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The silent risk of bone loss How should we manage patients?

The silent risk of bone loss How should we manage patients?. Carlos Rabaça Serviço Urologia IPOFG Coimbra. Bone health is at risk throughout the disease course. Advancing disease. Average 3 - 5 years. PSA rising again. Recurrent disease. Restage patient Consider chemotherapy

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The silent risk of bone loss How should we manage patients?

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

  2. Bone health is at risk throughout the disease course Advancing disease Average3 - 5 years PSA rising again Recurrent disease Restage patient Consider chemotherapy Check forbone metastases Average7 years PSA begins to rise Localized disease ADT usually initiated Check for bone mets Check for CTIBL New patient; PSA rising Watchful waiting Treatment Check for cancer or age-relatedbone loss Patients With Prostate Cancer Have Many Factors That Can Undermine Bone Health 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 46% 42% 37% 37% 27% 21% BMD Assessmenta Patients with newly diagnosed advanced PC 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):690-694.

  4. Metastatic Hormone-Resistant Prostate Cancer Metastases ADT—bone loss 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 20 - 30% 10 - 40% < 30% Hormone therapy (HT) Radical therapy

  7. Natural Distribution of PCa in PSA Era Localized Advanced Metastatic 40 - 60% 30 - 40% < 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 0 1991 1992 1993 1994 1995 1996 1997 1998 1999 Year of diagnosis Adapted from Shahinian VB, et al. Cancer. 2005;103(8):1615-1624.

  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;161:1219-1222.

  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% 2.4 2.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 0 0.2 Relative risk In favor of no ADT In favor of ADT N = 3,779 PC patientstreated with GnRH agonist N = 8,341 PC patientswith no GnRH agonist Smith M, et al. J Urol. 2006;175:136-139.

  16. ADT increases risk of fracture

  17. Pathologic Fractures Increase the Risk of Mortality in Patients With Prostate Cancer Riskincrease P value 1.29 29% .04 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 0 0.2 Hazard ratio (patients) Increased mortality Decreased 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 ADTIBLLarge 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 BMDat 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.

  29. Denosumab Protected Against ADTIBL vs Placebo at All Sites Evaluated Lumbar spinea Total hipa 10 10 8 8 6 6 Dmab 4 4 Dmab Percentage change in BMDfrom baseline Percentage change in BMDfrom baseline Difference at 24 mo,6.7 percentage points 2 2 Difference at 24 mo,4.8 percentage points 0 0 –2 –2 Placebo Placebo –4 –4 –6 –6 0 1 3 6 12 24 36 0 1 3 6 12 24 36 Month Month 10 10 Femoral necka Distal 1/3 radiusa 8 8 6 6 4 4 Dmab Dmab Percentage change in BMDfrom baseline Percentage change in BMDfrom baseline 2 2 Difference at 24 mo, 0 0 3.9 percentage points Difference at 24 mo, 5.5 percentage points –2 –2 Placebo Placebo –4 –4 –6 –6 0 1 3 6 12 24 36 0 12 24 36 Month Month ADTIBL, androgen deprivation therapy-induced bone loss.aP ≤ .001 for all sites. Smith MR, et al. N Engl J Med. 2009;361(8):745-755.

  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 3.9 4 New vertebral fracture, % 3.3 1.9 2 1.5 1.0 0.3 0 12 24 36 Month No. of patients 13 2 22 7 26 10 For Dmab vs placebo, HR = 0.15 0.31 0.38 Smith MR, et al. N Engl J Med. 2009;361(8):745-755.

  31. The silent risk of bone lossHow 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.

  32. The silent risk of bone lossHow 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 lossHow 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.

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