Osteoporosis Review

Osteoporosis “Silent disease” until complicated by fractures Most common bone disease in humans Characterized by: Low bone mass Microarchitectural deterioration Compromised bone strength Increased risk for fracture Want to treat before manifests symptoms Bone mass only part of the picture—other factors into play

Failure To Diagnose and Treat Studies show failure to diagnosis and treat osteoporosis in older patients who have suffered a fracture In study of 4 Midwestern health systems: 1/8 – 1/4 of hip fracture pts received BMD testing < ¼ were given calcium/D supplements < 1/10 treated with antiresorptive medications US Department of Health and Human Services: Bone Health and Osteoporosis: A Report of the Surgeon General, Office of the Surgeon General, 2004.

Risk Factors Major Additional History of fracture as an adult Fragility fracture in first degree relative Caucasian/Asian postmenopausal woman Low body weight (< 127 lb) Current smoking Use of oral corticosteroids > 3 mo. Additional Impaired vision Estrogen deficiency at early age (< 45 YO) Dementia Poor health/frailty Recent falls Low calcium intake (lifelong) Low physical activity > 2 alcoholic drinks per day Many of these are nonmodifiable. Already working against you.

Factors Associated with Bone Loss in Men Genetics Smoking/alcohol Calcium intake Physical activity/strength Testosterone production Estrogen production Hypogonadism is best-characterized risk factor for osteoporosis and osteoporotic fractures in men. Other risk factors same as women.

Medical Conditions Associated with Increased Risk of Osteoporosis COPD Cushing’s syndrome Eating disorders Hyperparathyroidism Hypophosphatasia IBS RA, other autoimmune connective tissue disorders Insulin dependent diabetes Multiple sclerosis Multiple myeloma Stroke (CVA) Thyrotoxicosis Vitamin D deficiency Liver diseases 50,000 IU weekly for six weeks Higher-dose vitamin D (700-800 IU) reduced the relative risk of both hip and nonvertebral fracture (RR 0.74, 95% CI 0.61-0.88 and RR 0.77, 95% CI 0.68-0.87, respectively). Not an inclusive list

Drugs Associated with Reduced Bone Mass Aluminum Anticonvulsants Cytotoxic drugs Glucocorticosteroids (oral/high dose inhaled) Immunosuppresants Gonadotropin-releasing hormone (e.g. Lupron) Lithium Heparin (chronic use) Supraphysiologic thyroxine doses Aromatase inhibitors Depo-Provera Anticonvulsants—inhibit vitD metabolism Thyroxine- keep towards upper end of normal Not an inclusive list

Risk Assessment/Diagnosis After menopause, all women should be evaluated clinically for osteoporosis risk to determine need for BMD testing 50-60% of men with osteoporosis have disorders known to reduce bone loss, such as hyperparathyroidism, intestinal disorders, malignancies, conditions resulting in immobilization BMD recommended in men with known risk factors and who have lost > 1.5 inches in height Diagnosis can be established in patients who have never had a fragility fracture by BMD measurement

World Health Organization Diagnostic Criteria DIAGNOSIS BMD CRITERIA * Normal within 1 SD of a “young normal” adult (T-score at -1.0 and above) Osteopenia between 1 and 2.5 SD below that of a “young normal” adult (T-score between -1 and -2.5) Osteoporosis 2.5 SD or more below that of a “young normal” adult (T-score at or below -2.5) Severe Osteoporosis 2.5 SD or more below that of a “young normal” adult and fracture(s) T-score is the number of SDs above or below the average BMD value for young, normal adults of the same sex BMD = Bone mineral density SD = Standard deviation *Measured at the hip, spine, or wrist OP is a continuum. With arbitrary lines put on bell-shaped curve as populations studied. Goal is to prevent seeing these T-scores. BMD expressed as relationship to two norms: the expected BMD for patient’s age and sex (Z-score) or for “young normal” adults of same sex (T-score). Difference between pt’s score and norm is expressed in SD above or below the mean. Women who have lost 1 ½ inches of height, women presenting with fractures Z-score: compares your score to age, sex, race-matched people. If don’t look like peers, look into secondary cause.

Who Should be Tested? Decision to test based on individual risk profile, never indicated unless results influence treatment decision BMD testing should be performed on: All women 65 YOA and older regardless of risk factors* Younger postmenopausal women with one or more risk factors (other than being white, postmenopausal and female) Postmenopausal women who present with fractures (confirm diagnosis, determine disease severity) Medicare covers BMD testing for the following individuals aged 65 and older: Estrogen deficient women at clinical risk for OP Individuals w/vertebral abnormalities Individuals receiving or planning to receive long-term steroid therapy Individuals w/primary hyperparathyroidism Individuals being monitored to assess response or efficacy of an approved OP drug therapy Recommendations and focus will be on women—will cover men towards end of the talk. *Medicare permits repeat BMD testing every 2 years.

NOF – Clinician’s Guide to Prevention and Treatment of Osteoporosis www.nof.org Released 2/21/08 (previous update in 2003) Guidelines expanded to include African-American, Asian, Latina and other postmenopausal women, also addresses men 50 years and older Dramatically alters approach to assessing fracture risk and treatment Will help identify people at high risk for developing osteoporosis/fractures and ensure appropriate treatment Uses absolute fracture risk methodology to enhance treatment decisions to individualize plan for each patient

NOF’s Clinician’s Guide Applies the recently released algorithm on absolute fracture risk call FRAX® by the WHO Also called 10-year fracture risk model and 10-year fracture probability Estimates the likelihood of a person to break a bone due to low bone mass over a period of 10 years Most useful to determine if treatment needed for those with low bone mass or osteopenia http://www.shef.ac.uk/FRAX/tool.jsp?locationValue=2

Universal Recommendations Adequate intake of calcium, vitamin D Weight-bearing and muscle-strengthening exercises to reduce risk of falls/fracture Provide strategies for fall prevention Avoidance of tobacco use/excessive alcohol use Talk to your provider about bone health Have a bone density test and take medication when appropriate Several interventions to reduce fracture risk can be recommended to the general population.

Adequate Intake of Calcium/Vitamin D Adequate intakes of dietary calcium and vitamin D, including supplements if necessary Elemental calcium per day (> 50 YOA) = at least 1200 -1500 mg Vitamin D3 per day (> 50 YOA) = 800 -1000 international units (IU) Vitamin D3 (cholecalciferol) plays major role in Ca absorption Controlled clinical trials have demonstrated the combination reduces fracture risk Inexpensive, well-tolerated Safe upper limits of Ca/day = 2500 mg D = 2000 IU

Calcium/D Product Selection Product (% elemental Ca) Elemental Calcium (mg) Vitamin D (units) Comments Calcium carbonate (40) -Tums Ultra -Caltrate 600 Plus -Oscal Plus D -Viactiv Chews 400 600 500 200 125 100 Requires acidic environment for dissolution and disintegration. Best to take with meals. Greater risk for constipation with carbonate form. Calcium citrate (24) -Citracal Plus D - Citracal Petites with VitD 315 Take without regard to meals. Serving size usually equals 2 capsules so label can be misleading to patients. Vitamin D -Multivitamin (D3) -Vitamin D 120-450 100-400 Some products also come in chewable, liquid, dissolvable tablet.

Vitamin D and Fall Risk In addition to its effect on BMD, may contribute to reduction in fracture risk Improved muscle function Reduction in risk for falls Meta-analyses of 5 clinical trials (> 60 YOA) showed significant reduction in risk for falling in those taking vitamin D plus calcium versus those taking placebo Vitamin D deficiency prevalent in older adult population Inadequate sun exposure, use of sunscreen Homebound, institutionalized Northern latitudes Maintain 25-hydroxyvitamin D3 at least > 40 ng/mL Treatment: 50,000 IU vitD weekly x 6-8 weeks, then assess need for chronic monthly therapy A conservative approach to vitamin D replacement would be to give 800 IU daily with a target serum 25-hydroxyvitamin D concentration >30 ng/mL. A more aggressive approach would be to maintain serum levels >30 ng/mL, recognizing that some patients need more than 800 IU daily. Treatment dose: 50,000 IU qweek x six weeks

Regular Weight-Bearing Exercise Defined as those in which bones and muscles work against gravity as feet and legs bear the body’s weight Include walking, jogging, Tai-Chi, stair climbing, dancing, tennis, yoga Improve agility, strength, balance May increase bone density modestly, reduce fall risk, enhance muscle strength, improve balance

Avoidance of Tobacco and Alcohol Tobacco products detrimental to skeleton, overall health NOF strongly encourages tobacco cessation programs as osteoporosis intervention Excessive alcohol intake also detrimental to bone health and requires treatment Negative estrogen effects

Who Should Be Treated? NOF Recommendations – 2008 Initiate therapy to reduce fractures in postmenopausal women/men > 50 with: BMD T-scores < -2.5 at hip or spine Prior vertebral or hip fracture Low bone mass (T-scores -1.0 to -2.5 at hip or spine) when: 10-year probability of hip fracture is > 3% 10-year probability of major osteoporosis-related fracture is > 20% Based on US-adapted WHO algorithm Lost 1 ½ inches of height www.nof.org

FDA-Approved Drugs for Osteoporosis Bisphosphonates Alendronate, Alendronate plus D (Fosamax®, Fosamax Plus D®) Risedronate, Risedronate with Calcium (Actonel®) Ibandronate (Boniva®) Selective Estrogen Receptor Modulators (SERMs) Raloxifene (Evista®) Calcitonin (Miacalcin®, Fortical®, Calcimar®) Parathyroid Hormone [PTH (1-34), teriparatide] Forteo® Estrogen/Hormone Therapy (ET/HT) Premarin®, Estrace®, Prempro® Risedronate w/ calcium (500 mg as carbonate)

Bisphosphonates – Antiresorptive Agents Agents FDA-approved for: Prevention and treatment of osteoporosis in postmenopausal women Treatment to increase bone mass in men with osteoporosis Treatment of glucocorticoid-induced osteoporosis in men and women receiving glucocorticoids Treatment of Paget’s disease of bone in men and women Mechanism: inhibits bone resorption by attaching to bony surfaces undergoing active resorption and inhibiting action of osteoclasts Leads to increases in bone density and reduced fracture risk Treatment of glucocorticoid-induced osteoporosis in men and women receiving glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and who have low bone mineral density. Treatment of glucocorticoid-induced osteoporosis in men and women The recommended dosage is one 5 mg tablet once daily, except for postmenopausal women not receiving estrogen, for whom the recommended dosage is one 10 mg tablet once daily. Paget’s disease of bone in men and women The recommended treatment regimen is 40 mg once a day for six months.

Bisphosphonates – Clinical Efficacy Controlled clinical trials indicate over 3-4 year period, alendronate ↑ bone mass and ↓ incidence of vertebral, hip, and all non-vertebral fractures by 50% Controlled clinical trials indicate risedronate ↑ bone mass and ↓ risk of vertebral fractures by 40% and non-vertebral fractures by 30% over 3-year period Ibandronate has been shown in controlled clinical trials to ↑ BMD and reduce the risk of vertebral fracture by 50% over 3-year period Alendronate appears to be well tolerated and effective for at least ten years Alendronate is well tolerated and effective for at least ten years. In an extension study of 247 postmenopausal women with osteoporosis, alendronate (5 or 10 mg/day) resulted in continued increases in bone mineral density over a ten-year period [29]. The total ten-year increase in lumbar spine density was 13.7 and 9.3 percent for the 10 and 5 mg/day groups, respectively. Increases in bone mineral density were greatest in the initial five years of the study (10 and 6.8 percent for the 10 and 5 mg/day groups, respectively). Fracture benefit appeared to be maintained throughout the study. In patients assigned to discontinue alendronate after year five, a gradual loss of effect was seen (as measured by markers of bone turnover and bone density). The safety and tolerability of alendronate were similar to those of placebo. Similar ten-year results were seen in the extension study of the Fracture Intervention Trial (FIT) [30]. During years 6 to 10 of follow-up, there were no significant differences in bone mineral density at most sites in patients receiving either 5 or 10 mg of daily alendronate, suggesting that after five years of alendronate therapy (10 mg daily or 70 mg weekly), it may be reasonable to decrease to a maintenance dose (5 mg daily or 35 mg weekly).

Bisphosphonates – Dosing Alendronate* Prevention 5 mg PO daily 35 mg PO weekly Treatment 10 mg PO daily 70 mg PO weekly 70 mg/2,800 IU vitamin D PO weekly Risedronate Prevention/Treatment Ibandronate Prevention/Treatment 2.5 mg PO daily 150 mg PO monthly Treatment 3 mg IV every 3 months *Alendronate also available in oral solution.

Bisphosphonates – Administration Must be taken at least one-half hour before the first food, beverage, or medication of the day with plain water only (1 hour prior for monthly ibandronate) Should only be taken upon arising for the day Tablet should be swallowed with a full glass of water (8 oz) and patients should remain upright, walking, standing, or sitting for at least 30 minutes (60 minutes for monthly ibandronate) Should supplement with calcium/vitamin D if dietary intake inadequate

Bisphosphonates – Adverse Effects Hypocalcemia (18%) Hypophosphatemia (10%) Musculoskeletal pain, cramps – recent FDA warning Gastrointestinal Abdominal pain Acid reflux Dypepsia Esophageal ulcer Gastritis Osteonecrosis of the jaw (IV bisphosphonates) Visual disturbances (rare) First two transient, mild GI more common, less severe (ranging from 1-4%) Osteonecrosis: “dead bone.” Researchers say cases are rare, and seem most common among patients receiving intravenous bisphosphonates such as Zometa or Aredia in conjunction with chemotherapy or radiation for breast cancer and multiple myelomas. Incidents also appear more likely to follow serious dental surgery, such as a tooth extraction. Recommend routine dental care. The mandible is more commonly affected than the maxilla (2:1 ratio), and 60% of cases are preceded by a dental surgical procedure. Oversuppression of bone turnover is probably the primary mechanism for the development of this condition, although there may be contributing comorbid factors. All sites of potential jaw infection should be eliminated before bisphosphonate therapy is initiated in these patients to reduce the necessity of subsequent dentoalveolar surgery. Conservative débridement of necrotic bone, pain control, infection management, use of antimicrobial oral rinses, and withdrawal of bisphosphonates are preferable to aggressive surgical measures for treating this condition. The degree of risk for osteonecrosis in patients taking oral bisphosphonates, such as alendronate, for osteoporosis is uncertain and warrants careful monitoring. Visual disturbances: Ocular side effects including pain, blurred vision, conjunctivitis, uveitis, and scleritis have been reported with most bisphosphonates. However, these complications appear to be rare.

Bisphosphonates Contraindications/Precautions Abnormalities of the esophagus which delay esophageal emptying, such as stricture or achalasia Inability to stand or sit upright for at least 30 minutes Patients at increased risk of aspiration Hypocalcemia Should be corrected prior to initiating therapy Renal insufficiency (Not recommended if CrCl < 30-35 ml/min) Achalasia=Failure of muscle bands to relax GERD not an absolute contraindication. Weigh pros/cons.

Bisphosphonates – Missed Dose Once weekly alendronate, risedronate Take on morning after remembering, then resume once weekly on regularly chosen day Once monthly ibandronate If next dose > 7 days away, take dose the morning following the date remembered Then return to original schedule If next dose < 7 days away, wait until next scheduled dose Must not take two 150 mg tablets within the same week

Zolendronic Acid (Reclast®) Approved for treatment of osteoporosis in postmenopausal women in August 2007 Single 5 mg infusion given IV over > 15 minutes, once yearly Should still supplement with calcium/vitamin D May be ideal for those with GI contraindications to the oral formulations

Price Comparison Drug Price Alendronate (Fosamax®) 10 mg once daily 70 mg once weekly 70 mg/2800 IU weekly 30 day supply: $72.99 30 day supply: $32.99 (generic) 30 day supply: $79.70 Risedronate (Actonel®) 5 mg once daily 35 mg once weekly 30 day supply: $65.99 30 day supply: $63.99 Ibandronate (Boniva®) 2.5 mg once daily 150 mg once monthly 30 day supply: $75.99 Check formulary www.drugstore.com

Bisphosphonates Very well tolerated in patients who adhere to proper administration techniques Proper patient counseling for correct administration is KEY to reduce risk of adverse effects and increase tolerability Place in Therapy: should be considered first-line for prevention/treatment of osteoporosis in patients with no contraindications

SERMs – Raloxifene FDA-approved for: Prevention and treatment of osteoporosis in postmenopausal women Mechanism: tissue-selective activity, acts as an estrogen agonist on bone Estrogen antagonist on breast, uterus decreases total and LDL-cholesterol but does not raise triglycerides Osteoporosis — Tamoxifen provides some protection against postmenopausal bone loss due presumably to its partial agonist activity (show figure 3) [41-44]. However, the increase in bone density with tamoxifen (about 1.2 percent in the lumbar spine at two years) is substantially less than that with estrogen or a bisphosphonate such as alendronate (5 to 7 percent at two years). Bone loss has been reported in some studies, in which tamoxifen was administered to premenopausal women [42], although the effect is not universal. Not FDA approved. The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 Trial is the only prospective study of tamoxifen in which fracture risk was examined. In this study, 13,328 women were randomly assigned to tamoxifen (20 mg/day) or placebo, with the primary objective to determine whether tamoxifen reduced the incidence of invasive breast cancer in high-risk women. In the latest report with seven years follow-up, women receiving tamoxifen had significantly fewer fractures of the hip, radius, and spine (80 versus 116 in the placebo group, RR 0.68, 95 percent CI 0.51 to 0.92)

Raloxifene – Clinical Efficacy Reduces risk of vertebral fracture by 30% in patients with previous spinal fracture, 55% in patients without prior spinal fracture over 3 years Increases BMD at all skeletal sites and reduces total and LDL cholesterol Less potent antiresorptive agent than bisphosphonates, although direct comparison studies lacking Role in heart disease, breast cancer under investigation decreased serum total and LDL cholesterol by 5% to 6% and 8% to 10%, respectively, compared to placebo. STAR study: Raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts but a nonstatistically significant higher risk of noninvasive breast cancer. The risk of other cancers, fractures, ischemic heart disease, and stroke is similar for both drugs

Raloxifene – Dosing/Administration For prevention and treatment 60 mg PO once daily Can be taken any time of day without regard to meals Should supplement with calcium/vitamin D if dietary intake inadequate

Raloxifene – Adverse Effects Frequency > 10% Hot flashes Arthralgias Sinusitis Frequency 1-10% Chest pain Insomnia Migraines Peripheral edema Diaphoresis **Has been associated with increased risk of thromboembolism (DVT, PE) and superficial thrombophlebitis; risk is similar to reported risk of HRT

Raloxifene Contraindications/Precautions History of DVT/PE or at high risk Cardiovascular disease History of uterine/cervical carcinoma Discontinue at least 72 hours prior to and during prolonged immobilization Price 30-day supply = $86.99 No generic available

Raloxifene Place in Therapy: considered first-line in women who cannot tolerate bisphosphonates and have no contraindications to therapy Combination therapy (usually a bisphosphonate with a non-bisphosphonate) can provide additional small increases in BMD when compared to monotherapy Impact of combination therapy on fracture rate unknown

Estrogen/Hormone Therapy (ET/HT) FDA approved for: Prevent osteoporosis Treatment of moderate/severe vasomotor symptoms of menopause Treatment of moderate/severe symptoms of vulvar and vaginal atrophy associated with menopause Consider topical preparations to treat vaginal symptoms rather than oral ET/HT

FDA Recommendations – ET/HT When prescribing medications for osteoporosis, physicians should consider all non-estrogen therapies first When prescribing ET/HT, use smallest dose for shortest amount of time to achieve treatment goals Prescribe ET/HT products only when benefits believed to outweigh risks for a specific patient

Calcitonin FDA-approved for: Mechanism: Treatment of osteoporosis in women who are > 5 years postmenopausal Treatment of Paget’s disease of bone Adjunctive therapy for hypercalcemia Mechanism: Peptide composed of 32 amino acids which binds to osteoclasts and inhibits bone resorption Promotes the renal excretion of calcium, phosphate, sodium, magnesium and potassium by decreasing tubular reabsorption Calcitonins from many species are effective in humans, but salmon calcitonin is the one most widely used. It is highly potent in humans because of its high affinity (forty times that of human calcitonin) for the human calcitonin receptor and its slow rate of clearance.

Calcitonin – Clinical Efficacy Has been shown to increase spinal bone mass and may decrease risk of vertebral fracture Conflicting data on efficacy of calcitonin at sites other than the spine Less effective than bisphosphonates in treatment of osteoporosis Beneficial, short-term effect on acute bone pain after osteoporotic fracture (vertebral) Why pain relief occurs is not well understood; one possibility is a rise in endorphin levels induced by calcitonin. Effect of nasal calcitonin on fracture risk NOT stated in the PI. PROOF: The 200-IU dose of salmon calcitonin nasal spray significantly reduced the risk of new vertebral fractures by 33% compared with placebo. 33% reduction in new vertebral fractures over 5-yr period. Only 511 (out of 1255) completed 5-yrs. Highest dropout groups were: “other” meaning could have changed to other therapies (fosamax, nasal spray approved), and adverse effects

Calcitonin – Dosing/Administration Intranasal 200 units (1 spray) alternating nares daily Store unopened bottles in refrigerator, protect from freezing Can store open bottles at room temperature for up to 35 days Activate pump of new bottles until full spray produced (allow to reach room temperature before priming) Each bottle contains at least 30 doses IM/SQ 100 units/every other day (minimum effective dose not well-defined) Should perform skin test prior to initiating therapy Should supplement with calcium/vitamin D if dietary intake inadequate intramuscular route is recommended over the subcutaneous route when the volume of calcitonin to be injected exceeds 2 mL. Patients should keep track of number of doses taken from the bottle; after 30 doses each spray may not deliver the correct amount of medication, even if bottle is not completely empty. Injectable-have EPI on hand

Calcitonin – Adverse Effects Most common: Nasal spray: rhinitis (12%), irritation of nasal mucosa (9%), epistaxis (3.5%), sinusitis (2.3%), back pain, arthralgia, headache Injection: nausea (10%), flushing (2-5%) Temporarily withdraw use of nasal spray if ulceration of nasal mucosa occurs Periodic nasal examinations recommended Demonstrated with long-term use of calcitonin in Paget's disease, is the development of antibodies and resistance to calcitonin [1]. Serum alkaline phosphatase concentrations rise when a patient with Paget's disease becomes resistant to calcitonin, which serves to warn the physician that calcitonin has lost its efficacy. Such a warning system does not exist in osteoporosis, because calcitonin has a minimal effect on biochemical markers of bone turnover. Some experts are reluctant to use calcitonin for the long-term treatment of osteoporosis because of the fear that undetected resistance will develop. However, some studies have shown that nasal calcitonin maintains efficacy in preventing perimenopausal bone loss after as long as five years of continuous use.

Calcitonin Contraindications Precautions Drug interactions Clinical allergy to calcitonin-salmon Precautions Nasal ulcerations Tachyphylaxis (parenteral dosage forms) Drug interactions No formal studies designed to evaluate DI Price per month 200 units/mL (2): $42.08 200 units/ACT (3.7): $81.59

Calcitonin Valid option for treatment of established osteoporosis, especially when accompanied by fracture pain Place in therapy: because of cost, adverse effects, inconvenience of nasal administration, recommend using calcitonin until pain is no longer a problem and then switching to a bisphosphonate for long-term therapy Place in therapy: Use for vertebral fracture pain if needed, other analgesics may be acceptable alternatives Not recommended for prev/treatment, in general May be synergistic with agents that inhibit bone resorption. May be used in combo.

Parathyroid Hormone [PTH (1-34)] Anabolic agent FDA-approved for: Treatment of osteoporosis in postmenopausal women at high risk for fracture previous osteoporotic fracture, multiple risk factors for fracture, extremely low BMD (< -2.5), or failed/intolerant to previous treatment Treatment of primary or hypogonadal osteoporosis in men at high risk of fracture Mechanism: recombinant formulation of endogenous parathyroid hormone (PTH) stimulates osteoblast function, increases gastrointestinal calcium absorption, increases renal tubular reabsorption of calcium Enhances bone turnover by initiating greater bone formation Endogenous 84-amino-acid parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone and kidney. Physiological actions of PTH include regulation of bone metabolism, renal tubular reabsorption of calcium and phosphate, and intestinal calcium absorption. The biological actions of PTH and teriparatide are mediated through binding to specific high-affinity cell-surface receptors. Teriparatide and the 34 N-terminal amino acids of PTH bind to these receptors with the same affinity and have the same physiological actions on bone and kidney. Teriparatide is not expected to accumulate in bone or other tissues. The skeletal effects of teriparatide depend upon the pattern of systemic exposure. Once-daily administration stimulates osteoblast over osteoclast activity.

PTH (1-34) – Clinical Efficacy Shown to decrease the risk of new vertebral fractures by 65% and nonvertebral fractures by 53% versus placebo after median exposure of 19 months Increases lumbar spine BMD as well as at the femoral neck, total hip, and total body Safety, efficacy of PTH (1-34) has not been demonstrated beyond 2 years of treatment All patients received 1000 mg calcium, 400 IU vitamin D daily -Most of the gains in BMD occur in the first few months, although anti-fracture efficacy is evident only after six months or more of treatment. Patients on bisphosphonates will often have incremental improvement in BMD even after 10 years of treatment; while it appears that the BMD changes with PTH begin to level off after 18 months.

PTH (1-34) – Dosing/Administration 20 µg SQ once daily for treatment of osteoporosis Thigh or abdominal wall Forteo® prefilled pen contains 28 daily doses Important to read Medication Guide and User Manual before starting and each time medication refilled Should be administered initially under circumstances where the patient can immediately sit or lie down, in the event of orthostasis (dizziness, palpitations are transient)

PTH (1-34) – Adverse Effects Most common Dizziness, rash, nausea, headache, leg cramps, arthralgia, rhinitis, transient hypercalcemia S/s of hypercalcemia: nausea, vomiting, constipation, low energy, or muscle weakness Most adverse effects in the clinical trials were mild and generally did not lead to the discontinuation of the drug Osteosarcoma risk in animals Lead to black box warning by FDA None of the AE in the trials caused d/c of the drug. Osteosarcoma concern: The most theoretically worrisome adverse event, is the development of osteosarcoma [38]. No cases have been reported in three years of post marketing experience with teriparatide. However, a high proportion of Fischer rats administered PTH from infancy through senescence (ie, eight weeks to two years) developed osteosarcoma at doses that were in the range of 30 to 4500 mcg/day for humans. Clearly higher doses for long duration were major risks for development of osteosarcoma in rats. It should be noted there are several case reports of coexistent osteosarcoma in patients who have primary hyperparathyroidism. Although outside groups have studied the potential risk for osteosarcoma in humans, and concluded there was minimal risk, the FDA contends that PTH therapy be limited to two years, pending further post-marketing studies.

PTH (1-34) – Warnings/Precautions Increased risk of osteosarcoma (rats) – clinical relevance unknown (no excess reports in humans) Avoid in: Paget’s disease of bone Prior radiation therapy to skeleton Bone metastases Hypercalcemia History of skeletal malignancy Pregnant/nursing

PTH (1-34) – Price One-month supply $539.99 Lilly offers Forteo® Patient Assistance Program for Medicare-eligible (LillyMedicareAnswers) and non-Medicare eligible patients LillyMedicareAnswers intended for patients who are enrolled in any Medicare Part D prescription drug plan and who meet certain eligibility requirements Expected to start early 2007 For non-Medicare patients, application process includes paper application and income restrictions Call 1-877-795-4559 or visit www.lilly.com for more details For current LillyAnswers patients enrolled in Medicare Part D who meet certain qualifying criteria and are prescribed either Forteo or Zyprexa, the company will continue LillyAnswers benefits until Lilly receives a favorable advisory opinion from OIG regarding theLillyMedicareAnswers program or such other date as Lilly may later determine.

PTH (1-34) Due to safety concerns, PTH treatment should be limited to those most severely affected and for a maximum of two years Combination therapy with a bisphosphonate not recommended as effects do not appear additive Cost, daily SQ injection may be prohibitive for some patients It appears that alendronate modifies PTH action such that blunting may occur when these drugs are combined. Benefit on increased BMD was seen with combination of Forteo and HRT. Studies shown that BMD decreases after PTH d/c, therapy with antiresorptive agent helped to preserve the gains. Alternative regimens requiring less frequent administration are currently under investigation—weekly, intermittently

PTH (1-34) Place in Therapy: Recommend PTH for women or men with severe osteoporosis (low bone mineral density [T-score < -2.5] and at least one fragility fracture) who are refractory to or unable to tolerate bisphosphonate therapy In patients considered to be bisphosphonate "failures," PTH may be started approximately 3 months after bisphosphonates are discontinued Antiresorptive therapy may be considered after discontinuation of PTH to maintain gains in BMD acquired with PTH alone in those at high risk for subsequent fracture

Approaches to Monitoring Therapy Always important to ask patients about adherence, encourage continuation of therapies to reduce fracture risk Monitoring of therapy should be considered, as up to 1/6 of women taking effective therapies continue to lose bone, especially if they smoke May measure bone mineral density at a single site after one year of therapy, but results may be misleading; usually done every 2 years Drugs may decrease a patient’s risk for fracture even when there is no apparent increase in BMD Biochemical markers of bone turnover can be used to monitor response to treatment. Current evidence suggests that both the decrease in turnover and increase in BMD induced by antiresorptive therapies contribute to their antifracture efficacy. Biochemical markers show considerable variability within individuals such that fairly large changes are required to indicate a treatment effect; however, with antiresorptive therapy, the changes are often substantial.

Glucocorticoid-Induced Osteoporosis – Recommendations ACR recommends the following interventions in patients taking prednisone doses of 5 mg/day or higher for more than 3 months Calcium/vitamin D (1500mg/day, 800 IU/day) Weekly formulations of bisphosphonate therapy Replacement of gonadal steroids in men, if deficient Calcitonin therapy, if bisphosphonates contraindicated or not tolerated Follow BMD to assess if bone loss continues

How Can Health Professionals Improve Bone Health? To help patients maintain strong, healthy bones, health care professionals should: Indentify and assist in recommending appropriate treatment for individuals at high risk for osteoporosis and other bone disorders Recognize risk factors that warrant osteoporosis screening Assess diet/lifestyle for effect on bone health Advise patients to take active steps to ensure bone health Be familiar with treatment of osteoporosis/low bone mass Actively look for other bone disease that can lead to bone loss/fractures

References Actonel® Prescribing Information (www.actonel.com) Ann Intern Med 1990;112:352 Ann Intern Med 2006;144:753 Boniva® Prescribing Information (www.boniva.com) Clinical Reviews in Bone and Mineral Metabolism 2004;2(4):291 Evista® Prescribing Information (www.evista.com) Forteo® Prescribing Information (www.forteo.com) Fortical® Prescribing Information (www.fortical.com) Fosamax® Prescribing Information (www.fosamax.com)

References JAMA 2004;291(16):1999 J Clin Densitom 2004;7(1):1-6 J Am Acad Orthop Surg 2006;14:347 Miacalcin® Prescribing Information (www.miacalcin.com) Reclast® Prescribing Information (www.reclast.com) National Osteoporosis Foundation (http://www.nof.org) NEJM 2003;348:1187 NEJM 2004;350(12):1189-99 Osteoporosis Int 1998;8:1