GMPA 624: Pharmacology III University of Charleston-Beckley Chapter 37: Osteoporosis Spring 2013

1. GMPA 624: Pharmacology IIIUniversity of Charleston-BeckleyChapter 37: OsteoporosisSpring 2013 Kevin W. Garlow Pharm.D kcgarlow@suddenlink.net

2. Introduction • Osteoporosis is a progressive systemic disease characterized by low bone density (i.e., osteopenia) and microarchitectural deterioration of bone that predisposes the patient to bone fragility and fracture even with minimal trauma.

3. Introduction • Per the National Health and Nutrition Examination Survey III (NHANES III), approximately 10 million Americans have osteoporosis. • Approximately 1 out of every 2 women and 1 out of every 5 men will experience an osteoporosis-related fracture during their lifetime. • The most common fractures are those involving the vertebrae (spine), proximal femur (hip), and distal forearm (wrist). • Osteoporosis-related fractures account for more than 432,000 hospital admissions per year, 2.5 million medical office visits, and 180,000 nursing home admissions. • Osteoporosis is associated with increased morbidity and mortality including back pain, loss of height, kyphosis, limited physical activity, restrictive lung disease, abdominal pain, loss of independence, etc.

4. Pathophysiology • Bone is comprised of protein (i.e., collagen), cells (i.e., osteoclasts, osteoblasts, osteocytes), and minerals (i.e., calcium, phosphorus). • Architecture of bone • Trabecular (aka. Cancellous)boneconsists of a meshwork of vertical and horizontal trabeculaefound primarily in the axial skeleton (e.g, spine). • Cortical (aka. Compact) bone formed in layers and serves as a protective shell around more delicate trabecular bone, and found primarily in the peripheral skeleton (e.g., radius).

5. Pathophysiology • After linear growth ceases in young adulthood, bone is in a constant state of remodeling, with repeated cycles of bone resorptionfollowed by deposition of new bone in an effort to: • Repair microfractures. • Remodel the architecture in response to stress. • Provide calcium in response to intra- and extracellular calcium needs. • Osteoclasts adhere to the bone and subsequently remove it (i.e., resorption) by acidification and proteolyticdigestion.

6. Pathophysiology • Subsequent to this,osteoblasts cover the excavated area to begin the process of new bone formation by secreting osteoidan unmineralizedbone matrix, made largely of collagen but also osteocytes which are osteoblasts that are incorporated into the newly-formed osteoid. • Osteoid is eventually mineralized into new bone subsequent to the deposition of hydroxyapatite a type of crystalline calcium-phosphate ceramic. • Alkaline phosphatase located on the membrane of osteoblasts is thought to play a role in mineralization process as well.

7. Pathophysiology • In young adulthood the rate of resorptionequals the rate of formation, and with peak bone mineral density occurring between the ages of 20-35yo. • However, due to aging, menopause, certain disease states, and medications, an imbalance may occur. • For example, without adequate calcium intake, resorption occurs as a compensatory mechanism to increase serum calcium.

8. Diagnosis • All postmenopausal women and men >50yo should be evaluated clinically for osteoporosis risk in order to determine the need for BMD testing. • Risk factors: • Lifestyle: Low calcium intake, vitamin D deficiency, excess vitamin A, excessive caffeine, excessive alcohol (>3 drinks/day), inadequate physical activity, cigarette smoking, low Body Mass Index, etc. • Medical: age, female (i.e, white & Asian), malnutrition, poor vision, orthostatic hypotension, impaired mobility, etc. • Environmental: Lack of assistive devices in bathrooms, loose throw rugs, low level lighting, obstacles in the walking path, slippery outdoor conditions, etc. • Genetic: Cystic Fibrosis, Homocystinuria, parental history of hip fracture, Porphyria, Hemochromatosis, etc.

9. Diagnosis • Risk factors (cont’d) • Hypogonadal states: Anorexia nervosa/bulimia, premature ovarian failure, Hyperprolactinemia, Klinefelter’s Syndrome, etc. • Endocrine disorders: Adrenal insufficiency, Cushing’s Syndrome, Hyperparathyroidism (i.e., stimulates bone resorption to increase calcium), Diabetes Mellitus, Hyperthyroidism (i.e., accerlates bone remodeling), etc. • Gastrointestinal disorders: Celiac disease, Inflammatory Bowel Disease, Primary Biliary Cirrhosis, Gastric Bypass, Malabsorption, Pancreatic disease, etc. • Hematologic disorders: Hemophilia, Multiple Myeloma, Leukemia, Lymphoma, Sickle Cell Disease, Thalassemia, etc. • Rheumatological disorders: Ankylosing Spondylitis, Lupus, Rheumatoid Arthritis, etc.

10. Diagnosis • Risk factors (cont’d) • Miscellaneous disorders: Emphysema, Muscular dystrophy, Amyloidosis End-Stage Renal Disease, Congestive Heart Failure, Multiple Sclerosis, etc. • Medications: Anticoagulants (e.g., heparin), anticonvulsants (e.g., phenytoin), barbiturates (e.g., phenobarbital), Lithium (i.e., reportedly secondary to lithium-induced hyperparathyroidism), Depomedroxyprogesterone, immunosuppressives (e.g., cyclosporine, tacrolimus), cancer chemotherapy drugs, glucocorticoids (i.e., >5mg prednisone or equivalent per day for >3 months), etc.

11. Diagnosis • Laboratory studies: serum and urine calcium, thyroidstimulating hormone, cortisol, creatinine, antibodies associated with gluten-sensitive enteropathy, 25-OH-vitamin D, etc. • Corrected calcium = [0.8 * (Normal Albumin - Pt's Albumin)] + Serum Ca • Body Mass Index (BMI) • Dual-energy x-ray absorptiometry (DXA) measurement of the hip and spine is the technology now used to establish or confirma diagnosis of osteoporosis (i.e, unless the patient already has a radiographically confirmed fracture), predict future fracture risk, and monitor patients by performing serial assessments [i.e., per AACE every 1-2 years until findings are stable (i.e., BMD increasing, no fractures) then every 2 years or at a less frequent interval].

12. Diagnosis • Body Mass Index (BMI) (cont’d) • The BMD is expressed in grams of mineral per square centimeter scanned (g/cm2) and as a relationship to one of two norms: • The expected BMD for the patient’s age and sex (Z-score). • The expected BMD for young normal adults of the same sex (T-score). • Note: T-scores should be reserved for diagnostic use in postmenopausal women and men>50yo. Z-scores should be reserved for use with other technologies and populations. • The difference between the patient’s score and the norm is expressed in standard deviations (SD) above or below the mean. • 1 SD equals 10-15% of the BMD value in g/cm2.

13. Diagnosis • Body Mass Index (BMI) (cont’d) • World Health Organization classifications based on BMD measurement at the spine, hip or forearm by DXA devices, for postmenopausal men and women >50yo. • Normal: • BMD is within 1 SD of a “young normal” adult (T-score at -1.0 and above). • Low bone mass (“osteopenia”): • BMD is between 1.0-2.5 SD below that of a “young normal” adult (T-score between -1.0 and -2.5) • Osteoporosis: • BMD is 2.5 SD or more below that of a “young normal” adult (T-score at or below -2.5).

14. Diagnosis • Body Mass Index (BMI) (cont’d) • Recommendations for BMD testing. • Women>65yo and men >70yo and older regardless of clinical risk factors. • Postmenopausal women and men age>50 based upon their clinicalrisk factors. • Postmenopausal women discontinuing estrogen should be considered for bone density testing. • Women in menopausal transition with a specific risk factor associated with increased fracture risk such as low body weight, prior low-trauma fracture or high risk medication. • Adults who have a fracture after age 50.

15. Diagnosis • Body Mass Index (BMI) (cont’d) • Recommendations for BMD testing. • Adults with a condition (e.g., rheumatoid arthritis) or taking a medication (e.g., glucocorticoids in a daily dose ≥ 5 mg prednisone or equivalent for ≥ three months) associated with low bone mass or bone loss. • Anyone being considered for pharmacologic therapy for osteoporosis. • Anyone being treated for osteoporosis, to monitor treatment effect. • Anyone not receiving therapy in whom evidence of bone loss would lead to treatment.

16. Prevention • Adequate calcium intake • NOF supports the National Academy of Sciences (NAS) recommendation that women >50yo consume at least 1,200mg/day of elementalcalcium. • Intakes in excess of 1,200-1,500mg/day have limited potential for benefit and may increase the risk of developing kidney stones or cardiovascular disease. • According to a German study published in the journal Heart (February 1, 2012;98:12 926-933) found that those who regularly took calcium supplements (in addition to dietary calcium) were 86 percent more likely to have a heart attack than those who did not, and that those who relied completelyon supplements for their daily calcium intake were 139percent more likely to have a heart attack.

17. Prevention: Calcium-containing Foods

18. Prevention • Adequate vitamin D • Vitamin D is required for adequate calcium absorption. • NOF recommends an intake of cholecalciferol 800 -1,000IU/day for adults >50yo. • Note: Per AACE many patients will require 1000-2000IU/day and sometimes up to what is considered the safe maximum of 4000IU/day. • Patients at risk of low vitamin D levels include the elderly, those with malabsorption syndromes (e.g., celiac disease), chronic renal insufficiency, housebound patients, chronically ill patients, and others with limited sun exposure.

19. Prevention • Adequate vitamin D • Forms of vitamin D: • Cholecalciferol (vitamin D3) • Synthesized in the skin in vertebrates after exposure to ultraviolet light, and obtained from dietary sources as well (e.g., eggs, liver, etc.) • Ergocalciferol (vitamin D2) • Synthesized by fungal plant sources in response to UV light (e.g., lichens, mushrooms, etc.), and obtained from fortified dietary sources as well. • Calcitriol (1,25-dihydrocholecalciferol) • The hormonally active form of cholecalciferol. • Goal: 25(OH)D level of 30-60ng/mlper AACE.

20. Prevention

21. Prevention: Vitamin D-containing Foods

22. Prevention • Limit alcohol intake to no more than 2 drinks per day. • Limit caffeine intake. • Smoking cessation. • Maintain an active lifestyle including weight-bearingexercises for at least 30 minutes per day.

23. Treatment: Who to treat? • Patients with a history of hipor vertebral fracture. • Patients without a history of fractures but with a T-score ≤ -2.5. • Patients with a T-score between -1.0 and -2.5 if FRAX score (1) major osteoporotic fracture probability is >20% OR (2) hip fracture probability is >3%.

24. Treatment: FraxR Score Calculator

25. Treatment: Available Agents

26. Alendronate (FosamaxR) • Indications: Alendronate is a bisphosphonate indicated for the: • Treatment and prevention of osteoporosis in postmenopausal women. • Treatment toincreasebonemass in men withosteoporosis. • Treatment of glucocorticoid-inducedosteoporosisin patientsreceivingdaily dosages of prednisone 7.5mg or equivalent and who have low bone mineral density. • Treatment of Paget's disease of bone. • MOA: Alendronate inhibits osteoclast activity thereby decreasing bone turnover (i.e., the number of sites at which bone is remodeled)and increasing bone mass as formation exceeds resorption.

27. Alendronate (FosamaxR) • Contraindications: • Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia. • Inability to stand or sit upright for at least 30 minutes. • Use of FosamaxRoral solution in patients at increased risk of aspiration. • Hypocalcemia • Hypocalcemia and vitamin D must be corrected before initiating therapy with FOSAMAXR. Adequate calcium and vitamin D are essential during treatment. • Hypersensitivity to any component of the product.

28. Alendronate (FosamaxR) • Warnings/precautions: • Bisphosphonates may cause local irritation of the upper gastrointestinal mucosa with risk of esophagitis and esophageal ulceration/erosions with or without bleeding Use with caution in patients with Barrett’s esophagus, dysphagia, etc. • Renal impairment: FosamaxR is not recommended in patients with a CrCl <35ml/min. • Pregnancy/lactation: • Pregnancy Category C: No studies in pregnant women. Use only if the potential benefit justifies the potential risk to the mother and fetus. • Lactation:It is not known whether alendronate is excreted in human milk. Use with caution.

29. Alendronate (FosamaxR) • Warnings/precautions: • Osteonecrosis of the jaw (ONJ) • May occur spontaneouslyor following a dental extraction. • Incidence: Over 90% of the cases are associated with the intravenous form of bisphosphonates, although they have been reported with oral agents as well. • Signs/symptoms: Slowly- or non-healing gum wounds, and eventually exposed bone. • Risk factors: invasive dental procedure (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures, etc.).

30. Alendronate (FosamaxR) • Warnings/precautions: • Osteonecrosis of the jaw (ONJ) (cont’d) • Recommendations: • There is no evidence that stopping the medication will reduce the risk of developing osteonecrosis of the jaw. • Bisphosphonates are incorporated into the bone matrix from which they are gradually released over a period of years(T1/2 = over 10 years). • For patients who develop ONJ while on bisphosphonate therapy refer to an oral surgeon.

31. Alendronate (FosamaxR) • Adverse effects (common): Abdominal pain (6.6%), nausea (3.6%), constipation (3.1%), diarrhea (3.1%), dyspepsia (3.6%), flatulence (4.1%), acid regurgitation (4.2%) including pyrosis (heartburn), esophageal ulceration (1.5%), gastric or peptic ulcer (1.1%), dysphagia (1%), abdominal distention (1.4%), and gastritis (1.1%). • Dosage: • Treatment of osteoporosis in postmenopausal women and treatment to increase bone mass in men with osteoporosis: 70mg po weekly • Prevention of osteoporosis in postmenopausal women: 35mg po weekly • Treatment of glucocorticoid-induced osteoporosis: • Postmenopausal women not receiving estrogen replacement therapy: 10mg poqd • All others: 5mg poqd

32. Alendronate (FosamaxR) • Duration of therapy: • The safety and effectiveness of FOSAMAXRfor the treatment of osteoporosis are based on clinical data of four years duration. • Bisphosphonates are incorporated into the bone matrix from which they are gradually released over a period of years. • Per the American Academy of Clinical Endocrinologists: • For patients with mild osteoporosis consider a “drug holiday” after 4-5 years of stability. • For patients with a high fracture risk, consider a “drug holiday” of 1-2 years after 10 years of treatment.

33. Alendronate (FosamaxR) • Patient education: • Patients should be instructed to take supplemental calcium and vitamin D if daily dietary intake is inadequate. • Take FosamaxRupon arising and at least 30 minutes before the first food, beverage, or medication of the day with 6-8 ounces of plain water only as some medications may reduce the absorption of FosamaxR. • Patients should not lie down for at least 30 minutes after taking FosamaxRand until after their first food of the day.

34. Calcitonin (MiacalcinR) • Calcitonin is a polypeptide hormone secreted by the parafollicular cells of the thyroid gland. • Miacalcin® (calcitonin-salmon) Nasal Spray is a synthetic polypeptide of 32 amino acids in the same linear sequence that is found in calcitonin of salmon origin. • Compared with human calcitonin, salmon calcitonin: • Differs by 13amino acid residues. • Is 40-50 times more potent. • Has a longer duration of action.

35. Calcitonin (MiacalcinR) • Mechanism of action: • Calcitonin, primarily through its action on bone, participates with parathyroid hormone to maintain homeostasis of blood calcium. High blood calcium levels result in increasedsecretion of calcitonin which, in turn, inhibits bone resorptionvia inhibition of osteoclast activity, thereby reducing the transfer of calcium from bone to blood. • In opposition to calcitonin and in response to low blood calcium parathyroid hormone (PTH) acts to increase serum calcium via stimulation of osteclast activity and increase bone resorption.

36. Calcitonin (MiacalcinR) • Mechanism of action: • Calcitonin has analgesic activity that is independent of its effect on bone resorption, and possibly secondary to increases in beta-endorphin levels and other factors. • Indications: • The treatment of postmenopausal osteoporosis in females greater than 5 years postmenopause with low bone mass. • MiacalcinR Nasal Spray should be reserved for patients who refuse or cannot tolerate, or in whom estrogens are contraindicated. • MiacalcinR Nasal Spray is recommended in conjunction with an adequate calcium and vitamin D intake.

37. Calcitonin (MiacalcinR) • Warnings/precautions: • Because calcitonin is a polypeptide, the possibility of a systemic allergic reaction exists (e.g., anaphylaxis, anaphylactic shock, etc.). • For patients with suspected sensitivity to calcitonin, skin testing should be considered prior to treatment utilizing a dilute, sterile solution of Miacalcin® Injection. • Pregnancy/lactation: • Pregnancy category C: Not recommended for use during pregnancy. • Nursing: Unknown as to if the drug is excreted in human milk, and is therefore not recommended.

38. Calcitonin (MiacalcinR) • Warnings/precautions (cont’d): • Periodic nasal examinations with visualization of the nasal mucosa, turbinates, septum and mucosal blood vessel status are recommended. • However, the development of mucosal alterations or transient nasal conditions occurred in up to 9% of patients who received MiacalcinRNasal Spray and in up to 12%of patients who received placebo. • However, the development of nasal ulcerations have been reported. • MiacalinR should be discontinued should the patient develop severe nasal ulcerations (e.g., >1.5mm in diameter, penetration below the mucosa, heavy bleeding, etc.). • Otherwise, for smaller ulcerations, MiacalcinR should be withdrawn until healing occurs and then resumed.

39. Calcitonin (MiacalcinR) • Adverse effects (common): rhinitis (12%), nasal symptoms (12%), epistaxis (3.5%), headache (3.2%), and sinusitis (2.3%). • Dosage: One spray (200 I.U.) daily intranasallyalternating nostrils daily.

40. References • http://www.nof.org/files/nof/public/content/file/344/upload/159.pdf • http://stg.centrax.com/ama/osteo/part4/module03/pdf/osteo_mgmt_03.pdf • http://www.who.int/chp/topics/Osteoporosis.pdf • http://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/ • http://ods.od.nih.gov/factsheets/Calcium-HealthProfessional/ • http://www.shef.ac.uk/FRAX/tool.jsp • http://www.nutripeople.co.uk/print/691 • http://www.merck.com/product/usa/pi_circulars/f/fosamax/fosamax_pi.pdf • http://www.aaom.com/patients/bisphosphonate-therapy-and-the-oral-cavity/ • http://www.pharma.us.novartis.com/cs/www.pharma.us.novartis.com/product/pi/pdf/miacalcin_nasal.pdf • https://www.aace.com/files/osteo-guidelines-2010.pdf