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It takes more than milk to improve bone health!! Lawrence Drudge-Coates Urological Oncology Clinical Nurse Specialist & Hon Lecturer King’s College Hospital NHS Foundation Trust, London, UK. Functions of bone Structural support Production of blood cells For heart, lungs and marrow Red bone marrow produces blood cells in a process known as haematopoiesis Protection of internal organs From mechanical damage, particularly the brain, heart and lungs Attachment of muscles Bones act as levers for muscles, allowing voluntary movement Storage of fatty acids Yellow bone marrow contains a reserve of fat for consumption during starvation states Acid-base balance Bone buffers the blood against excessive pH changes by absorbing or releasing alkaline salts Mineral storage The skeleton is the largest depot for minerals in the body; 99% of calcium, 85% of phosphorus and 50% of magnesium are stored in the bones EAUN E-learning course (2013): www.uroweb.org/nurses/educational-resources-for-nurses Detoxification Bone tissues can store heavy metals, such as lead, which can be gradually released and excreted Normal Bone Health For normal bone health – a process called remodeling is required…… To cope with constant mechanical stress To repair tiny fractures (Micro-fractures) Ensures skeletal integrity Maintains mineral homeostasis Regulated by cytokines & systemic hormones!!! Continuous throughout life!! EAUN E-learning course (2013): www.uroweb.org/nurses/educational-resources-for-nurses Bone Remodeling………. Maintained by tightly coupled programmed balance between osteoblastic and osteoclastic cellular activity. Key cells ….. Osteoblasts: cells that produce bone Osteoclasts: cells that break down bone (Bone resorption) Bone Remodeling - Maintaining the integrity of bone “The Osteoblast & Osteoclast” Resorption 30 - 43 days Activation Osteoclasts Reversal Resting Apoptotic Osteoclasts Stromal Stromal andand bone bone lining lining cellscells Formation Preosteoblasts Osteoblasts 90 -145 days Mineralization Osteoid Adapted from Baron R. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 5th ed. 2003;1-8. Raisz LG. J Clin Invest. 2005;115:3318-3325. Eriksen EF, Axelrod DW, Melsen F. Bone Histomorphometry. New York, NY:Raven Press; 1994:13-14. Cancer Therapy Induced Bone Loss (CTIBL) In Prostate Cancer…………… ADT therapy in Prostate Cancer Indications for ADT Metastatic disease Locally advanced disease (T3-T4 stage) • N+, M0 stage: Standard adjuvant therapy in more than 2 positive nodes to radiation therapy or radical prostatectomy as primary local therapy • Symptomatic patients • M+ stage: Standard option; mandatory in symptomatic patients • PSA-Doubling Time (DT) <1 yr • Extensive T3-T4 disease • High PSA level (>25-50 ng/mL) • As concomitant/adjuvant treatment (3 years) to radiation treatment; shown to have a survival advantage for risk patients Selected patients with localised disease: (T1a –T2c stage) • Symptomatic patients, who need palliation of symptoms, unfit for curative treatment • For high-risk patients, neoadjuvant hormonal treatment and concomitant hormonal therapy plus radiotherapy result in increased overall survival ADT, androgen deprivation therapy; PSA, prostate-specific antigen 1 Mottet N et al. EAU guidelines on prostate cancer. 2014 . http://www.uroweb.org/guidelines/online-guidelines: (last accessed 4/2014) So which treatments are we looking at ? Prostate cancer Androgen deprivation therapy (ADT): LHRH injections − Leuprolide − Goserelin − Triptorelin Orchidectomy Pathophysiology of cancer treatment induced bone loss – in Prostate Cancer = European Association of Urology Nurses : e-learning course: Bone Health and Urological Cancer 2012. < The problem however exists before ADT is started…. Prevalence of Osteoporosis at Baseline and Under ADT in Prostate Cancer: Cross-Sectional Data Duration of ADT (yr) Patients (%) Osteoporosis Osteopenia Normal None 35.4 45.2 19.4 2 42.9 39.3 17.8 4 49.2 34.4 16.4 6 59.5 29.7 10.8 8 65.7 28.5 5.7 10 80.6 19.4 0 Morote J, et al. Urology. 2007;69:500-504. Bone loss in men and women at 1 year Bone loss due to hormone ablation therapy 10 Bone loss at 1 year (%) 8 6 7.4% 7.7% ♂ Naturally occurring bone loss 4.6% 4 ♂ 2.6% 2% 2 0.5% 1% 0 Normal men Postmenopausal women Menopausal women AI therapy postmenopause Androgen deprivation therapy in men AI therapy + GnRH agonist premenopause Higano CS. Nat Clin Pract Urol 2008;5:24-34; Eastell R, et al. J Bone Miner Res 2006;21:1215-23; Maillefert JF, et al.J Urol 1999;161:1219-22; Gnant M, et al. Lancet Oncol 2008;9:840-9; Shapiro CL, et al. J Clin Oncol 2001;19:3306-11. Premature menopause secondary to chemotherapy Fracture rate per person per year (%) ADT consistently increases fracture risk in men with prostate cancer 19.4 20 17.2 18 16 14 12 12.7 12.6 10 No ADT ADT 7.9 8 6.5 6 4 2 0 Shahinian 20051 (1–5 year) Smith 20062 (> 12 year) Alibhai 20103 (6.7 year) 1. Shahinian VB et al. N Engl J Med 2005;352:154–64. 2. Smith MR et al. J Clin Oncol 2005;23:7897–903. 3. Alibhai SMH et al. J Urol 2010;184:918–24. ADT, androgen-deprivation therapy Effects of osteoporosis: Vertebral and hip fractures Osteoporotic compression fractures Osteoporotic compression fracture with ‘wedge’ deformity EAUN e-learning bone health course 2013. Available at: http://www.uroweb.org/nurses/educational-resources-for-nurses/ Osteoporotic fracture of the left femur Hip Fractures Impact Mortality and Life Expectancy • 1-2 yr mortality in men is ~ 30% to 38% [1-3] • Hip fracture affects life expectancy dramatically[4,5] • Aged 60-69 yrs: 11.5 yrs of decreased life expectancy • Aged 70-79 yrs: 5.0 yrs of decreased life expectancy 1. Forsen L, et al. Osteoporosis Int. 1999;10:73-78. 2. Schurch MA, et al. J Bone Miner Res. 1996;11: 1935-1942. 3. Soderqvist A, et al. Gerontology. 2009;55:496-504. 4. Cree M, et al. J Am Geriatr Soc. 2000;48:283-288. 5. Center JR, et al. Lancet. 1999;353:878-882. NICE Guidelines (2014) : Prostate cancer: diagnosis and management Osteoporosis 1.4.12: Do not routinely offer bisphosphonates to prevent osteoporosis in men with prostate cancer having androgen deprivation therapy. 1.4.13 • Consider assessing fracture risk in men with prostate cancer who are having androgen deprivation therapy, in line with Osteoporosis (NICE clinical guideline 146) Consider measuring BMD with DXA before starting treatments that may have a rapid adverse effect on bone density (for example, sex hormone deprivation for treatment for breast or prostate cancer). 1.4.14 • Offer bisphosphonates to men who are having androgen deprivation therapy and have osteoporosis. 1.4.15 • Consider denosumab for men who are having androgen deprivation therapy and have osteoporosis if bisphosphonates are contraindicated or not tolerated. Clinical guideline Published: 8 January 2014 nice.org.uk/guidance/cg175. www.nice.org.uk/guidance/cg175/resources/prostate-cancer-diagnosisand-management-35109753913285 - access 3/11/2015. Metabolic changes from ADT…. • Weight gain (2.4% gain) • More fat Mass (10% up) • Muscle loss (3% decline) • Insulin resistance (26-65% higher fasting) • Triglycerides (26% increase) • Cholesterol (10% increase) Choi M . Korean J Urol. 2015 Jan; 56(1): 12–18. Assessment tools Establish patient history Bone mineral density (BMD) WHO/Fracture Risk Assessment Dual energy X-ray absorptiometry (DEXA) scanning FRAX: 10-year fracture probability WHO Fracture Risk Assessment tool. Available at: http://www.shef.ac.uk/FRAX (Accessed Aug 2014). Assessment and monitoring Nurses have a key role in fracture risk assessment Comorbidities Fracture history Medications Lifestyle Detailed patient history Assessment tools Referral Tanna N. Nurs Times 2009;105:28−31. Detailed patient history Major risk factors Hypogonadism (hormone ablation therapy) Prior fragility fracture (after age 40 yrs) Age (> 65 yrs) Low bone mineral density (T-score < -2.5) Family history of fracture Vertebral compression fracture Osteopaenia apparent on X-ray Saad F, et al. J Clin Oncol 2008;26:5465−76; Tanna N. Nurs Times 2009;105:28−31. Most major risk factors result from: Medications Comorbidities Less likely to be modifiable Detailed patient history Minor risk factors Rheumatoid arthritis Low dietary calcium and vitamin D Smoker Most minor risk factors result from lifestyle choices Excessive alcohol intake (> 2 units per day) Excessive caffeine intake (> 4 cups/day) Weight (< 57 kg) Weight loss (> 10% of weight at age 25 yrs) Saad F, et al. J Clin Oncol 2008;26:5465−76; Tanna N. Nurs Times 2009;105:28−31. More likely to be modifiable Measuring Bone Mineral Density (BMD) • DEXA scanning provides an estimate of BMD • low BMD scores can accurately predict the risk of future fracture* • Axial DEXA - Gold standard Measures spine - Most sensitive to early bone loss Hip : - Best predicts hip fracture and fracture at other skeletal sites - Preferential for decision making T-score: interpreting DEXA results T-score The number of standard deviations that separate the patient from the mean value of a healthy population − every unit decrease is associated with 10−12% loss of bone density World Health Organization. Guidelines for preclinical evaluation and clinical trials in osteoporosis, 1998. Non-pharmacological treatment options: Diet and lifestyle modification Calcium and vitamin D Addressing modifiable risk factors Weight-bearing exercise and falls prevention Limit alcohol and caffeine consumption Smoking cessation Hadji P, et al. Ann Oncol 2008;19:1407–16. Daily sources of calcium and vitamin D Calcium Vitamin D Yogurt, plain, low fat Cod liver oil Sardines, canned in oil, with bones Salmon (sockeye), cooked Cheddar cheese Mackerel, cooked Milk, non-fat Tuna fish, canned in water Milk, low fat Milk, vitamin D-fortified Yogurt, fruit, low fat Orange juice, vitamin D-fortified Orange juice, calcium-fortified Sardines, canned in oil Salmon, pink, canned, with bones Liver, beef, cooked Cottage cheese, 1% milk fat Egg (vitamin D in yolks) Spinach, cooked Cheese, Swiss Recommended intake: 1.2–1.5 g/day Recommended intake: 800 IU/day Supplementation may be needed Adapted from NIH. Dietary supplement factsheet: calcium; vitamin D. Available at http://dietary-supplements.info.nih.gov/factsheets/calcium.asp; http://ods.od.nih.gov/factsheets/vitamind.asp (Accessed Sept 2014); Boehnke Michaud L and Goodi S. Am J Health Syst Pharm 2006;63:534−46. Exercise recommendations Aim to increase …. muscle strength safely, decrease immobility-related complications, and prevent fall and fracture To help reduce the risk of falls and fractures the following exercises are recommended: Weight-bearing Muscle-strengthening Aerobic exercise does not support its role for improving BMD, although aerobic exercise can improve overall health Therapeutic exercise should also address osteoporosis-related deformities of spinal posture, which can increase risk of fall and fracture. The effect of strengthening exercise is augmented by proper intake of Calcium & Vitamin D As with pharmacological interventions, therapeutic exercise programmes should be individualised Exercises for people at high risk of fracture and who may have broken bones already • Strength-training exercises (exercises using body weight as resistance). - Wrist curls inc weights, Leg lifts. • Weight-bearing aerobic activities -walking, stair climbing • Flexibility exercises - stretching • Stability and balance exercises to reduce the risk of falling. Exercise and osteoporosis (2014) www.nos.org.uk/~/document.doc?id=770 Exercises to avoid • High-impact, fast - moving exercises such as jumping, running, jogging or skipping - increase compression in your spine and lower extremities. • Exercises in which you bend forwards and twist your waist, such as touching your toes or doing sit-ups - These movements put pressure on the bones in your spine. Exercise and osteoporosis (2014) www.nos.org.uk/~/document.doc?id=770 Bone targeted therapies Bisphosphonates • Bisphosphonates exert their effects by specifically inhibiting osteoclast activity (bone resorption) and inducing apoptosis (cell death) • Bisphosphonates have been shown to increase bone mineral density in clinical trials • It has not been determined if the use of bisphosphonate reduces the rate of fractures in men who receive ADT • Supplementation with calcium and vitamin D is essential Denosumab • Denosumab is a human monoclonal antibody that inhibits RANK Ligand, preventing osteoclast formation, function and survival • Denosumab is indicated for treatment of: • Men with prostate cancer receiving hormone ablation therapy, and who are at increased fracture risk • Administration is subcutaneous, at a dose of 60 mg every 6 months (for both post-menopausal women and CTIBL in prostate cancer) • Supplementation with calcium and vitamin D is essential Cancer Induced Bone Loss (CIBL) Bone Metastases………… Common sites of bone metastases • Spine • Pelvis • Ribs • Skull • Upper arm • Long leg bones Red areas show sites of highest blood flow Yellow areas show sites of medium blood flow Scan of a person with metastatic bone disease. Light areas show tumour metastasis in the bone tissue American Academy of Orthopaedic Surgeons. Metastatic bone disease. http://orthoinfo.aaos.org/topic.cfm?topic=A00093 Mundy GR. Cancer 1997;80(8 Suppl):1546-1556. Goals of management Pain control Prevent fractures and spinal cord compression Optimise quality of life Prevent hypercalcaemia of malignancy Reich CD. Clin J Oncol Nurs 2003;7:641-6. Maintain and promote mobility Assessing men with bone metastases History and physical assessment Skeletal complications Signs and symptoms Pain Assessment tools Imaging Common techniques EAUN E-learning course (2013): www.uroweb.org/nurses/educational-resources-for-nurses The concept of Skeletal-related events, or bone complications ADT-induced bone loss fractures Bone metastases Skeletal-related events (SREs) Radiation to bone Pathological fracture Spinal cord compression Surgery to bone Increased cancer burden Increased pain Decreased HRQoL Increased health resource utilisation SREs can have serious consequences Bone metastasis SREs Cost of SREs Decreased mobility Increased pain Increased hospitalisation rate and duration Decreased quality of life Increased mortality Pain should always be assessed!! Assessment is the key to providing effective pain control Repeat assessments are necessary as pain evolves Medical diagnosis Psychological assessment Pain diagnosis & treatment Cleary JF. Cancer Control 2000;7:120−31; Payne R. J Pain Symptom Manage 2000;19(1 Suppl):S12−5. Presentation of bone pain Bone issue Type of pain Bone metastasis/ bone lesions Usually dull and constant with increased intensity at night or with weight bearing Tends to develop gradually and becomes more severe within weeks to months Pathological fracture Acute and sharp with a specific focal point Spinal cord compression Initially localised, and typically increases in intensity over time May become more radicular if lumbosacral spine involved Bilateral, gripping girdle discomfort if thoracic epidural lesions Reich CD. Clin J Oncol Nurs 2003;7:641−6; Prasad D and Schiff D. Lancet Oncol 2005;6:15−24. Management Options for Bone Pain Type of Pain Treatment Options Weight bearing Surgery Palliative radiotherapy Pain medications (NSAIDs, narcotics) Neuropathic Surgery Palliative radiotherapy Pain medications (gabapentin, pregabalin, duloxetine); narcotics often less helpful Diffuse bone pain Palliative radiotherapy Pain management (NSAIDs, narcotics, muscle relaxants, radiopharmaceuticals, bone-modifying agents) Vertebral fracture Kyphoplasty/vertebroplasty Palliative radiotherapy Pain management (NSAIDs, narcotics, muscle relaxants) NCCN. Clinical practice guidelines in oncology: adult cancer pain. v.2.2012. Radium-223 Targets Bone Metastases radium-223 reduced the risk of death by 30% and prolonged time to first symptomatic skeletal event by 5.8 months. Range of α-particle Radium-223 Bone surface • Limited penetration of α emitters (~ 2-10 cell diameters) results in highly localized killing of tumour cells with minimal collateral damage to normal tissue in surrounding area Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8. Thank you for your attention!