1. Peggy Piascik PhD PPS 946 1/20/16

2.  Discuss the pathophysiology, risk factors, and screening for osteoporosis  Explain prevention strategies  Determine when it is appropriate to initiate drug therapy  Describe pharmacologic management of osteoporosis including mechanisms, benefits, and ADRs of the various treatment options  Discuss current guidelines from NOF and NAMS for osteoporosis treatment.  Develop a treatment plan for a patient with osteoporosis

3.  Most common bone disease  Primary – due to loss of bone mass  Secondary – due to medications (corticosteroids) or disease (malabsorption)  Characterized by low bone mass, deterioration of bone tissue, disruption of bone architecture, ↓bone strength, ↑ risk of fracture  >10 million Americans with additional 33.6 million at risk (low bone density at the hip)  1:2 Caucasian women and 1:5 men will have osteoporosis-related fracture  Silent disease – fracture is often first sign  Recall pathophysiology of bone – osteoclasts, osteoblasts, bone resorption and remodelling

4.  BMD – bone mineral density, most common measure of bone quality  Peak BMD achieved by age 30  WHO diagnostic classification  at hip or lumbar spine < 2.5 standard deviations below mean BMD of young adult reference population (called T score)  Z score is used for women under 50 (BMD compared to mean BMD of women same age)

5.  World Heath Organization definitions:  Normal: T-score = >-1.0  Low bone mass: T-score = -2.5  Osteoporosis: T-score = <-2.5  Measurement is done at hip (femoral neck or total hip), spine, or radius  One SD ↓ in BMD (T score ↓ by 1) = 10-12% ↓ in BMD  ↑ fracture risk by 1.5-2.6 X

6.  All women age >65, regardless of risk factors (men>70yr)  Postmenopausal women with medical causes of bone loss (steroid use, hyperparathyroidism) regardless of age  Postmenopausal women age >50 with additional risk factors  Postmenopausal women with a fragility fracture (from fall from standing height)  DXA scan is gold standard  Retest? 2-5 yrs in untreated ▪ 2 years after start of therapy to monitor response ▪ Never if a change in the results of testing are unlikely to change patient care

7.  Responsible for 90% of hip and spine fractures in women 65-84  4% of women 50-59 yrs  52% pf women >80 yrs  Hip fractures – 25% increase in mortality within 1 year; 25% in LTC, 50% loss of mobility  Fractures cause pain, loss of mobility and loss of independence, change in mood and self-esteem

8.  Identify and reduce risk factors  Initiate lifestyle changes as appropriate  Decrease fracture risk  Relieve symptoms  Increase BMD or reduce further bone loss  Optimize therapy for prevention and treatment of osteoporosis

9.  Age (50-90 years) and sex  Weight & Height - BMI  Low femoral neck BMD  Prior fragility fracture + parental hx of hip fracture  Current smoker  Long-term use of glucocorticoids  Rheumatoid arthritis  Other causes of secondary osteoporosis  Alcohol intake of more than two drinks daily Adapted from World Health Organization Collaborating Centre for Metabolic Bone Diseases Also genetics, menopause status, vit D and Ca intake affect osteoporosis

10.  For all postmenopausal women regardless of of BMD and risk factors  Living a bone-healthy life  Diet, exercise, smoking cessation, fall prevention  Never too early to start  Importance often unappreciated

11.  Limit caffeine, cola, carbonated beverages, alcohol, and sodium  Calcium –dairy products are good sources  Vitamin D – sunlight/dietary sources often inadequate  Vitamin K – deficiency increases risk  Protein – high intake protects against fracture  Soy – contains weak estrogenic principles

12.  Decreases risk of fracture and falls by improving muscle strength, coordination, balance, and mobility.  Importance of optimizing peak bone mass from birth up to early 30s  Moderate intensity weight-bearing exercise is recommended  30 minutes on most days  Resistance activity  Twice weekly for 20-30 minutes

13.  Smoking is an independent risk factor to developing osteoporosis  ↓BMD, menopause 2 yrs earlier  Up to 80% increased relative risk for hip fracture  Dose and duration dependent  Why?  ↓ sex hormone levels  ↓ calcium absorption  Direct effect on osteoblasts

14.  Especially important in the elderly  Home considerations  Lighting, rugs, handrails, storage  Cognitive effects of drug therapy  Importance of pharmacist medication review after a fall  Hip protectors

15.  Drug therapy is recommended by the National Osteoporosis Foundation (NOF) if:  History of hip or vertebral fracture  T-score < -2.5  T-score -1.0 - -2.5 at the femoral neck or spine, age 50 and older with 10-year hip fracture probability ≥ 3% or a 10-year major osteoporosis-related fracture probability ≥ 20%  http://www.shef.ac.uk/FRAX/ http://www.shef.ac.uk/FRAX/

18. 1. Calcium and Vitamin D 2. Bisphosphonates 3. Estrogens 4. Selective Estrogen Receptor Modulators (SERMS) 5. Calcitonin 6. Parathyroid hormone 7. Monoclonal antibody - Prolia

19. Women Adolescent women 1300mg 19-50 YO1000mg All women >50YO1200mg Adult Men 19-50 YO1000mg >70 YO1200mg Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes: Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press, 2010.

20. Estimate dairy products at 300mg/serving

21. Average daily dietary calcium intake in adults age 50 and older is 600- 700mg/day. 75-80% of dietary calcium comes from dairy products.

22.  ADRs: Dyspepsia, Constipation, Kidney Stones  Drug Interactions – PPI, H2RA, TCN, FQ, iron  Counsel patients to divide doses to <600mg at each dose  Additional benefits - ↓blood pressure and cholesterol

23.  Calcium carbonate – 40% elemental - DOC  Absorption is acid-dependent  Patient Counseling: Take with meals  Calcium citrate – 24% elemental  Absorption is acid-independent  Less GI upset  Calcium gluconate – 9% elemental

24.  Cholecalciferol (D3) and Ergocalciferol (D2)  Calcitriol - does not require renal activation  Dosage:  Adults<50: 600 IU (400-4000)  Adults 51-70: 600 IU (800-4000)  Adults >70: 800 IU (800-4000)  Upper limit of 4000mg  Non-skeletal benefits - Muscle strength, CV function, ↓ cancer risk, ~ positive immunomodulating effects  Dietary sources – milk (400IU/qt), cereal, salt-water fish, liver Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes: Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press, 2010.

25.  "Except for postmenopausal women, there is inadequate evidence to estimate the benefits of vitamin D or calcium supplementation to prevent fractures in noninstitutionalized adults," Dr. Moyer writes. "Due to the lack of effect on fracture incidence and the increased incidence of nephrolithiasis in the intervention group of the WHI trial, the USPSTF concludes with moderate certainty that daily supplementation with 400 IU of vitamin D 3 and 1000 mg of calcium has no net benefit for the primary prevention of fractures in noninstitutionalized, postmenopausal women.“ Recommendation statement on behalf of the USPSTS online February 26 in the Annals of Internal Medicine

26.  MOA: inhibit osteoclast activity to reduce bone loss and resorption  Incorporated into bone and therefore have long T1/2  ↓ fracture risk and ↑ BMD  Significant ↑ in BMD at spine and hip in dose- dependent manner  available oral and injectable; daily, monthly and yearly injections

27. Tx of OsteoporosisPrevention Alendronate (Fosamax)*70 mg Weekly OR 10 mg Daily35 mg Weekly 5 mg Daily Alendronate +D70 mg/2800 OR 5600 IU Weekly Risedronate * (Actonel) 35 mg Weekly OR 5 mg Daily 75mg 2days/month OR 150mg/month 150mg q month 35 mg Weekly 5 mg Daily Risedronate + Ca35mg weekly + Ca carbonate 1250mg Days 2-7 Ibandronate (Boniva)150mg /mo PO 3 mg IV every 3 months 150 mg q month Zoledronic acid (Zometa, Reclast) 5mg IV Yearly over at least 15 min5mg IV over 15 min q 2 years

28.  Counseling points for oral agents  Take medication on empty stomach with at least 6 oz of water  Do not eat, drink, or lay down for 30 min (60 min ibandronate)  Do not take at the same time as other medications  Maintain good oral hygiene  ADRs  GI effects (esophagitis, ulcers, dysphagia)  Fever, chills, injection site reactions  Musculoskeletal pain  Osteonecrosis of the jaw – primarily in cancer patients receiving IV drug  Missed doses  One day for weekly agents, 7 days for monthly agent

29.  Review regimen at least yearly  Patients at low-risk for fractures may be able to D/C bisphosphonates after 5-7 years of treatment.  High-risk women should continue therapy  If therapy is D/Ced, perform DXA scan Q2 years  If bone density falls >8% in one year, >10% in 2 years, or >5% below pretreatment levels, consider restarting therapy  May also consider rotating agents  Adherence rates low – especially daily regimens

30.  FDA-approved for prophylaxis of osteoporosis  Should only be considered for women with significant risk of osteoporosis who cannot take non-estrogen therapies  Use the lowest dose possible – not studied compared to high dose  Choice of agent and route make no difference  Stopping therapy  increased bone loss, so continuous therapy may be valuable  No longer recommended as first line therapy  CEE 0.45mg + bazedoxifene 20mg (Duavee)  Estrogen +SERM  osteoporosis prevention  One tablet daily

31.  MOA:  Selectively binds to estrogen receptors ▪ Estrogen agonist at the bone tissue ▪ Estrogen antagonist in the breast and uterine tissues – could ↓ invasive breast cancer and uterine cancer ▪ Antagonist on vasculature - ↑ hot flashes  Approved for prevention and treatment  Only SERM with FDA approval - 60mg po daily  PE/DVT – Black box warning  Low Adherence Rate: at one year, ~54%

32.  Salmon calcitonin  Miacalcin, ® Fortical ® nasal spray 200 IU (1 spray) daily  Miacalcin SQ injection 100 IU every other day  MOA:  Acts like endogenous calcitonin – inhibits bone resorption ▪ 40x the affinity for the human calcitonin receptor ▪ Slower clearance than human calcitonin ▪ ↓ s serum calcium and bone resorption  Second-line treatment of osteoporosis in women >5 years post-menopause

33.  Precautions:  Salmon allergy: ▪ Possible cross-reactivity ▪ Have Epi-Pen ready and perform skin test prior to initiation  ADRs:  Nasal spray: epistaxis, rhinitis, nasal irritation, taste perversion  Injection: N/V, injection site reaction, flushing, stomach discomfort

34.  PTH1-34, Teriparatide (Forteo®)  20 mcg SQ daily into thigh/abdomen, up to 24 months in duration  MOA:  Acts like endogenous PTH to maintain calcium and phosphate homeostasis  Stimulates bone formation by ↑ serum calcium and ↓ serum phosphorus  Inhibits apoptosis of osteoblasts  Reserved for severe osteoporosis in those who cannot tolerate or who have failed bisphosphonates

35.  Contraindications:  History of osteosarcoma, Paget’s disease, history of bone radiation therapy – black box warning  ADRs:  Hypotension, tachycardia post-injection  N/V, HA  Hypercalcemia

36.  MAb against RANKL ( receptor activator of nuclear factor-  B ligand)  member of tumor necrosis factor superfamily expressed on the surface of osteoblasts  RANKL binding to RANK on surface of osteoclasts  ↑ proliferation and differentiation of osteoclasts  Blocking RANKL-RANK binding  ↓bone resorption by osteoclasts  Indication - women at high risk for fracture, hx of fracture or intolerant of other therapies  60mg subQ injection given Q6 months (Ca 1000mg and 400IU vitamin D daily)  Now approved under trade name Xgeva:   bone mass in women at high risk for fx who are receiving adjuvant aromatase inhibitor therapy for breast cancer   bone mass in men at high risk for fx who are receiving androgen deprivation therapy for non-metastatic prostate cancer

37.  ADRs – pain (back, musculoskeletal, extremity), hypercholesterolemia, cystitis, pancreatitis  CI – uncorrected pre-existing hypocalcemia  Precautions - serious infections, derm rxns, osteonecrosis of the jaw  Risk in Pregnancy?  Category C, no studies, consider risk/benefit  Pregnancy Surveillance Program

38.  No head-to-head trial with other therapies  Appears to have similar efficacy  Alternative for patients who cannot tolerate or get adequate benefit from other therapies  Long term ADRs and benefit of drug holiday unknown  No data on combination therapy  More expensive

39.  Obtain a complete Hx, PE, and DXA scan, if appropriate  Evaluate risk factors  Consider supplementation and non- pharmacologic therapies  Initiate pharmacologic therapy,if appropriate  Consider ADRs  Consider barriers to adherence, including dosing regimen and cost  Follow-up

40. 1. Low calcium intake 2. Smoking 3. High caffeine intake 4. Obesity

41. 1. 15 2. 30 3. 40 4. 50 5. 60

42. 1. Osteoporosis 2. Osteopenia 3. Osteomyelitis 4. Osteomalacia

43. 1. 1000mg, 600IU 2. 1200mg,600IU 3. 1200mg,800IU 4. 1500mg,400IU 5. 1500mg,600IU

44. 1. Vitamin D and Ca 2. alendronate 3. HT 4. calcitonin 5. Raloxifene 6. Exercise and fall prevention

45. SJ, a 50 yof, has a T score of -1.7. She has started calcium therapy and wants to know if she should do something in addition?  What questions do you want to ask SJ?  What advice do you have for SJ?