies suggests that skeletal complications of bone metastases can significantly reduce patient survival1-3
Recently, Saad and colleagues conducted a retrospective analysis of survival for patients in a large, randomized, controlled trials of zoledronic acid in patients with bone metastases from prostate cancer based on the occurrence of pathologic fractures on study to assess the effect of fractures on survival3
In patients with prostate cancer, the hazard for death associated with a pathologic fracture in the regression analysis (without adjustment for baseline characteristics) indicated a statistically significant 29% increased risk of death, respectively (P = .04)3
Therefore, skeletal fractures caused by bone metastases may have a negative impact on patient survival
REFERENCES
1. Janni W, Hepp F, Rjosk D, et al. The fate and prognostic value of occult metastatic cells in the bone marrow of patients with breast carcinoma between primary treatment and recurrence. Cancer. 2001;92:46-53.
2. Jacobson AF, Shapiro CL, Van den Abbeele AD, Kaplan WD. Prognostic significance of the number of bone scan abnormalities at the time of initial bone metastatic recurrence in breast carcinoma. Cancer. 2001;91:17-24.
3. Saad F, Chen Y, Hei YJ. Fractures negatively impact survival in patients with multiple myeloma or bone metastases from solid tumors. ECCO Abstract 1265.
Hazard ratio (patients)
Decreased mortality
Increased mortality
Saad F, et al. Cancer. 2007; Aug 30 [Epub ahead of print].

18. Fractures increase mortality

19. Fractures and post-fracture mortality in prostate cancer patients receiving ADT

20. Bone loss due to ADT has clinically-significant consequences
60% of men who survived > 30 days after hip fracture had impaired mobility

21. Can Bone Loss Increase the Risk of Metastasis to Bone?

22. Reduction in bone resorption prevents outgrowth of marrow micrometastases???

23. How should we manage patients?

24. 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.

25. Options to help reduce bone loss

26. Effect of biphosphonates on bone mineral density in men with prostate cancer

27. RANK Ligand inhibitor Denosumab

28. 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
Randomized, double-blind
Denosumab 60 mg SC q 6 mo (n = 734) R
Placebo (n = 734)
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):

29. Denosumab Protected Against ADTIBL vs Placebo at All Sites Evaluated
Lumbar spinea
Total hipa 10 10 8 8 6
Dmab 6 4 4
Dmab
Percentage change in BMD from baseline
Percentage change in BMD from baseline 2
Difference at 24 mo, 6.7 percentage points 2
Difference at 24 mo, 4.8 percentage points –2 –2
Placebo –4 –4
Placebo –6 –6 1 3 6 12 24 36 1 3 6 12 24 36
Month
Month 10
Femoral necka 10
Distal 1/3 radiusa 8 8 6 6 4
Dmab 4
Percentage change in BMD from baseline
Percentage change in BMD from baseline
Dmab 2 2
Difference at 24 mo,
3.9 percentage points
Difference at 24 mo, –2 –2
5.5 percentage points
Placebo
Placebo –4 –4 –6 –6 1 3 6 12 24 36 12 24 36
Month
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): 29

30. Denosumab Significantly Decreased Vertebral Fractures vs Placebo
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
Dmab
P = .004
P = .004
P = .006 6 4
3.9
New vertebral fracture, %
3.3
1.9 2
1.5
1.0
0.3 12 24 36
Month
No. of patients 13 2 22 7 26 10
For Dmab vs placebo, HR =
Smith MR, et al. N Engl J Med. 2009;361(8): 30

31. 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): ; 2. Israeli RS. Rev Urol. 2008;10(2):99-110; 3. Heidenreich A, et al. Eur Urol. 2008;53(1):68-80.

32. 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.

33. 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.