1. Osteoporosis Ahmed Shaman Department of Clinical Pharmacy shaman@ksu.edu.sa

2. Background Reading & References Drugs for Postmenopausal Osteoporosis. Treatment Guidelines from The Medical Letter 2008:6(74);67-74. Sundeep Khosla, M.D., and L. Joseph Melton III, M.D., M.P.H. Osteopenia. N Engl J Med 2007;356:2293-300. Dipiro Chapter 93

3. Introduction Osteoporosis is a common and often silent disorder causing significant morbidity and mortality and reduced quality of life It is associated with increased risk and rate of bone fracture Common sites of fracture include the spine, hip, and wrist The fractures associated with osteoporosis have an enormous impact on individual patients Acute pain Chronic pain Loss of mobility Height loss Depression Nursing home placement Death

4. Physiology & pharmacology of bone formation

6. Bone Mineral Density

10. Measurement of Bone Mineral Density Bone mineral density can be measured at various sites throughout the skeletal system Central (hip and/or spine) Peripheral (heel, forearm, or hand) Various methods Dual-energy x-ray absorptiometry (DXA) central and peripheral sites Quantitative ultrasound Peripheral quantitative computed tomography Radiographic absorptiometry Single-energy x-ray absorptiometry Central DXA is recommended for diagnosis due to inconsistencies in T-scores measured between different sites and by different methods Peripheral sites

11. Interpreting BMD Data T-scores and Z-scores are used T-score is the number of standard deviations from the mean bone mineral density in healthy young white women The Z-score is a similar measure that is corrected for age and gender of the patient Skeletal DisordersT-scores Normal≥ -1 OsteopeniaBetween -2.5 and -1.0 Osteoporosis< -2.5

12. Clinical Presentation and Diagnosis of Osteoporosis General Many patients with osteoporosis are asymptomatic unless they experience a fragility fracture Symptoms Symptoms of fragility fracture include pain at the site of the fracture or immobility Signs Height loss (greater than 2 cm) Spinal kyphosis (“dowager’s hump”) Fragility fracture especially of the hip or spine Laboratory Tests Lab tests are only useful to rule out secondary causes of osteoporosis Diagnostic Tests Bone densitometry using DXA reveals a T-score at least -2.5 SD below the mean

13. Laboratory Evaluation Identifying or excluding secondary causes Hyperparathyroidism Low 25-hydroxyvitamin D levels Hyperthyroidism Cancer

14. TREATMENT Pharmacologic and nonpharmacologic therapies are aimed at: 1.Preventing fractures and their complications 2.Maintaining or increasing bone mineral density 3.Preventing secondary causes of bone loss 4.Reducing morbidity and mortality associated with osteoporosis

15. Treatment Lifestyle modification Calcium Vitamin D Bisphosphonates Alendronate Risedronate Ibandronate Zoledronic Acid

16. Treatment (2) Hormonal Therapy Raloxifene Estrogen Calcitonin Parathyroid Hormone Testosterone in some men

17. Lifestyle Modification

18. Drugs Causing Fall Medications associated with increased risk of falling Drugs affecting mental status antipsychotics, benzodiazepines, tricyclic antidepressants, sedative/hypnotics, anticholinergics, and corticosteroids Drugs causing orthostatic hypotension Some cardiovascular and antihypertensive

19. Calcium & Vitamin D Elderly patients or patients receiving proton pump inhibitors or H2-receptor antagonists may have added difficulty absorbing calcium supplements due to reduced stomach acidity→ Ca citrate or Ca acetate more soluble Over 65 yearsAdults under 65 years Calcium1,500 mg / day1,000 mg / day Vitamin D800 – 1,000 IU / day400 – 800 IU / day

22. Calcium Adverse Events Constipation, bloating, cramps, and flatulence Changing to a different salt form may alleviate symptoms for some patients Calcium salts may reduce the absorption of Iron Some antibiotics, such as tetracycline and fluoroquinolones (up to 50%) Thyroid hormone → separate time of administration

23. Bisphosphonates Bisphosphonates are first-line therapy for osteoporosis due to established efficacy in preventing hip and vertebral fractures Decrease bone resorption by binding active sites & inhibiting osteoclasts IV & PO formulations

24. Bisphosphonates

25. Bisphosphonates – Adverse Effects Oral: heartburn, esophageal irritation & esophagitis. Must take with about 180–240 mL of water after overnight fast & in upright position Afterwards stay upright 30-60 minutes & don’t take anything by mouth except water IV: infusion reactions, atrial arrhythmias Either (especially IV & with chronic use) Osteonecrosis of the jaw Risk factors include Chemotherapy, radiotherapy, corticosteroids, infection or pre- existing dental disease

26. Bisphosphonates Bisphosphonates are not recommended for use in patients with esophageal abnormalities, hypocalcaemia, renal insufficiency or failure (creatinine clearance less than 30–35 mL/min) Bisphosphonates should not be taken with other medications or dietary supplements(↓absorption)

27. Bisphosphonates

28. Hormones Raloxifene: Selective estrogen receptor modulator (SERM) Estrogen-like effects on bone (reduce bone resorption and decrease overall bone turnover) Prevents & treats osteoporosis, ↓ vertebral fractures by 30% AE: Hot flashes, leg cramps & edema Increase risk of thrombosis Increase risk of fatal stroke

29. Hormones Estrogen (HRT) Replacement in postmenopausal women Prevents hip and veterbral fractures by 33% Give with progestin if intact uterus to prevent endometrial cancer No longer recommended due to adverse effects Increase risk of cardiac death, MI, stroke, pulmonary embolism & breast cancer WHI and HERS studies

31. Other Pharmacotherapy Calcitonin Inhibits osteoclasts IM, SC (neutralizing antibodies) and intranasal Treatment; causes nasal irritation AEs including flushing, urinary frequency, nausea, vomiting, abdominal cramping, and irritation at the injection site Teriparatide Parathyroid Hormone, stimulates bone formation Risk of hypercalcemia, orthostatisc hypotention Treatment; black box warning for osteosarcoma

32. Treatment Overview For everyone Calcium, Vitamin D Osteopenia (T score – 1.0 to 2.49) Add Lifestyle Modification Consider pharmacotherapy risk vs benefit Osteoperosis (T score - 2.5 or more) or fracture Add pharmacotherapy (likely bisphosphonate)