Carrie Tompkins Stricker, PhD, RN Director of Clinical Programs Oncology Nurse Practitioner LIVESTRONG Survivorship Center of Excellence Clinical Assistant Professor, School of Nursing Abramson Cancer Center University of Pennsylvania Philadelphia, Pennsylvania Clinical Management of Skeletal Integrity in Prostate Cancer: The Role of the Oncology Nurse in Optimizing Patient Outcomes This program is supported by an educational donation from

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Overview  2 major bone health issues in prostate cancer patients: –Bone loss –Bone metastases

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Epidemiology of Prostate Cancer  Incidence –Estimated 217,730 new cases in 2010 –Most common cancer in men  Clinical features –Median age at diagnosis: 67 yrs –80% diagnosed while cancer confined to the prostate –Overall, 5-yr survival: 98.8%  Given long-term survival, disease- and treatment-related morbidity are substantial concerns SEER. Available at: Saylor PJ, et al. J Natl Compr Canc Netw. 2010;8:

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Prostate Cancer Treatment  Clinically localized stage I and II –Surveillance, XRT, radical prostatectomy –XRT ± ADT in intermediate-risk patients  High-risk recurrence, including stage III –XRT with ADT, radical prostatectomy ± ADT  Metastatic: stage IV –ADT with medical or surgical castration is first-line therapy –Supportive care: prevention and treatment of SREs in prostate cancer with bone metastases NCCN. Available at:

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Prostate Cancer and Bone Health  2 major issues –Bone loss with ADT –Bone metastases

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Bone Loss and ADT  The extent of the problem –> 1/3 of the 2 million men with prostate cancer in the US are currently treated with ADT –ADT causes marked reductions in testosterone –Testosterone is critical to the maintenance of BMD –Hypogonadism causes loss of BMD and increased fracture risk –1/4 of all hip fractures in the US are in men –Mortality after hip fracture is ~ 37.5% in men Saylor PJ, et al. J Natl Compr Canc Netw. 2010;8:

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Bone Loss in Prostate Cancer  Men without ADT –1/4 to 1/3 have osteoporosis –Risk factors –Older than 70 yrs of age, low calcium intake  ADT –Most rapid loss in Yr 1 (up to 9.6%) –Average 2% to 3% loss/yr thereafter –Similar rate as perimenopausal women –19.4% rate of fracture (vs 12.6% in men without ADT) Saylor PJ, et al. J Natl Compr Canc Netw. 2010;8: Stricker CT. In: Brown C, editor. A guide to oncology symptom management. Pittsburgh, Penn: ONS Press; pp

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Pathophysiology of Bone Loss  Normal bone physiology and remodeling  Pathophysiology of bone loss with ADT

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Bone Remodeling  Continuous throughout life  Maintained by tightly coupled balance between osteoblastic and osteoclastic activity –Osteoblasts: cells that create bone –Osteoclasts: cells that break down bone  Ensures skeletal integrity  Maintains mineral homeostasis Stricker CT. In: Brown C, editor. A guide to oncology symptom management. Pittsburgh, Penn: ONS Press; pp

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Normal Bone Remodeling Osteoclastic bone resorption New bone formation Hattner R, et al. Nature. 1965;206:

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Abnormal Bone Remodeling Leads to Osteoporosis Osteoporosis Osteoclastic bone resorption Osteoblastic new bone formation OUTWEIGHS

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Nursing considerations  Only 14% to 26% of men receiving ADT are screened or treated for osteoporosis  Most fractures occur in men receiving ADT who do not have osteoporosis  Guidelines are available for assessment and management of bone loss Saylor PJ, et al. J Natl Compr Canc Netw. 2010;8: Stricker CT. In: Brown C, editor. A guide to oncology symptom management. Pittsburgh, Penn: ONS Press; pp

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer WHO Definitions of BMD NormalBMD within 1 SD of a “young normal” adult (T-score of -1.0 and above) OsteopeniaBMD is between 1.0 and 2.5 SD below that of a “young normal” adult (T-score between -1.0 and -2.5) OsteoporosisBMD is 2.5 SD or more below that of a “young normal” adult (T-score at or below -2.5)

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer WHO FRAX Tool  WHO-developed tool  Goal: to evaluate fracture risk of patients based on individual patient models –Integrates femoral neck BMD and –Clinical risk factors –Age, race, sex –Personal and parental history of fracture –Smoking (current) and alcohol use (≥ 3 units/day) –BMI –History of glucocorticoid use, rheumatoid arthritis WHO. Available at: Kanis JA, et al. Osteoporosis Int. 2008;19:

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer National Guidelines: Threshold for Initiating Therapy  National guidelines recommend initiating therapy with –A low T-score (≤ -1.0) at the femoral neck or spine and either –10-yr probability of hip fracture ≥ 3% or –10-yr probability of major osteoporotic fracture ≥ 20% NCCN. Available at: National Osteoporosis Foundation. Available at:

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Nursing Implications  Educating the patient about bone health–promoting strategies is critical –Recommended calcium and vitamin D levels –Amounts and sources, including supplements –Promotion of weight-bearing exercise –Avoidance of negative health behaviors –Smoking, excessive alcohol intake  Promoting tolerability of and adherence to –Calcium/vitamin D supplements –Exercise –Prescribed pharmacologic therapy (if initiated)  Ongoing monitoring of vitamin D Stricker CT. In: Brown C, editor. A guide to oncology symptom management. Pittsburgh, Penn: ONS Press; pp

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Adapted from National Osteoporosis Foundation updated recommendations for calcium and vitamin D intake. Available at: (updated July 27, 2007). NOF Recommendations for Calcium and Vitamin D Intake AgeCalciumVitamin D* Younger than 50 yrs1000 mg/day IU/day 50 yrs or older1200 mg/day IU/day *Vitamin D3 is the best form of vitamin D for bone health and can be obtained from supplements as well as dietary sources such as fortified milk, egg yolks, and saltwater fish.

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Hormonal Deprivation: Effects  Loss of gonadal hormones increases bone resorption –Osteoblastic cell activity and life span are decreased, resulting in less new bone –Osteoclastic activity is less suppressed, increasing rate of resorption  Osteoporosis/osteopenia becomes common  Risk for fracture rises Stricker CT. In: Brown C, editor. A guide to oncology symptom management. Pittsburgh, Penn: ONS Press; pp

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Denosumab  High-affinity human monoclonal antibody that binds RANKL –RANKL promotes maturation, activation, and survival of osteoclasts  Specific: does not bind to TNF-α, TNF-β, TRAIL, or CD40L  Inhibits formation and activation of osteoclasts  Administered 60 mg SQ every 6 mos  Denosumab is currently approved for postmenopausal women with osteoporosis at high risk for fracture

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Denosumab and ADT  Randomized clinical trial  N = 1468 men with prostate cancer receiving ADT –High risk for fracture (70 yrs or age or older, fracture history, or low BMD)  Denosumab 60 mg SQ every 6 mos vs placebo  Denosumab improved –BMD at the lumbar spine, total hip, femoral neck, and radius –Incidence of new vertebral fractures Smith MR, et al. J Urol. 2009;182:

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Bone Metastases and Prostate Cancer  Metastatic prostate cancer causes a high rate of bone turnover [1] –Osteoclasts and osteoblasts both activated  65% to 75% of all cases of advanced prostate cancer patients have bone metastases [2] –Mainly osteosclerotic/osteoblastic [3] –Caused by a relative excess of osteoblast activity, leading to abnormal and weak bone formation [1,3] 1.Saylor PJ, et al. Prostate Cancer Prostatic Dis. 2010;13: Coleman RE. Cancer Treat Rev. 2001;27: Ibrahim T, et al. Cancer. 2010;116:

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Types of Cancer-Related Bone Disease Osteolytic  Breast and myeloma  Bone destruction mediated by osteoclasts Osteoblastic  Prostate and breast  Bone formation mediated by osteoblasts

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Bone Metastases: Osteolytic vs Osteoblastic Breast cancer, myelomaProstate cancer

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Common Sites of Bone Metastasis  Usually heavily vascularized areas [1] –Ribs: 58% –Vertebrae: 54% –Pelvis: 40% –Less frequently to appendicular skeleton: 32%  In prostate cancer, most common site is vertebral fractures [2] 1.Nakamoto Y, et al. Clin Nucl Med. 2003;28: ; 2.Saylor PJ, et al. Prostate Cancer Prostatic Dis. 2010;13:20-27.

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Consequences of Bone Metastases  Bone pain, at times severe  Pathological fractures  Spinal cord compression  Hypercalcemia  Anticancer therapy to treat bone pain (including surgery or radiotherapy to bone)  Limited mobility  Decreased quality of life Note: SREs in red Gralow JR, et al. J Natl Compr Canc Netw. 2009;7(suppl 3):S1-S32. Saylor PJ, et al. Prostate Cancer Prostatic Dis. 2010;13:20-27.

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer ADT and Metastatic Prostate Cancer  ADT (ie, medical or surgical castration) is standard first- line therapy for metastatic prostate cancer  ADT exacerbates the elevated risk for fracture seen with bone metastases in metastatic prostate cancer  Bisphosphonate therapy for bone metastases associated with metastatic prostate cancer –Is not standard for castration-sensitive metastatic prostate cancer –Is standard therapy for castration-recurrent metastatic prostate cancer –Zoledronic acid IV 3-4 wks Saylor PJ, et al. J Natl Compr Canc Netw. 2010;8:

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer IV Bisphosphonates  Zoledronic acid proven beneficial in reducing skeletal complications in bone mets with metastatic prostate cancer  Randomized trial in prostate cancer with bone mets –4 mg, 8 mg, or placebo every 3 wks for 15 mos (8 mg decreased to 4 mg because of renal toxicity) [1] –Of 122 patients who completed 24 mos, 38% compared with 49% on placebo developed skeletal complications [2] 1.Saad F, et al. J Natl Cancer Inst. 2002;94: Saad F, et al. J Natl Cancer Inst. 2004;96:

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer IV Bisphosphonates: Adverse Effects  Generally well tolerated  Bone pain: NSAIDs often relieve  Nausea (minor)  Flulike symptoms  Anemia  Hypocalcemia  Renal toxicity  ONJ Papapetrou PD. Hormones (Athens). 2009;8: Saylor PJ, et al. J Natl Compr Canc Netw. 2010;8:

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Bisphosphonate-Associated Renal Toxicity  Ranges from asymptomatic elevation of creatinine to dialysis dependence  Occurs as early as following first dose (in 1/4 of cases)  15-min infusion time critical for prevention –Higher rates of renal toxicity with 5-min infusion  Dosing of zoledronic acid –Dose based on ClCr ClCrDose ClCr > 60 mL/min4.0 mg ClCr mL/min3.5 mg ClCr mL/min3.3 mg ClCr mL/min3.0 mg ClCr <30 mL/minNot recommended

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Bisphosphonate-Associated Renal Toxicity  Withhold therapy for –ClCr < 30 mL/min or –≥ 0.5-mg rise from a normal baseline creatinine or –≥ 1.0-mg rise from abnormal baseline creatinine –Further doses held until creatinine returns to within 10% of baseline Kyle RA, et al. J Clin Oncol. 2007;25:

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Guidelines for Prevention of ONJ  American Association of Oral and Maxillofacial Surgeons position paper –Recommend baseline dental evaluation prior to bisphosphonate therapy –If extractions needed, wait 2-3 wks before initiating therapy –Avoid invasive dental procedures while receiving bisphosphonates, when possible –Discontinue bisphosphonate therapy 3 mos on either side of elective dental surgery Wang EP, et al. J Oral Maxillofac Surg. 2007;65:

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Future Directions  Monitoring therapy with biochemical markers of bone remodeling  Denosumab for prevention and management of bone metastases in prostate cancer

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Biochemical Markers of Bone Remodeling  Bone formation –Osteocalcin –Bone-specific alkaline phosphatase –N-terminal and C-terminal propeptides  Bone resorption –N-terminal and C-terminal cross-linking telopeptides  Biochemical markers correlate with bony disease progression and SREs in clinical trials  Not yet routine in clinical practice Gralow JR, et al. J Natl Compr Canc Netw. 2009;7(suppl 3):S1-S32. Saylor PR. Prostate Cancer Prostatic Dis. 2010;13:20-27.

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Current Studies in Metastatic Prostate Cancer  Phase III: denosumab vs zoledronic acid in metastatic prostate cancer with bone mets with endpoint of SREs [1] –Denosumab superior to zoledronic acid in preliminary report [2] –Time to first on-study SRE (HR: 0.82; 95% CI: ) –Rate of multiple SREs (HR: 0.82; 95% CI: ) –Tolerability –ONJ rare and nephrotoxicity not yet observed with denosumab 1. ClinicalTrials.gov. NCT Fizazi K, et al. ASCO Abstract LBA4507.

clinicaloptions.com/oncology Clinical Management of Skeletal Integrity in Prostate Cancer Summary and Nursing Implications  Men with prostate cancer are at increased risk for bone disease, including osteopenia, osteoporosis, fracture, and bone metastases  Treatments are available to prevent fracture and other SREs in men with prostate cancer and are rapidly evolving  The role of the nurse is critical in –Patient education, including nonpharmacologic therapies –Promoting adherence to therapy –Prevention, early detection, and management of bone disease and complications –Prevention, early detection, and management of toxicity from therapy

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