Bone Metastases and Mortality: Can We Be Doing More?
Leonard G. Gomella, MDChairman, Department of UrologyPresident Society of Urologic OncologySidney Kimmel Cancer CenterThomas Jefferson University Hospital
Crisco poles fail to stop Eagles fans from climbing post-NFC Championship
Economic Burden of CaP to Bone
Bone Health Issues In Prostate Cancer
• Use of ADT and osteoporosis risk– Epidemiology– Prevention strategies
• Morbidity and mortality of bone metastasis and prostate cancer– Epidemiology and physiology of bone metastasis– Basis of new bone targeted agents– Minimizing risk of bone metastasis– Practical aspects of radium 223
Bone Health Issues In Prostate Cancer
• Use of ADT and osteoporosis risk– Epidemiology– Prevention strategies
• Morbidity and mortality of bone metastasis and prostate cancer– Epidemiology and physiology of bone metastasis– Basis of new bone targeted agents– Minimizing risk of bone metastasis– Practical aspects of radium 223
Proportion of Patients with Fractures 1 to 5 Years After CaP Diagnosis
Shahinian et al. N Engl J Med. 2005;352:154-164.
0
3
6
9
12
15
18
Any Fracture
Fracture Resulting in Hospitalization
Freq
uen
cy (
%)
+2.8%; P < 0.001
+6.8%; P < 0.001 ADT (n = 6650)
No ADT (n = 20,035)
12.6
21
5.2
19.4
2.4
Survival After Hip Fracture
9Trombetti A et al. Osteoporos Int. 2002;13:731-737
Hip fractured Women
Hip fractured Men
Women
Men
Expected survival in the general population
2 4 6 8 100.00
0.25
0.50
0.75
1.00Su
rviv
al p
roba
bilit
y
Time after hip fracture (years)0
Men on ADT Are at IncreasedRisk of Fracture
• Men on ADT have a greater risk for fractures than postmenopausal women– 19.4% of men on ADT who survived at least 5 years after
diagnosis are at risk for a fracture
• Key risk factors for fracture include – Time on ADT– Degree of bone loss – Age
• Men on ADT fracture at a rate of 5-8% annually– Urologists may underestimate fracture risk as men on ADT
do not report fractures to their urologist
• Fractures can reduce survival by more than 3 yearsShahinian VB, et al. N Eng J Med. 2005; 352:154-64. Guise TA, et al. Rev Urol. 2007;110:1860-1867. Morote J, et al. Urology. 2007;9:163-80. Oefelein MG, et al. J Urol. 2002;168:1005-1007.
Prevalence of Osteoporosis Increases with ADT Duration
Morote J, et al. Urology. 2007;69:500-504.
Patients with prostate cancer and androgen deprivation therapy haveincreased risk of fractures—a study from the fractures and fall injuries
in the elderly cohort (FRAILCO)
Osteoporos Int. 2019 Jan;30(1):115-125
• 180,000 Swedish men• Patients with prostate
cancer without ADT did not have increased risk of any fracture
Diagnosing Osteoporosis
• In clinical practice, Bone Mineral Density (BMD) remains the gold standard.
• BMD is one of the best determinants of bone strength
• Correlates with fracture risk
• BMD predicts fracture as reliably as blood pressure predicts stroke
US Dept of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General 2004. Marshall et al. BMJ 1996: 312: 1254-1258
WHO Criteria for Osteoporosis by DXA
14Kanis JA et al. J Bone Miner Res. 1994;9:1137-1141
T-ScoreNormal -1 and above
Low bone mass -1 to -2.5
Osteoporosis < -2.5
Established osteoporosis < -2.5 and one or more fractures
WHO/FRAX® Risk Assessment
https://www.sheffield.ac.uk/FRAX/tool.aspx?country=9 Accessed January 8, 2018
Osteoporosis and Bone Metastasis Prevention and Treatment
• Vitamin D supplementation– 20%-35% decrease fracture risk with >480 IU Vitamin D– Maximum bone density achieved with Vitamin D levels >
40, lowers risk of fracture– The spine is not affected by Vitamin D– Calcium absorption in the gut is directly dependent of
Vitamin D. If deficient, need 3000 mg Calcium to get absorbed, if sufficient (>32) only need 1000 mg calcium
• Recommend 1000 IU – 1200 IU daily– Obtain a 25(OH)D (only accurate way to evaluate) not
1,25(OH)D which is normal/elevated in Vit. D deficiency.
Bischoff-Ferrari HA et al. JAMA .2005;293:2257. Dawson-HughesB, et al. Osteoporosis Int. 2005;16:713. Heaney RP. J Am Coll Nutr. 2003;22:142-146Holick MF Mayo Clin Proc. 2006;81:353-73.
Osteoporosis and Bone Metastasis Prevention and Treatment
Calcium Supplementation• Recent data: calcium supplementation of >1000 mg increased risk of
CVD mortality by 20% in men.• Some now recommend: obtain most of calcium through diet,
supplement if needed with calcium 600 mg daily– Not widely promoted
• My OTC Choice: Caltrate 600+D3 – (800 IU cholecalciferol)
Larson S. JAMA InterMed.2013;173(8):647-648.
Bisphosphonates• Inhibits osteoclast activity, reducing bone resorption
and turnover• Increase BMD: spine by 5-8%; hip 3-6% after 3 years.• Reduced incidence of vertebral fractures by 40-70%• Do not give if GFR <30• Need dental exam before starting and every 6 months
Black DM, et al. J Clin Endocrinol Metab. 2000;85:4118-4124. Harris ST et al. JAMA. 1999;282:1344-52. Chesnut CH et al. J Bone Min Res. 2004;19:1241-1249. Black DM, et al. N Eng J Med. 2007;356:1809-1818.
Common Bisphosphonate Side Effects
• Dysphagia• Esophagitis, ulceration• Nausea, dyspepsia• Uveitis• Osteonecrosis jaw• Hypocalcemia• Renal impairment• Musculoskeletal pain• Class Warnings:
– Infrequent bone, joint and/or muscle pain– Osteonecrosis of the jaw– Atypical fractures of femoral shaft.
19
Denosumab• Monoclonal antibody that binds to RANK
ligand to inhibit formation, function, and survival of osteoclasts therefore reducing bone resorption
• Increases bone density by 6.7% at the spine after 2 years
• Decreased incidence of vertebral fractures by 68%, hip by 40%
Cummings SR, et al. N Eng J Med. 2009;361: 751. Smith, MR et al. N Eng J Med 2009; 361:745.
Common Osteoporosis Agents in Men
Two Forms/Indications for Denosumab
• Prolia®: Men on ADT or osteoporosis• 60 mg SC Q 6 mo
Denosumab
• Xgeva® : Men w/mets , not men w/ osteoporosis
• 120 mg SC Q moDenosumab
National Osteoporosis Foundation Fracture Prevention Guidelines for Men
• Consider FDA-approved medical therapies based on the following– A vertebral or hip fracture– Femoral neck or spine T-score ≤ -2.5– FRAX 10-yr probability of a hip fracture ≥ 3%
or 10-yr probability of any major fracture ≥ 20%
National Osteoporosis Foundation Clinician’s Guide to Prevention and Treatment of Osteoporosis. 2010.
Healthy Bone Program:ADT hip fracture reduced >70%
• DEXA scans for all men aged > 70 years • Men aged >50 years undergo screening if additional risk factors are
present, including ADT. • DEXA repeated every 5 years. – T-score from -2.0 to -2.5: low bone mineral density – T-score of < - 2.5 for a diagnosis of osteoporosis.– T-scores > - 2.5 are advised on smoking cessation, regular exercise, adequate
calcium intake (1200 mg/d), and adequate vitamin D intake (400-800 IU/d). – T-scores < -2.5 are treated with pharmacologic intervention;
• the first-line treatment is a bisphosphonate, and the patient is followed up by an endocrinologist.
Zhumkhawala AA, Urology. 2013 May; 81(5):1010-7.
Bone Health Issues In Prostate Cancer
• Use of ADT and osteoporosis risk– Epidemiology– Prevention strategies
• Morbidity and mortality of bone metastasis and prostate cancer– Epidemiology and physiology of bone metastasis– Basis of new bone targeted agents– Minimizing risk of bone metastasis– Practical aspects of radium 223
Skeletal-Related Events and Clinical Consequences of Bone Metastases
Skeletal-Related Events• Pathologic fractures*• Spinal cord compression*• Radiation therapy to bone*• Surgery to bone*• Hypercalcemia• Change in antineoplastic therapy
Other Clinical Symptoms• Bone pain • Analgesic usage• Quality-of-life deterioration• Shortened survival
*Universally accepted skeletal-related events; Modified from Clinical Care Options in Oncology clinicaloptions.com
Impact of PCa Bone Metastasis on Survival
Norgaard J Urol 2010; 184 (1); 162
Site of Pca Metastasis and Survival
CaP And Bone Metastasis• > 90% of patients with mCRPC have bone metastases
and experience skeletal-related events (SRE) • SREs include spinal cord compression, pathological
fracture, and need for surgery or radiotherapy • Bone metastases are a major cause of death, disability,
decreased quality of life, and increased treatment cost • The anti-resorptive, bone-targeted therapies
(zoledronic acid and denosumab) – Do not improve survival – Do not delay metastasis– In some studies may delay or prevent SREs and others
have not shown an advantage
J Clin Oncol. 2014 Apr 10;32(11):1143-50
CaP And Bone Metastasis
• About 50% of men with CRPC will develop metastasis within 2 years of CRPC diagnosis
• Median survival with mCRPC varies from 9 to 30 months on average
• More than 30% of men with CRPC thought to be M0 (non metastatic) actually harbor mets and are actually M1– Based on ENTHUSE (endothelin trial)
RADAR Study
Crawford ED Urology 2014 83(3):664
Alk Phos and PSA: Predict risk of Bone Mets
Bone antiresorptive therapy with CRPC
Fizazi K, et al. Lancet. 2011;337:813-822.
Phase 3 Study of Zoledronic Acid Versus Denosumab: Time to First SRE
• Common side effects that are similar between treatment groups: anemia, bone pain, nausea, decreased appetite, constipation
• More hypocalcemia with denosumab (13% vs 6%)– Calcium and Vitamin D will decrease likelihood – No fatal episodes
• Osteonecrosis of jaw (ONJ) incidence low– 2% denosumab vs 1% zoledronic acid, P=0.09
• Acute phase reactions– 8% denosumab vs 18% zoledronic acid
Fizazi K, et al. Lancet. 2011;337:813-822.
Zoledronic Acid Versus Denosumab: Adverse Events
Bottom Line: Radium-223 Is Short Range But Deadly
• Highly localized cell killing with minimal damage to surrounding hematopoietic tissueα-particles cause double-strand DNA breaks in nearby tumour cells
• Limited penetration of α emitters (~ 2-10 cell diameters) results in highly localized killing of tumor cells with minimal collateral damage to normal tissue in surrounding area
2-10 cell diameter range of alpha-particle
Radium-223
Perez et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007
ALSYMPCA
Overall Survival in mCRPC
Radium-223
Median OS: 14.9 months
Placebo
Median OS: 11.3 months
HR = 0.7095% CI, 0.581, 0.832
P = 0.00007
Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39
Radium-223 614 578 504 369 274 178 105 60 41 18 7 1 0 0
Placebo 307 288 228 157 103 67 39 24 14 7 4 2 1 0
%
0
10
20
30
40
50
60
70
80
90
100
Parker et al. N Engl J Med. 2013;369:213-223. 50
ALSYMPCA Time to First Symptomatic Skeletal Event in mCRPC
0
10
20
30
40
50
60
70
80
90
100Pa
tient
s w
ithou
t Ske
leta
l Eve
nt (%
)
Months since Randomization0 3 6 9 12 15 18 21 24 27 30
Radium-223
Placebo
Radium-223 (N = 614)
Placebo(N = 307)
Hazard Ratio (95% CI)
Median time to first SRE
15.6 months
9.8months
0.66 ( 0.52-0.83)
Parker et al. N Engl J Med. 2013;369:213-223.51
Radium-223 and Bisphosphonates: No combined effect on survival in ALSYMPCA
but positive effect on Symptomatic SRE’s
Sartor et al. Lancet Oncology 15:738, 2014
Can J Urol. 2016 Jun;23(3):8301-5
Conclusions
• In patients on ADT consider monitoring DEXA; start with basic
management strategies before Rx
– Weight bearing, limit smoking, EtoH, Vit D and Calcium
• Strongly consider antiresorptive therapy with M1
– Many consider it standard with mCRPC
• Radium 223 useful in mCRPC with symptoms and significant bone
mets
– Sequencing of mCRPC agents under study
– Combinations w/other mCRPC agents appears safe
• Institutional programmatic support to utilize Radium-223 in the
clinic
ARS 1Choose the correct statement concerning osteoporosis and fractures
1. Fracture risk in men on ADT stabilizes dose not increase after 2 years
2. Men on ADT have a greater risk for fractures than postmenopausal women
3. There is no difference in mortality between men and women who suffer an osteoporotic hip fracture
4. Bone mineral density (BMD) is unreliable as a marker for fracture risk in men on ADT
ARS 2
When using denosumab in the management of ADT induced osteoporosis
1. Dental exam is not needed as ONJ does not occur.2. Hypocalcemia is more common with denosumab than with
bisphosphonates.3. Either Prolia or Xgeva can be used.4. Calcium and Vitamin D supplementation should not be used.
ARS 3A 75 yo male presents with newly diagnosed hormone naive metastatic prostate cancer to bone. After a dental exam and baseline BMD a reasonable approach is:
1. Start on Prolia with calcium and Vitamin D.2. Start on Xgeva with calcium and Vitamin D.3. Start on bisphonates with calcium and Vitamin D.4. 1 or 35. 2 or 3
