Androgen Deprivation Therapy and Bone Health

Transcription

1 Androgen Deprivation Therapy and Bone Health Tracey L. Krupski, M.D., MPH Departments of Urology and Health Services University of Virginia Health Sciences Center Overview for May 17, 2015 Overview of bone turnover Diagnosis and etiology of osteoporosis Epidemiology of bone complications and prostate cancer Role of antiresorptive agents

2 Osteoporosis in General Bone Mass Dense Bone Fragile Bone University of Washington Department of Medicine: (January 13, 2005 Osteoporosis in General Bone Turnover

3 Osteoporosis in General Bone Turnover Osteoblasts Osteoclasts Estrogen enhances survival Cortisol induces apoptosis IGF-1 improves function Testosterone modulates growth factors for proliferation Estrogen inhibits Cortisol promotes unchecked activity TSH stimulates PTH stimulates Calcitonin inhibits Overview for May 17, 2015 Overview of bone turnover Diagnosis and etiology of osteoporosis Epidemiology of bone complications and prostate cancer Role of antiresorptive agents

4 Osteoporosis in General Definition World Health Organization Osteopenia denotes a bone mineral density (BMD) between 1.0 and 2.5 standard deviations below the mean for young adults, while osteoporosis is greater than 2.5 standard deviations below the mean (T score < -2.5) Lifetime risk for a hip, wrist or vertebral fracture is 30-40% Osteoporosis in General Burden

5 Osteoporosis in General Diagnosis Through Imaging Dual energy x-ray absorptiometry (DEXA) Common in clinical trial and epidemiological studies Standard reference point is the is BMD at the femoral neck T scores are intended for use in postmenapausal women and men aged > 50 (other technologies use Z-score) Osteoporosis in General Diagnosis Through Imaging Neck Trochanteric University of Washington Department of Medicine: (January 13, 2005) Intertrochanteric

6 Osteoporosis in General Diagnosis Through Imaging Quantitative computed tomography (QCT) Best for spine (reproductibility issue) Disadvantages are more radiation and limited sites Broadband ultrasound attenuation (BUA) May be cost effective but few comparison studies Osteoporosis in General Diagnosis Through Imaging University of Washington Department of Medicine: (January 13, 2005)

7 Osteoporosis in General Diagnosis Through Imaging T score- the difference in number of SD s between individual and mean value of year old same sex Z score- difference in SD s between individual and mean value of same age group Osteoporosis in General Risk factors Validated in assessment algorithms Low BMD Prior vertebral fracture Long-term glucocorticoid use Age Do not adversely affect the efficacy of intervention in RCT Family hx of fracture biochemical markers of bone turnover Prior non-vertebral fx peripheral measurements of bone mineral (US at heel) BMI Smoking

8 Osteoporosis in General Etiology Modifiable Risk Factors Cigarette smoking Physical activity Dietary deficiencies of Vit D/Ca Medications (steroid, diuretics) Risk of falling Non modifiable Risk Factors Age Sex Ethnicity Family History Frame size FRAX/tool.aspx?country=9

9 Osteoporosis in General Etiology: role of sex steroids TESTOSTERONE Pubertal developmentleading to greater comparative BMD Regulates periosteal growth of cortical bone Mediates growth factors necessary for osteoblast proliferation ESTROGEN Menopause leads to unchecked osteoclast activity Bioavailable (not bound to sex hormone binding globulin) critical Bioavailable estrogen independent predictor of BMD in men Osteoporosis in General Etiology Etiology Mechanism Primary Osteoporosis Senile or Idiopathic Reduced IGF-1- osteoblastic dysfunction Secondary Osteoporosis Steroid excess Osteoblast apoptosis Alcoholism Impaired absorption of Ca, PO4 Gastrointestinal disease Impaired absorption of Ca, PO4 Idiopathic hypercalcemia Stimulates calcitonin, Decrease PTH Hyperthyroidism Stimulates osteoclasts Multiple Myeloma Directly decrease BMD Skeletal metastasis Directly decrease BMD Hypogonadism Decreased aromitization of testosterone

10 Osteoporosis in General Definitions Fracture No universal definition for an osteoporotic fracture Usually defined as low energy fracture ( I.e. fall from a standing height) Vertebral, hip, and distal forearm fractures are quintessential osteoporotic fracture Skeletal related events Spinal cord compression, pathological fractures, surgery or radiation to bone, change in antineoplastic to treat pain or immobility Osteoporosis National Osteoporosis Foundation Recommend FDA approved medical therapies in the following: History of vertebral or hip fracture Femoral neck or spine Tscore of year probability of hip fracture 3% 10 year probability of any fracture 20% (FRAX:

11 Overview for May 17, 2015 Overview of bone turnover Diagnosis and etiology of osteoporosis Epidemiology of bone complications and prostate cancer Role of antiresorptive agents Prostate Cancer WHY IS THIS A POPULATION OF INTEREST?

12 Prostate cancer disease trajectory Primary Therapy Salvage Therapy Palliation Diagnosis Recurrence Progression Death f Prostate Cancer Bone implications are associated only with disease progression Rationale: Hypogonadism and decreased density Seed and soil

13 Osteoporosis and Prostate Cancer Prostate Cancer Bone Metastasis Androgen Deprivation Therapy Seed and Soil theory

14 Prostate cancer populations Patient starting ADT Patient progressing to metastatic Low testosterone= bone mass Cancer deposit weakens bone Skeletal Related Events Progression of Disease Initiation of ADT Decrease Testosterone Hypogonadism Decrease Bone Density Castrate Resistant Prostate Cancer Metastatic Disease Direct disruption of normal bone SRE

15 Prostate cancer populations Hormone sensitive Metastatic hormone sensitive Castrate resistant prostate cancer Denosumab Figure 1:Adapted from: Boyle WJ et al. Nature 2003;423:337-42*

16 Zoledronic Acid Two primary therapies Mechanism Bisphosphonates Denosumab Chemistry Chemical agent Monoclonal antibody Selectively binds bone mineral, and is taken up by mature osteoclasts at sites of bone resorption, inhibiting osteoclast activity Indications 1. Hypercalcemia of malignancy 2. Multiple myeloma, 3. Bone metastases of solid tumors, 4. Paget s disease of bone 5. Osteoporosis in postmenopausal women, 6. Prevention of osteoporosis in postmenopausal women 7. Osteoporosis in men, 8. Treatment and prevention of glucocorticoid-induced osteoporosis* Selectively binds RANKL, preventing RANK/RANKL interaction, thereby inhibiting the development, activation, and survival of osteoclasts 1. Osteoporosis in postmenopausal women at high risk for fracture, 2. Prevention of SREs in patients with bone metastases from solid tumors

17 Two primary therapies Side effects Acute phase reaction (fever, chills, myalgia and arthralgias), ocular inflammation, renal insufficiency, electrolyte imbalance and osteonecrosis of jaw Diarrhea, nausea, vomiting, fatigue/asthenia, hypophosphatemia, dyspnea, cellulitis, hypocalcemia, osteonecrosis of jaw Administration Oral or IV (depending on the bisphosphonate). Oral: daily, weekly, or monthly IV:, quarterly or yearly Subcutaneous (60 mg every 6 monthly) Cost Approximately $450 per dose Approximately $1600 per month (based upon wholesale acquisition costs) Osteoporosis and Prostate Cancer Hormone Naive Prostate Cancer 100 Percentage Conde(34) Wei(8) Smith(41) Hussain(174) At least Osteopenic Osteoporotic

18 Osteoporosis and ADT Bone Loss % Change in BMD per year Treatment No of Pt LS DEXA Hip DXA Jones et al, 1994 none 300 n/a 0.7 Diamond et al, 1998* CAB 12 n/a 6.5 Higano et al 1999 CAB Maillefert et al, 1999 LhRH Daniell et al, 2000* LhRH, Orch 16 n/a 3.4 Berruti et al, 2002 LhRH Smith et al 2003 LhRH/CAB Osteoporosis and ADT Osteoporosis (DEXA) Osteoporosis and ADT Percentage LhRH CAP 0 Berruti (35) Morote (110)

19 Osteoporosis and ADT Osteoporosis, Fracture, and ADT 30 Cumulative Proportion of Osteoporosis/Osteopenia Percent Years Osteoporosis/osteopenia 1.9 years ADT Osteoporosis/osteopenia > 1.9 years ADT

20 Osteoporosis, Fracture, and ADT Cumulative Proportion of Fractures over Time 50 Percent Any Fracture 1.9 years of ADT Any Fracture > 1.9 years of ADT Years Osteoporosis, Fracture, and ADT ASCO 2004 Analyzed 7774 men with non-metastatic CAP without ADT and 3887 men with non-metastatic CAP initiating ADT Followed from Adjusted for survival Hazard Ratio for developing fractures 1.4 ADT patients were 40% more likely to develop a clinical fracture

21 Osteoporosis, Fracture, and ADT RESULTS: Relative Risk of Fracture (adjusted) GhRH agonist 1-4 doses 1.07 GnRH agonist 5-8 doses 1.22 GnRH agonist >8 doses 1.45 Orchiectomy 1.54 This correlates well with presentation at ASCO 04 by Smith et al which found HR 1.4 in same 2 groups Osteoporosis and ADT Consequences Mortality Excess mortality of 30% for men within 1 st year of hip fracture Vertebral fractures also confer increased mortality Morbidity Loss of independent living 1/3 of hip fractures relegated to LTC facility Deformities, pain, low self-esteem decrease HRQOL C

22 Metastatic hormone sensitive PC CALGB (ALLIANCE) Zoledronic acid 4 mg IV q 4 weeks vs placebo Primary endpoint showed that zoledronic acid conferred no benefit to first SRE No difference in Overall Survival Calcium and Vit D are reasonable Initiating ADT Bisphosphonates (alendronate or risedronate) or denosumab are generally recommended therapy for men receiving ADT. Osteoporosis Foundation Clinician's guide to prevention and treatment of osteoporosis. Nguyen PL, Alibhai SM, Basaria S, et al. Adverse Effects of Androgen Deprivation Therapy and Strategies to Mitigate Them. Eur Urol 2014.

23 Bisphosphonates Bisphosphonates, notably zoledronic acid, has been shown to increase BMD and prevent bone metastases compared with placebo (Neto et al. 2012, Saad et al. 2004) It is the current standard of care Rare adverse events include jaw necrosis, esophageal erosion, renal insufficiency (which is common in cancer patients) Denosumab RANKL antagonist; osteoclast inhibitor Advantage over bisphosophates: No effect on renal function Subcutaneous administration (vs. IV for zoledronic acid) No acute phase reactions Side effects include jaw necrosis, hypocalcemia, atypical fractures

24 Fizazi et al. 2012, The Lancet Primary end-point: skeletal related events (SRE pathologic fractures, spinal cord compression, radiotherapy or surgery to bone) Methods: Randomized control trial (RCT) in castration-resistant prostate cancer patients 120mg denosumab vs. 4mg zoledronic acid every 4 weeks Both groups on baseline supplemental calcium and vitamin D Results Time to SRE was 17.1mo for zoledronic acid vs. 20.7mo for denosumab 36% had SRE on denosumab and 41% on zoledronic acid Improved pain symptoms with denosumab Similar rates of side effects

25 Cost Denosumab is much more costly than bisphosphonates Markov model: base estimated cost per QALY of denosumab is $1,058,741 (Snedecor et al. 2012) Other options SERMS

26 Counseling Encourage a healthy lifestyle, regular weight bearing exercise (30 minutes on most days of the week), decreased alcohol consumption, adequate nutrition (protein, calcium, and vitamin D), smoking cessation, and fall prevention. Counseling 800 international units of vitamin D daily and 1200 mg elemental calcium daily for most postmenopausal women to 1200 mg daily of calcium and vitamin D 800 to 1000 international units daily for all men receiving ADT. InstituteofMedicine.ReportataGlance,Repo rtbrief:dietaryreferenceintakesforcalcium andvitamin D, released 11/30/ VitaminD/ReportBrief.aspx (Accessed on December 01, 2010).

27 Conclusions In patients, recommend calcium, vitamin D, and exercise regimen. Bone density FRAX tool to determine fracture risk and need for further therapy More studies are needed to see the respective effect of denosumab vs. bisphosphonates on bone mineral density Bone metastases Denosumab is superior than zoledronic acid in preventing pathologic fractures from metastases Decision to use bisphosphonate vs. denosumab must be balanced with the significant cost associated with denosumab Citations A. Barlev, X. Song, B. Ivanov, V. Setty, K. Chung. Payer costs for inpatient treatment of pathologic fracture, surgery to bone, and spinal cord compression among patients with multiple myeloma or bone metastasis secondary to prostate or breast cancer. J Manag Care Pharm, 16 (9) (2010), pp K. Fizazi, M. Carducci, M. Smith et al., Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study, The Lancet, vol. 377, no. 9768, pp , Allan Lipton a,, Karim Fizazi b, Alison T. Stopeck c, Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: A combined analysis of 3 pivotal, randomised, phase 3 trials. European journal of cancer. Volume 48, Issue 16, November 2012, Pages A. Serpa Neto, M. Tobias-Machado, M. A. P. Esteves et al., Bisphosphonate therapy in patients under androgen deprivation therapy for prostate cancer: a systematic review and meta-analysis, Prostate Cancer and Prostatic Diseases, vol. 15, no. 1, pp , 2012 Snedecor, Sonya J; Carter, John A; Kaura, Satyin; et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a costeffectiveness analysis. Journal of medical economics Volume: 16 Issue: 1 Pages: Published: 2013 (Epub 2012 Sep 05) F. Saad, D. M. Gleason, R. Murray et al., Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer, Journal of the National Cancer Institute, vol. 96, no. 11, pp , 2004.