Role of Pharmacists in Maintaining Bone Health in Patients with Cancer

Transcription

1 Role of Pharmacists in Maintaining Bone Health in Patients with Cancer Presented as a Live Webinar Wednesday, April 17, pm EDT Planned and conducted by ASHP Advantage. Supported by an educational grant from Amgen.

2 Role of Pharmacists in Maintaining Bone Health in Patients with Cancer WEBINAR INFORMATION How do I register? Go to and click on the Register button. After you submit your information, you will be ed computer and audio information. What is a live webinar? A live webinar brings the presentation to you at your work place, in your home, through a staff inservice program. You listen to the speaker presentation in real time as you watch the slides on the screen. You will have the opportunity to ask the speaker questions at the end of the program. Please join the conference at least 5 minutes before the scheduled start time for important announcements. How do I process my Continuing Education (CE) credit? Continuing pharmacy education for this activity will be processed on ASHP s new elearning system and reported directly to CPE Monitor. After completion of the live webinar, you will process your CPE and print your statement of credit online at To process your CPE, you will need the enrollment code that will be announced at the end of the webinar. View full CE processing instructions What if I would like to arrange for my colleagues to participate in this webinar as a group? One person serving as the group coordinator should register for the webinar. That group coordinator will receive an confirmation with instructions for joining the webinar. A few minutes before the webinar begins, the group coordinator should launch the webinar link. Once the webinar has been activated, the coordinator will have the option to open the audio via VoIP (Voice Over IP) on the webinar toolbar or use a touch tone phone with the provided dial-in information. At the conclusion of the activity, the group coordinator will complete a brief online evaluation and report the number of participants at that site. Each participant will process his or her individual continuing education statement online. What do I need in order to participate in the webinar? 1. Computer with internet access and basic system requirements. When you register, the webinar system will assess your system to ensure compatibility. 2. Telephone to dial the toll-free number and listen to the presentation (if you choose not to use Voice Over IP [VoIP] via your computer). Webinar System Requirements Be sure to view the webinar system requirements for Windows, Mac, ios, and Android prior to the activity. 1

3 Role of Pharmacists in Maintaining Bone Health in Patients with Cancer ACTIVITY FACULTY Kamakshi V. Rao, Pharm.D., BCOP, CPP Oncology and Bone Marrow Transplant Clinical Pharmacist University of North Carolina Hospitals and Clinics Chapel Hill, North Carolina Kamakshi V. Rao, Pharm.D., BCOP, is Oncology and Bone Marrow Transplant Clinical Pharmacist at the University of North Carolina (UNC) Hospitals and Clinics located in Chapel Hill, North Carolina. At UNC, Dr. Rao s clinical practice focuses in the area of adult bone marrow and stem cell transplantation. Additionally, Dr. Rao serves is the director of the UNC PGY1 pharmacy residency program and is a preceptor for UNC pharmacy students, PGY1, and PGY2 residents. At UNC, Dr. Rao serves on numerous patient care and oncology-focused subcommittees. Dr. Rao earned her Doctor of Pharmacy degree from Rutgers University Ernest Mario School of Pharmacy in Piscataway, New Jersey. She then completed a pharmacy practice residency at the Medical College of Virginia followed by an oncology pharmacy fellowship at The Cancer Institute of New Jersey in New Brunswick. She became a board-certified oncology pharmacist in She is an active member of the American Society of Health-System Pharmacists (ASHP), Hematology/Oncology Pharmacy Association (HOPA), and American Society for Blood and Marrow Transplantation (ASBMT). Dr. Rao has participated in and presented at a number of meetings, including ASHP, HOPA, ASBMT, American Society of Hematology (ASH), and American Society of Clinical Oncology (ASCO), and has published in numerous journals. Invite colleagues or listen again! This webinar will be available as an on-demand activity in May 2

4 Role of Pharmacists in Maintaining Bone Health in Patients with Cancer DISCLOSURE STATEMENT In accordance with the Accreditation Council for Continuing Medical Education s Standards for Commercial Support and the Accreditation Council for Pharmacy Education s Guidelines for Standards for Commercial Support, ASHP Advantage requires that all individuals involved in the development of activity content disclose their relevant financial relationships. A person has a relevant financial relationship if the individual or his or her spouse/partner has a financial relationship (e.g., employee, consultant, research grant recipient, speakers bureau, or stockholder) in any amount occurring in the last 12 months with a commercial interest whose products or services may be discussed in the educational activity content over which the individual has control. The existence of these relationships is provided for the information of participants and should not be assumed to have an adverse impact on presentations. All faculty and planners for ASHP Advantage education activities are qualified and selected by ASHP Advantage and required to disclose any relevant financial relationships with commercial interests. ASHP Advantage identifies and resolves conflicts of interest prior to an individual s participation in development of content for an educational activity. The faculty and planners report the following relationships: Kamakshi V. Rao, Pharm.D., BCOP, CPP Dr. Rao declares that she has no relationships pertinent to this activity. Susan R. Dombrowski, M.S., B.S.Pharm. Ms. Dombrowski declares that she has no relationships pertinent to this activity. Erika L. Thomas, M.B.A., B.S.Pharm. Ms. Thomas declares that she has no relationships pertinent to this activity. ASHP staff has no relevant financial relationships to disclose. 3

5 Role of Pharmacists in Maintaining Bone Health in Patients with Cancer ACTIVITY OVERVIEW This activity will focus on the role of pharmacists in maintaining bone health in patients with cancer. The two primary groups of patients to be discussed include patients at different levels of risk for bone loss due to cancer or cancer therapies and patients at risk for skeletal-related events (SREs) due to bone involvement or metastases. For each of these, the safety and efficacy of available treatment options to decrease the risk will be described. New and emerging information related to the use of bonemodifying agents for preventing bone metastases, as well as the essentials for evaluating the pharmacoeconomics of bone-modifying therapies, will be presented. LEARNING OBJECTIVES After attending this application-based educational activity, attendees should be able to Identify patients at risk for bone loss due to cancer therapies or bone metastases. Describe available treatment options for patients at risk for bone loss due to cancer therapies and for patients at risk for skeletal-related events due to bone involvement or metastases. Discuss ongoing research regarding the use of bone-modifying agents in patients with cancer. Outline a plan for minimizing the toxicity of bone-modifying agents in patients with cancer. CONTINUING EDUCATION ACCREDITATION The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This activity provides 1.0 hour (0.1 CEU) of continuing pharmacy education credit (ACPE activity # L01-P). Attendees must complete a Continuing Pharmacy Education Request online and may immediately print their official statements of continuing pharmacy education (CPE) credit following the activity. Complete instructions for processing CE can be found on the last page of this handout. 4

6 Bone Health in Cancer Patients patient, disease, and treatment related and Diagnosis Available agents Prevention and Treatment Strategies Cancer treatment induced bone loss Metastatic disease induced bone loss / skeletal related events (SREs) Normal Bone Physiology Normal bone homeostasis is a balance between Osteoblasts: new bone formation Osteoclasts: bone resorption Process is regulated by the RANKL pathway Receptor activator factorkappa B ligand (RANKL) Osteoprotegerin (OPG) Lustberg M et al. J Clin Oncol 2012;30: Balance between RANKL and OPG RANKL and OPG are both produced by osteoblasts RANKL binds to RANK receptor on osteoclasts, to stimulate bone resorption OPG is a decoy receptor for RANKL. Binding of RANKL to OPG therefore inhibits osteoclast induced bone resorption, allowing bone formation to predominate The ratio/balance between RANKL and OPG is the foundation of normal bone remodeling Incidence of Bone Disorders in the General Population Osteoporosis bone mineral density (BMD) >2.5 standard deviations below the mean for normal young white women Affects 10 million individuals over age 50 in the US Osteopenia bone mineral density standard deviations below the mean for normal young white women Affects 33.6 million people over age 50 in the US Fracture Occurs in 1.5 million individuals annually due to bone disease Lifetime Risk of Fracture at Age 50 Type of Fracture White Women White Men Hip (%) Vertebra (%) Forearm (%) Any of the 3 above Cummings SR et al. Lancet 2002;359: for Bone Disease Patient Related Factors for Bone Disease in Cancer Patients Patient Related Factors Endocrine Genetic Lifestyle Nutritional Menopause Family history Smoking Low calcium Endocrine Genetic Lifestyle Nutritional Menopause Family history Smoking Low calcium Race Alcohol Low vitamin D Race Alcohol Low vitamin D Sex Sedentary lifestyle Sex Sedentary lifestyle Low body weight Low body weight Prolonged immobilization Lustberg M et al. J Clin Oncol 2012;30: Lustberg M et al. J Clin Oncol 2012;30:

7 Audience Response Question #1 Which of the following malignancies is NOT associated with a high rate of skeletal related events? A. Breast cancer B. Multiple myeloma C. Colorectal cancer D. Prostate cancer for Bone Disease in Cancer Patients Disease Related Factors Some diseases preferentially metastasize to bone, resulting in lytic bone disease and skeletal related events (SREs) including fracture Breast Cancer Prostate Cancer Lung Cancer Multiple Myeloma for Bone Disease in Cancer Patients Disease Related Factors Endocrine Genetic Lifestyle Nutritional Other Menopause Family history Race Sex Low body weight Smoking Alcohol Sedentary lifestyle Prolonged immobilization Low calcium Low vitamin D Breast cancer Prostate cancer Lung cancer Multiple myeloma for Bone Disease in Cancer Patients Treatment Related Factors Chemotherapy Induced Bone Loss () Hormonal Therapy Aromatase Inhibitors (AI) in breast cancer Androgen Deprivation Therapy (ADT) in prostate cancer Chemotherapy Induced Ovarian Failure (CIOF) Glucocorticoid exposure Hematopoietic Stem Cell Transplant (SCT) Adult Survivors of Childhood Cancers Lustberg M et al. J Clin Oncol 2012;30: Hormonal Therapy in Breast Cancer ATAC Trial: randomized 6,241 ER+ postmenopausal women to 5 years of anastrozole or tamoxifen Fractures occurred in 11% of anastrozole patients compared to 7.7% of tamoxifen patients (p<0.001)at 68 months of follow up After treatment ceased, fracture rates equalized between arms Hormonal Therapy in Breast Cancer Other trials have evaluated risk for bone related events with letrozole and exemestane, and have demonstrated mixed results Studies were largely underpowered to detect differences in bone events Retrospective review showed that women treated with AIs were 2.5 times more likely to suffer a fracture compared to those treated with tamoxifen Eastell R et al. JCO 2008;26: , Eastell et al. Ann Oncol 2011;22: Carney et al. Hawaii Med J 2007;66:

8 Hormonal therapy in Prostate Cancer Numerous trials have evaluated the effect of ADT on bone mineral density and fracture risk: Prospective study compared patients receiving >1yr of ADT to matched controls Analysis of 15,716 men with fractures and 47,149 controls showed prostate cancer to be a significant factor associated with increased risk of fracture Yrs of ADT None 2y 4y 6y 8y 10y N N=124 N=112 N=61 N=37 N=35 N=21 % Normal % Osteopenia %Osteoporosis Chemotherapy Induced Ovarian Failure (CIOF) Effect of chemotherapy on ovarian function depends on age, class of chemotherapy, and cumulative exposure Risk of CIOF increases with age due to decreased ovarian reserve In pediatric patients, treatment before puberty reduces likelihood of CIOF (Hodgkin s, pediatric acute lymphocytic leukemia (ALL)) In women who retain menstrual function after chemotherapy, natural menopause may occur at an earlier age than matched controls Morote J et al. Urology 2007;69: Lustberg MB. JCO 2012;30: Hormonal Effects of Therapy and Bone Loss Overall, treatments for cancer that affect hormonal status have a marked effect bone mineral density, leading to increased risks of osteopenia, osteoporosis, and fracture Corticosteroids Commonly used in a wide variety of malignancies, including ALL, lymphomas, and other malignancies Mechanism of bone loss may include Inhibition of OPG production and stimulation of RANKL production Suppression of androgen and estrogen secretion, leading to increased bone resorption Lustberg MB. JCO 2012;30: Corticosteroids Several trials have shown the impact of corticosteroids on bone mineral density De Vries et al evaluated fracture risk in patients in the UK receiving intermittent doses of steroids Fracture risk was highest in patients receiving daily prednisone doses >30mg and cumulative exposure of >5g Fracture Type Osteoporotic 3.63 Relative Risk Hip/Femur 3.13 Vertebral High Dose Chemotherapy / Hematopoietic Stem Cell Transplant (HCT) Numerous factors increase the risk of bone loss in patients undergoing HCT: High dose chemotherapy/radiation Calcineurin inhibitors (tacrolimus, cyclosporine) Gonadal failure Prolonged corticosteroid use Bone loss occurs within 6 12 months after HCT. BMD recovery occurs first in the lumbar spine, then in the femoral neck For patients requiring longer term therapy with steroids and calcineurin inhibitors, BMD may remain low and not return to normal De Vries et al. Arthritis Rheum 2007;56: McCline BL et al. BMT 2011;46:1 9 7

9 Adult Survivors of Childhood Cancers ALL is one of the most common pediatric malignancies, for which treatment includes Prolonged glucocorticoid therapy Bone toxic chemotherapy (methotrexate, alkylating agents) t) Radiation Stem cell transplantation 25% of childhood ALL survivors and 42% of adult survivors of pediatric stem cell transplant are diagnosed with osteoporosis. for Bone Disease in Cancer Patients Treatment Related Factors Endocrine Genetic Lifestyle Nutritional Other Menopause Oopherectomy GnRH agonists Hypoestrogenic states Androgen deprivation Early menopause Hypogonadism Family history Race Sex Low body weight Smoking Alcohol Sedentary lifestyle Chronic corticosteroid use Prolonged immobilization Low calcium Low vitamin D Breast cancer Prostate cancer Lung cancer Multiple myeloma Stem Cell Transplant Pediatric ALL Lustberg M et al. J Clin Oncol 2012;30: Lustberg M et al. J Clin Oncol 2012;30: and Diagnosis DEXA Scan Evaluation The gold standard of bone mineral density measurement is dual energy x ray absorptiometry (DEXA) scanning Recommended every 2 years in the general population of women Recommendations vary for screening in patients with cancer T Score BMD compared with what is normally expected in a healthy young adult of your sex* Diagnosis Criterion (BMD) Normal T score better than 1 Osteopenia T score between 11 and Osteoporosis T score < 2.5 Severe Osteoporosis T score < osteoporotic fracture Z Score number of standard deviations above or below what's normally expected for someone of a particular age, sex, weight, and ethnic or racial origin * World Health Organization definitions, National Osteoporosis Foundation: and Diagnosis FRAX Tool FRAX World Health Organization Fracture Risk Assessment Tool Computer based tool which integrates clinical information, with or without measured BMD, to calculate the 10 year probability of major osteoporotic fracture and hip fracture Takes into account modifiable and nonmodifiable risk factors Recommendations for Group Population Treatment Indication USPSTF Women over 65 years DEXA every 2 T score < 2.5 years ASCO High Risk Women age >/= 65 age at high risk initiating AI therapy Annual DEXA scan T score < 2.5 Premenopausal women with ovarian suppression NCCN Women initiating AI therapy Men receiving ADT DEXA every 2 years Any of the following: T score < 2.0 FRAX 10y hip fracture probability >3% FRAX 10y probability of major osteoporotic fracture >20% World Health Organization FRAX WHO Fracture Risk Assessment Tool USPSTF. for Osteoporosis. Jan 2011, VanPoznak et al. J Clin Oncol 2011;29:1221 7, NCCN clinical practice guidelines in oncology (breast and prostate ca, v2.2013) 8

10 Treatment Options Options for treatment have grown over the past 10 years Bisphosphonates Denosumab Selective Estrogen Receptor Modulators (SERMs) Teriparatide Bisphosphonates Mechanism of Action Decrease bone resorption and increase bone mineralization by inhibiting osteoclast activity les/mm_bone_health/pages/page%202.aspx. Accessed 4/5/13 Bisphosphonates Available Currently available bisphosphonates Agent Alendronate (Fosamax) PO FDA approved osteoporosis treatment dose Prevention: 5mg Qday/35mg Qweek Treatment: 10mg Qday/70mg Qweek Risedronate (Actonel) PO 5mg Qday / 35mg Qweek / 150mg Qmonth Ibandronate (Boniva) PO/IV Pamidronate (Aredia) IV (malignancy only) Zoledronic Acid (Zometa, Reclast) IV 150mg PO Qmonth / 3mg IV Q3months 60 90mg IV Q3months Nonmalignant: 5mg Q 2 years Malignant: 5mg Qyr, 4mg Q3 6 months Majority of trials in cancer patients have used IV bisphosphonates xicity Renal Tox Zoledronic acid Acute tubular necrosis associated with higher doses and faster infusions Slow recovery with discontinuation Pamidronate Nephrotic syndrome, irreversible Bisphosphonates Toxicities emia Hypocalc Lethargy, weakness, tetany Increased riskinin patients with vitamin D deficiency Consider supplementation with calcium/vitamin D if not being used for hypercalcemia of malignancy Osteonecrosis of the Jaw Pain, numbness, exposed bone Incidence reported at 1 10% Increased risk in those with previous jaw trauma or dental surgery/extraction Cumulative dose relation IV bisphosphonates> PO bisphosphonates Denosumab Monoclonal antibody directed towards RANKL Denosumab Dosing and Toxicities Dosing 60mg SC Q6 months (Prolia ) Treatment of osteoporosis in patients t at risk ikfor fracture Bone loss induced by AIs or ADT 120mg SC Q4 weeks (Xgeva ) Treatment of metastatic disease to prevent skeletal related events Toxicities Hypocalcemia Infusion reactions Osteonecrosis of the jaw Lewiecki EM. Clin Pharmacol Ther 2012;91(1):

11 Raloxifene Selective estrogen receptor modulator Bind to estrogen receptor, and act as either an estrogen agonist (in bone) or antagonist (in breast and uterine tissue) Increased BMD Decreased spine fractures No impact on nonspinal fractures Dose:60mg PO Qday Toxicities Hot flashes, increased VTE and stroke risk Teriparatide Recombinant parathyroid hormone analog Dose: 20mcg SC Qday Current indications include treatment of Postmenopausal osteoporosis in women Hypogonadal osteoporosis in men Prolonged glucocorticoid induced osteoporosis Minimal data in cancer or chemotherapy associated bone loss Audience Response Question #2 Treatment and Prevention Strategies What can practitioners do to help minimize the risk of nephrotoxicity associated with zoledronic acid? A. Avoid use in mild renal insufficiency B. Dilute in larger volume before administration C. Slow infusion rate Cancer Treatment Induced Bone Loss AI induced bone loss ADT induced bone loss CIOF SCT associated bone loss Metastatic or Bone Involvement Induced Bone Loss Breast cancer Prostate cancer Multiple myeloma Zoledronic Acid (ZA) for AI Induced Bone Loss Z FAST/ZO FAST trials Zoledronic Acid (ZA) for AI Induced Bone Loss Z FAST/ZO FAST trials Postmenopausal breast cancer patients receiving letrozole 2.5mg PO Qday x5 years Immediate treatment: ZA starts immediately (4mg IV Q6 months x 5 years) Delayed treatment: ZA starts when patients experience: 1. T score < non traumatic fracture 3. Asymptomatic fracture at 36 months Primary endpoint: % change in spine BMD at 12 months Secondary endpoint: % change in total hip BMD Z FAST results N=602 Upfront ZA progressively increased lumbar spine and total hip BMD Delayed ZA had significant decreases in LS and TH BMD ZA produced substantial increase in BMD regardless of baseline Tscore, osteoporosis risk factors, or chemotherapy status. ZO FAST results N= 1065 patients Brufsky. Cancer 2012;118: , Coleman. Ann Oncol 2013;24(2): Cancer 2012;118: , Ann Oncol 2013;24(2):

12 AI Induced Bone Loss Denosumab s role Hormone Ablation Bone Loss Trial in Breast Cancer (HALT BC) Phase III trial in 252 women with early stage ER+ Breast Ca, on AI therapy, with evidence of low bone mass (T score of 1 to 2.5) Denosumab 60mg SC Q6 months x4 vs. placebo Primary endpoint: % change in lumbar spine BMD at 12 months AI Induced Bone Loss Denosumab s role % Change in LS BMD from baseline for all patients at 24 months Proportion of patients preserving LS BMD at 24 months Ellis GK et al. J Clin Oncol 2008;26(30): Ellis GK et al. J Clin Oncol 2008;26(30): Zoledronic Acid (ZA) for ADT Induced Bone Loss 222 patients with M0 prostate CA either: Within 1 year of starting ADT Within 2 weeks of orchiectomy Zoledronic Acid 4mg IV Q3 months x 48 weeks (n= 112) Placebo (n= 110) Primary Endpoint: % change in lumbar spine BMD Secondary Endpoint: % change in total hip BMD Zoledronic Acid (ZA) for ADT Induced Bone Loss Results demonstrate significantly increased BMD in patients treated with ZA vs. placebo % change from baseline BMD Lumbar Spine Zoledronic acid Placebo Total Hip P value < < Israeli RS et al. Clinical Genitourinary Cancer 2007;5(4):271 7 Israeli RS et al. Clinical Genitourinary Cancer 2007;5(4):271 7 ADT Induced Bone Loss Denosumab (HALT PC) Randomized, double blind study in patients with prostate cancer on ADT, without metastatic disease Denosumab 60mg SC Q6 months vs. placebo 1468 men (734 denosumab, 734 placebo) Primary endpoint: % change from baseline in LS BMD Time point ADT Induced Bone Loss Denosumab (HALT PC) Cumulative incidence of new vertebral fractures Placebo 12 months 1.9 N=13 Denosumab 0.3 N=2 P value months N=22 N=7 36 months N=26 N=10 At 24 months, 6.7% difference in bone mineral density between denosumab and placebo, favoring denosumab Smith MR et al. N Engl J Med 2009;361(8): Smith MR et al. N Engl J Med 2009;361(8):

13 Zoledronic Acid (ZA) for Chemotherapy Induced Ovarian Failure CALGB Trial Premenopausal women with breast cancer receiving adjuvant therapy ZA 4mg Q3 months x 8 starting at 1 3 months after randomization ZA4mg Q3monthsx8starting starting at months after randomization Primary Endpoint: % change in LS BMD at 1 year Secondary Endpoint: % change in LS BMD at 3 years Shapiro CL. Eur J Cancer 2011;47: Zoledronic Acid (ZA) for Chemotherapy Induced Ovarian Failure No CIOF at 1 year N=286 (66%) Total Randomized N=439 Total BMD at baseline at 1 year N=302 Total BMD at baseline 3 years N=177 Shapiro CL. Eur J Cancer 2011;47: CIOF at 1 year N=150 (34%) Median percentage difference in BMD ZA early ZA late P < y < y Stem Cell Transplant and Bone Loss Pamidronate for Prevention Trial evaluated bisphosphonate use to prevent bone loss after allogeneic SCT 116 patients undergoing allogeneic SCT Pamidronate 90mg IV monthly x12+ calcitriol litil+ calcium li Calcitriol + calcium BMD at 3,6,12, and 24 months post SCT Included evaluation of potential covariates, including age, agvhd, cgvhd, average daily steroid dose, duration of cyclosporine use Stem Cell Transplant and Bone Loss Pamidronate for Prevention Mineral Density Change in LS Bone mo P= mo P=0.056 Tx stopped 12 mo P= mo P=0.212 Pamidronate no pamidronate Grigg AP. J. Clin Endocrinol Metab 2006;91: Grigg AP. J. Clin Endocrinol Metab 2006;91: Stem Cell Transplant and Bone Loss Stem Cell Transplant and Bone Loss Italian group evaluated 4 different regimens to prevent bone loss in 60 women who had undergone allosct. All patients received calcium/vitamin D +: Group 1: nothing Group2: estradiol 2mg QDay/dihydroprogesterone10mg Qdayx14d/month Group 3: risedronate 35mg PO weekly Group 4: zoledronic acid 4mg IV Q month x3 months Tauchmanova L et al. Bone Marrow Transplantation 2006;37:81 88 Tauchmanova L et al. Bone Marrow Transplantation 2006;37:

14 Audience Response Question #3 TP is a 57 year old Asian woman with a diagnosis of locally advanced breast cancer who is on hormonal therapy with tamoxifen, and is receiving adjuvant chemotherapy with cyclophosphamide clophosphamide and doxorubicin. or What is the best option for TP for prevention of bone loss? A. Calcium + vitamin D B. DEXA scan every 2 years C. Alendronate 70mg PO every week D. Zoledronic acid 4mg IV every 6 months Treatment and Prevention Strategies Cancer Treatment Induced Bone Loss AI induced bone loss ADT induced bone loss CIOF SCT associated bone loss Metastatic or Bone Involvement Induced Bone Loss Breast cancer Prostate cancer Multiple myeloma Metastatic or Bone Involvement Induced Bone Loss Skeletal Related Events (SREs) Fracture Pathologic Vertebral Non vertebral Radiation therapy to bone Surgery to bone Spinal cord compression Hypercalcemia of malignancy Lewiecki EM. Clin Pharmcol Ther 2012;91(1): Preventing SREs Multiple Myeloma & Breast Cancer Randomized, double dummy trial of zoledronic acid vs. pamidronate in multiple myeloma and breast cancer In multiple myeloma, Zoledronic acid and pamidronate found dto be not significantly ifi different for occurrence of SREs in MM In Breast Cancer ZA reduced risk of by 20% over 2 years compared to pamidronate If administered before the onset of pain, ZA reduced SRE incidence by 41% compared to pamidronate Preventing Prostate Cancer Trial Zometa CGP032/INT05 2 Denosumab Population Treatment Primary Endpoint Result 643 men with metastatic HRPC Zoledronic acid 4mg IV Zoledronic acid 8mg IV Placebo Proportion of patients with > 1 SRE occurred in 33.2% of ZA pts and 44.2% of placebo pts (p=0.021) 350 men with metastatic HRPC Pamidronate IV vs placebo Q3 weeks Change from baseline self reported pain score No difference between arms 1901 men with HRPC Denosumab 120mg SC Q4 weeks vs. zoledronic acid 4mg IV Q4 weeks Time to first SRE on study *noninferiority and superiority analysis planned Time to SRE prolonged with denosumab by 3.6 months (p= noninfer, p=0.008 superiority) Rosen LS et al. Cancer 2003;98: Saad F et al. J Natl Cancer Inst 2002;94: , 2. Small EJ et al. J Clin Oncol 2003;21: , 3. Fizazi K et al. Lancet 2011;377(9):

15 Preventing Denosumab vs. Zoledronic Acid 3 phase III trials have evaluated denosumab vs. zoledronic acid in patients with metastatic disease, comparing denosumab 120mg SC vs zoledronic acid 4mg IV every 4 weeks N= 5723 (2862 denosumab, 2861 zoledronic acid) Breast cancer, prostate cancer, solid tumor, or myeloma with evidence of > 1 bone lesion Denosumab was superior to ZA in reducing risk of SRE by 17% (HR 0.83, 95%CI ), p<0.001 Reducing median time to first SRE (27.66 months for ZA vs months for denosumab) reducing risk of multiple SREs Rates of adverse events were similar between groups Increased rate of hypocalcemia with denosumab Increased rate of renal toxicity and acute phase reactions with zoledronic acid Bone targeted agents as Anticancer therapy Data exists to support the use of bone modifying agents to prevent bone metastases in patients with Multiple myeloma Breast cancer Prostate cancer Lipton A et al. Eur J Cancer 2012;48: Bone targeted agents as Anticancer therapy: Myeloma MRC IX trial N=1960 Comparison between clodronate 1600mg/day PO and zoledronic acid 4mg IV every 3 4 weeks with induction, then every 4 weeks Zoledronic acid Improved PFS by 12% Decreased risk of death by 16% Increased OS by 5.5 months Long term follow up showed that >2 years of therapy may confer further benefit in those with bony disease at time of randomization Bone targeted agents as Anticancer therapy: Breast Cancer Trial ABCSG 12 AZURE N Treatment arms Primary Endpoint Results Other tamoxifen + zoledronic acid tamoxifen alone goserelin + zoledronic acid goserelin alone 36% relative risk reduction in risk of disease progression 62 month follow up showed persistent benefit Various adjuvant therapies +/ zoledronic acid Disease free survival Zoledronic acid did not produce DFS benefit at interim analysis Preplanned subset analysis revealed significant benefit in postmenopausal women (HR 0.71, p<0.05) Morgan GJ et al. Lancet Oncol 2011;12(8):743 52, Morgan GJ et al. Blood 2012;119: Gnant M et al. Lancet Oncol 2011;12(7):631 41, Coleman R et al. Ann Oncol 2013;24: , Coleman R et al. NEJM 2011;365: Bone targeted agents as Anticancer therapy: Breast Cancer Taken together, data show that zoledronic acid, when added to adjuvant therapy, may improve DFS and disease related outcome Question remaining: which particular subset of patients will benefit most from bone directed therapy? Bone targeted agents as Anticancer therapy: Prostate Cancer Trial Zometa 704 ZEUS Denosumab N 398 (planned 991) 1300 (ongoing) 1435 Trial type Population Treatment Primary Endpoint Results Randomized controlled trial Nonmetastatic HRPC with rising PSA Zoledronic acid 4mg Q4 weeks vs. placebo Time to first metastatic lesion Poor accrual, no differences seen Randomized, controlled, open label High risk localized hormone sensitive prostate cancer Zoledronic acid 4mg Q3 months vs placebo x48 mos % of patients developing bone metastasis during study period Data analysis ongoing Smith MR et al. JCO 2005;23: , Wirth M et al ASCO Abstract 184, Smith M et al. Lancet 2011;379:39 46 Phase III, double blind, randomized controlled trial Nonmetastatic HRPC with high risk of metastasis Denosumab 120mg SC Q4 weeks vs. placebo Metastasis free survival Denosumab prolonged metastasis free survival by 4.2 months & delayed time to metastasis 14

16 Bone targeted agents as Anticancer therapy Overall, data points to a potential benefit in patients with breast cancer Data in prostate cancer are still preliminary Trials il in progress. But, NEVER FORGET! REMEMBER, modifiable risk factors should be addressed with all patients Weight bearing exercise Physical activity Supplemental calcium and vitamin D Cost of In Summary Agent Zoledronic acid 4mg Denosumab 60mcg Denosumab 120mcg Calcium 1200mg/Vitamin D Cost $844/dose $990/dose $1980/dose $20/month Bone loss related to cancer and cancer therapy is an important and widespread issue Pharmacists should screen for cancer associated and treatment associated bone loss and encourage patients with cancer to adhere to recommendations for screening, prevention, and treatment of bone loss Proper selection of agents to treat and prevent osteoporosis, bone metastases, and skeletal related events can lead to significant improvements in patient outcomes Source: Red Book Online ( 15

17 Role of Pharmacists in Maintaining Bone Health in Patients with Cancer SELECTED REFERENCES Brufsky AM, Harker WG, Beck JT et al. Final 5-year results of Z-FAST trial: adjuvant zoledronic acid maintains bone mass in postmenopausal breast cancer patients receiving letrozole. Cancer. 2012; 118: Carney JF, Davis J. Emerging bone health issues in women with breast cancer in Hawai'i. Hawaii Med J. 2007; 66: Coleman R, de Boer R, Eidtmann H et al. Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results. Ann Oncol. 2013; 24: Coleman RE, Marshall H, Cameron D et al. Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med. 2011; 365: Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic fractures. Lancet. 2002; 359: De Vries F, Bracke M, Leufkens HG et al. Fracture risk with intermittent high-dose oral glucocorticoid therapy. Arthritis Rheum. 2007; 56: Eastell R, Adams JE, Coleman RE et al. Effect of anastrozole on bone mineral density: 5-year results from the anastrozole, tamoxifen, alone or in combination trial J Clin Oncol. 2008; 26: Eastell R, Adams J, Clack G et al. Long-term effects of anastrozole on bone mineral density: 7-year results from the ATAC trial. Ann Oncol. 2011; 22: Ellis GK, Bone HG, Chlebowski R et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol. 2008; 26: Fizazi K, Carducci M, Smith M et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011; 377: Gnant M, Mlineritsch B, Stoeger H et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol. 2011; 12: Grigg AP, Shuttleworth P, Reynolds J et al. Pamidronate reduces bone loss after allogeneic stem cell transplantation. J Clin Endocrinol Metab. 2006; 91: Israeli RS, Rosenberg SJ, Saltzstein DR et al. The effect of zoledronic acid on bone mineral density in patients undergoing androgen deprivation therapy. Clin Genitourin Cancer. 2007; 5: Lewiecki EM, Bilezikian JP. Denosumab for the treatment of osteoporosis and cancer-related conditions. Clin Pharmacol Ther. 2012; 91:

18 Role of Pharmacists in Maintaining Bone Health in Patients with Cancer Lipton A, Fizazi K, Stopeck AT et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer. 2012; 48: Lustberg MB, Reinbolt RE, Shapiro CL. Bone health in adult cancer survivorship. J Clin Oncol. 2012; 30: Morgan GJ, Child JA, Gregory WM et al. Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial. Lancet Oncol. 2011; 12: Morgan GJ, Davies FE, Gregory WM et al. Effects of induction and maintenance plus long-term bisphosphonates on bone disease in patients with multiple myeloma: the Medical Research Council Myeloma IX Trial. Blood. 2012; 119: Morote J, Morin JP, Orsola A et al. Prevalence of osteoporosis during long-term androgen deprivation therapy in patients with prostate cancer. Urology. 2007; 69: National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: breast cancer. v (accessed 2013 Apr 9). National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prostate cancer. v (accessed 2013 Apr 9). National Osteoporosis Foundation. Clinician s guide to prevention and treatment of osteoporosis (accessed 2013 Apr 9). Rosen LS, Gordon D, Kaminski M et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer. 2003; 98: Saad F, Gleason DM, Murray R et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002; 94: Shapiro CL, Halabi S, Hars V et al. Zoledronic acid preserves bone mineral density in premenopausal women who develop ovarian failure due to adjuvant chemotherapy: final results from CALGB trial Eur J Cancer. 2011; 47: Small EJ, Smith MR, Seaman JJ et al. Combined analysis of two multicenter, randomized, placebocontrolled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol. 2003; 21: Smith MR, Egerdie B, Hernandez Toriz N et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009; 361: Smith MR, Kabbinavar F, Saad F et al. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol. 2005; 23:

19 Role of Pharmacists in Maintaining Bone Health in Patients with Cancer Smith MR, Saad F, Coleman R et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. 2012; 379: Tauchmanova L, De Simone G, Musella T et al. Effects of various antireabsorptive treatments on bone mineral density in hypogonadal young women after allogeneic stem cell transplantation. Bone Marrow Transplant. 2006; 37:81-8. U.S. Preventive Services Task Force. for osteoporosis. January (accessed 2013 Apr 9). Van Poznak CH, Temin S, Yee GC et al. American Society of Clinical Oncology clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol. 2011; 29: can+society+of+clinical+oncology+clinical+practice+guideline+update+on+the+role+of+bone- Modifying++in+Metastatic+Breast+Cancer (accessed 2013 Apr 9). Wirth M, Tammela T, DeBruyne F et al. Effectiveness of zoledronic acid for the prevention of bone metastases in high-risk prostate cancer patients. A randomized, open-label, multicenter study of the European Association of Urology (EAU) in cooperation with the Scandinavian Prostate Cancer Group (SPCG) and the AUO. A report of the ZEUS study. Presented at the 2008 American Society of Clinical Oncology 2008 Genitourinary Cancers Symposium. San Francisco, CA: February 14-16, Abstract 184. World Health Organization. FRAX WHO fracture risk assessment tool. (accessed 2013 Apr 9). 18

20 Role of Pharmacists in Maintaining Bone Health in Patients with Cancer SELF- ASSESSMENT QUESTIONS 1. Compared to tamoxifen, aromatase inhibitors are associated with which of the following? a. Similar rates of bone loss. b. Higher rates of bone loss. c. Lower rates of bone loss. d. No difference. 2. Results of the Z-FAST and ZO-FAST demonstrated that a. Early initiation of zoledronic acid was equal to delayed initiation in reducing bone loss. b. Delayed initiation of zoledronic acid was associated with better efficacy against bone loss with less toxicity. c. Early initiation of zoledronic acid was associated with better efficacy against bone loss with similar toxicity. 3. RF is a 58 year old woman with a diagnosis of locally advanced breast cancer that is ER+. She is started on adjuvant chemotherapy and anastrazole. Based on the results of the AZURE trial, what patient specific characteristic might help you decide if RF should receive a bisphosphonate? a. Age. b. Metastatic disease. c. Menopausal status. d. Type of adjuvant treatment. 4. The incidence of chemotherapy Induced Ovarian Failure depends on which of the following factors? Answers 1. b 2. c 3. c 4. d a. Age. b. Class of chemotherapy. c. Cumulative exposure. d. All of the above. 19

21 Role of Pharmacists in Maintaining Bone Health in Patients with Cancer Instructions for Processing CPE Credit All CPE credit processed on the elearning site will be reported directly to CPE Monitor. To claim pharmacy credit, you must have your NABP e-profile ID, birth month, and birth day. If you do not have an NABP e-profile ID, go to for information and application. Please follow the instructions below to process your CPE credit for this activity. 1. The ASHP elearning site allows participants to obtain statements of continuing pharmacy education (CPE) conveniently and immediately using any computer with an internet connection. Type the following link into your web browser to access the e-learning site: elearning.ashp.org. 2. If you already have an account registered with ASHP, log in using your username and password. If you have not logged in to any of the ASHP sites before and/or are not a member of ASHP, you will need to set up an account. Click on the Register link and follow the registration instructions. 3. Once logged in to the site, enter the enrollment code for this activity in the field provided and click Redeem. Note: The Enrollment Code was announced at the end of the live activity. Please record the Enrollment Code in the grid below for your records. 4. The title of this activity should now appear in a pop-up box on your screen. Click on the Go button or the activity title. 5. Click on the Evaluation link. Complete the evaluation and click Submit. A green should now appear beside Evaluation. You can now claim your credit. 6. Look for your profession on the right side of the screen and click the appropriate Claim button. Reminder: To claim credit, you will need to enter your NABP e-profile ID, birth month, and birth day. Once you have entered this information the first time, it will auto fill in the future. 7. Review the information for the credit you are claiming, and fill in your NABP e-profile ID, birth month, and birth day. If the information all appears to be correct, check the box at the bottom and click Claim. You will see a message if there are any problems claiming your credit. 8. After successfully claiming credit, you may print your statement of credit by clicking on Print Statement of Credit. If you require a reprint of a certificate, you can return here at any time to print a duplicate. Please note that printed certificates may not be necessary because your CPE credit will be reported directly to CPE Monitor. Date of Activity Wednesday, April 17, 2013 Activity Title Role of Pharmacists in Maintaining Bone Health in Patients with Cancer Enrollment Code Credit Hours _ 1.0 NEED HELP? Contact ASHP Advantage at elearning@ashp.org. 20