OSTEOPOROSIS FOR THE GENERALIST

23. WHEN TO INITIATE THERAPY HIP T-SCORES < –2.0 NO OP RISK FACTORS HIP T-SCORES < –1.5 AT LEAST ONE OP RISK FACTOR PRIOR VERTEBRAL OR HIP FRACTURE According to the International Society for Clinical Densitometry (ISCD) 2002 position statement, the serially measured bone mineral density (BMD) change must exceed the least significant change (LSC) (as determined by an in vivo precision study) to be reported as significant. To compare follow-up BMD results with baseline, one must determine whether change over time represents biologic change or instrument noise. This is done by performing an in vivo precision study that determines precision of a particular machine and technologist. However, precision error alone does not indicate whether measured change is significant. For that, multiply the precision error by a factor to calculate the LSC. The LSC value is then used for monitoring patients on a particular DXA machine. For patients measured on that device, if change in BMD (not T-score) at follow-up exceeds the LSC, that change is considered real. Changes of lower magnitude than the LSC are considered within the measurement variation of the instrument.1 When calculating the LSC, the consensus is to use a 95% confidence interval. This value has been the most widely used in clinical densitometry, represents a higher standard, and potentially decreases the number of patients being considered for diagnostic evaluation because of apparent loss of BMD while on therapy. If the LSC is determined at 95% confidence, the precision error is multiplied by 2.77. By contrast, for 80% confidence, the precision error is multiplied by 1.81.1 1. J Clin Densitometry. 2002;5:S29-S38.According to the International Society for Clinical Densitometry (ISCD) 2002 position statement, the serially measured bone mineral density (BMD) change must exceed the least significant change (LSC) (as determined by an in vivo precision study) to be reported as significant. To compare follow-up BMD results with baseline, one must determine whether change over time represents biologic change or instrument noise. This is done by performing an in vivo precision study that determines precision of a particular machine and technologist. However, precision error alone does not indicate whether measured change is significant. For that, multiply the precision error by a factor to calculate the LSC. The LSC value is then used for monitoring patients on a particular DXA machine. For patients measured on that device, if change in BMD (not T-score) at follow-up exceeds the LSC, that change is considered real. Changes of lower magnitude than the LSC are considered within the measurement variation of the instrument.1 When calculating the LSC, the consensus is to use a 95% confidence interval. This value has been the most widely used in clinical densitometry, represents a higher standard, and potentially decreases the number of patients being considered for diagnostic evaluation because of apparent loss of BMD while on therapy. If the LSC is determined at 95% confidence, the precision error is multiplied by 2.77. By contrast, for 80% confidence, the precision error is multiplied by 1.81.1 1. J Clin Densitometry. 2002;5:S29-S38.

24. NOTE: NOT ALL PATIENTS NEED DRUGS TO TREAT THEIR BONE MINERAL ISSUES.

25. FDA-APPROVED DRUGS FOR OSTEOPOROSIS IN POSTMENOPAUSAL WOMEN BISPHOSPHONATES RISEDRONATE ALENDRONATE ESTROGEN THERAPY ESTROGEN+PROGESTIN THERAPY SELECT. ESTR. REC. MOD. (SERM) RALOXIFENE HCL

33. ASSOCIATION OF VERTEBRAL FRACTURES WITH SUBSEQUENTFRACTURE RISK This table compiles results from several different sources. It indicates that the occurrence of a vertebral fracture significantly increases the risk of both subsequent vertebral and hip fractures. 1. Ross PD, Davis JW, Epstein RS, Wasnich RD. Preexisting fractures and bone mass predict vertebral facture incidence in women. Ann Intern Med 1991;114:919-923 2. Lindsay R, Silverman SL, Cooper C, Hanley DA, Barton I, Broy SB, Licata A, Benhamou L, Geusens P, Flowers K, Stracke H, Seeman E. Risk of New Vertebral Fracture in the year following a fracture. JAMA 2001;285:320-323 3. Kanis JA. Osteoporosis and its consequences. In: Osteoporosis. Cambridge. Blackwell Healthcare Communications. 1997: 1-20 This table compiles results from several different sources. It indicates that the occurrence of a vertebral fracture significantly increases the risk of both subsequent vertebral and hip fractures. 1. Ross PD, Davis JW, Epstein RS, Wasnich RD. Preexisting fractures and bone mass predict vertebral facture incidence in women. Ann Intern Med 1991;114:919-923 2. Lindsay R, Silverman SL, Cooper C, Hanley DA, Barton I, Broy SB, Licata A, Benhamou L, Geusens P, Flowers K, Stracke H, Seeman E. Risk of New Vertebral Fracture in the year following a fracture. JAMA 2001;285:320-323 3. Kanis JA. Osteoporosis and its consequences. In: Osteoporosis. Cambridge. Blackwell Healthcare Communications. 1997: 1-20

40. BIOCHEMICAL MARKERS OF BONE TURNOVER1 Main point: This graph highlights the difference in mechanisms of action of alendronate and teriparatide by showing effects of biochemical markers of bone turnover. The objective of this study was to contrast the effects of teriparatide and those of a potent aminobisphosphonate, alendronate, on bone mineral density and biochemical markers of bone turnover. This was a randomized, double-blind, active comparator study. Postmenopausal women with osteoporosis (N = 203) were randomized to receive either daily teriparatide [rDNA origin] 20 mcg and oral placebo (N = 102) or daily alendronate 10 mg and injectable placebo (N=101) for 18 months. All participants received calcium (1000/mg) and vitamin D (400 to 800/IU) supplementation. Study endpoints were % change from baseline in overall and volumetric bone mineral density and biochemical markers of bone turnover. In the graph above, alendronate significantly decreased NTx, a marker of resorption, after 1 month and PINP, a marker of formation, after 3 months. Teriparatide significantly increased both markers of bone remodeling. Concentrations of PINP increased 105% above baseline at 1 month and peaked at 6 months (218%). The increases in NTx (58% at peak) reach significance only after 3 months of treatment. The different effects of the two drugs on bone remodeling were evident after 1 month of treatment, with significant differences between the groups for each marker at 1, 3, 6, and 12 months ( p< 0.001). According to the article (direct quote): "The significant increases in trabecular BMD observed with teriparatide are accompanied by activating bone formation and increasing trabecular bone volume, while the smaller increases in BMD seen with alendronate are the result of the inhibition of bone turnover, resulting in the filling of remodeling spaces and increased mineralization of bone matrix.” Biochemical markers of bone turnover reflect the different mechanisms of action of teriparatide and alendronate. Information regarding mechanisms of action does not provide evidence of comparative fracture protection. Reference: 1. McClung MR, et al. Opposite Bone Remodeling Effects of Teriparatide and Alendronate in Increasing Bone Mass. Arch Intern Med. 2005;165:1762-1768.Main point: This graph highlights the difference in mechanisms of action of alendronate and teriparatide by showing effects of biochemical markers of bone turnover. The objective of this study was to contrast the effects of teriparatide and those of a potent aminobisphosphonate, alendronate, on bone mineral density and biochemical markers of bone turnover. This was a randomized, double-blind, active comparator study. Postmenopausal women with osteoporosis (N = 203) were randomized to receive either daily teriparatide [rDNA origin] 20 mcg and oral placebo (N = 102) or daily alendronate 10 mg and injectable placebo (N=101) for 18 months. All participants received calcium (1000/mg) and vitamin D (400 to 800/IU) supplementation. Study endpoints were % change from baseline in overall and volumetric bone mineral density and biochemical markers of bone turnover. In the graph above, alendronate significantly decreased NTx, a marker of resorption, after 1 month and PINP, a marker of formation, after 3 months. Teriparatide significantly increased both markers of bone remodeling. Concentrations of PINP increased 105% above baseline at 1 month and peaked at 6 months (218%). The increases in NTx (58% at peak) reach significance only after 3 months of treatment. The different effects of the two drugs on bone remodeling were evident after 1 month of treatment, with significant differences between the groups for each marker at 1, 3, 6, and 12 months ( p< 0.001). According to the article (direct quote): "The significant increases in trabecular BMD observed with teriparatide are accompanied by activating bone formation and increasing trabecular bone volume, while the smaller increases in BMD seen with alendronate are the result of the inhibition of bone turnover, resulting in the filling of remodeling spaces and increased mineralization of bone matrix.” Biochemical markers of bone turnover reflect the different mechanisms of action of teriparatide and alendronate. Information regarding mechanisms of action does not provide evidence of comparative fracture protection. Reference: 1. McClung MR, et al. Opposite Bone Remodeling Effects of Teriparatide and Alendronate in Increasing Bone Mass. Arch Intern Med. 2005;165:1762-1768.

41. BONE TURNOVER MARKERS

50. THEREFORE DEXA CAN ONLY TELL US HOW MUCH CALCIUM LIES BETWEEN THE SOURCE AND THE DETECTOR—IT CANNOT TELL US ANYTHING ABOUT HOW THAT MASS OF CALCIUM IS ARRANGED.IS CALCIUM ARRANGEMENT IMPORTANT?

51. Main point: FORTEO forms normal-quality bone as demonstrated in the images shown from the same patient at baseline and completion of course of therapy of FORTEO® (teriparatide [rDNA origin] injection). These are microCT images of paired iliac crest bone biopsies, obtained at baseline and after 21 months of treatment with FORTEO, from a 65-year-old postmenopausal woman who had a BMD response that is representative of the treatment group.1 The lumbar spine BMD increased by 7.4%1 (group mean was 9.7 ? 7.4%2) and total hip BMD increased 5.2%1 (group mean was 2.6 ? 4.9%2). References: 1. Jiang Y, et al. Recombinant Human Parathyroid Hormone (1-34) [Teriparatide] Improves Both Cortical and Cancellous Bone Structure. J Bone Miner Res. 2003;18:1932-1941. 2. Neer RM, et al. Effect of Parathyroid Hormone (1-34) on Fractures and Bone Mineral Density in Postmenopausal Women With Osteoporosis. N Engl J Med. 2001;344:1434-1441.Main point: FORTEO forms normal-quality bone as demonstrated in the images shown from the same patient at baseline and completion of course of therapy of FORTEO® (teriparatide [rDNA origin] injection). These are microCT images of paired iliac crest bone biopsies, obtained at baseline and after 21 months of treatment with FORTEO, from a 65-year-old postmenopausal woman who had a BMD response that is representative of the treatment group.1 The lumbar spine BMD increased by 7.4%1 (group mean was 9.7 ? 7.4%2) and total hip BMD increased 5.2%1 (group mean was 2.6 ? 4.9%2). References: 1. Jiang Y, et al. Recombinant Human Parathyroid Hormone (1-34) [Teriparatide] Improves Both Cortical and Cancellous Bone Structure. J Bone Miner Res. 2003;18:1932-1941. 2. Neer RM, et al. Effect of Parathyroid Hormone (1-34) on Fractures and Bone Mineral Density in Postmenopausal Women With Osteoporosis. N Engl J Med. 2001;344:1434-1441.

67. CASE ML 55 YO FEMALE 6 YEARS POST MENOPAUSAL HAS BEEN STABLE ON IV BISPHOSPHONATE FOR 3 YEARS. COMES IN HORRIFIED, AND WANTS TO STOP ALL OSTEOPOROSIS TREATMENT, BECAUSE “I HAVE A TOOTH THAT NEEDS TO BE REPAIRED, AND WHEN HE DOES IT, ALL MY TEETH ARE GOING TO FALL OUT AND I WILL BE IN HORRIBLE PAIN.” SHE READ IN COSMOPOLITAN THAT THERE IS A TERRIBLE DENTAL PROBLEM WITH OP DRUGS, AND THAT ALL WOMEN SHOULD IMMEDIATELY SEE THEIR DOCTORS ABOUT IT BEFORE THEIR HEADS FALL OFF.

132. Main point: FORTEO forms normal-quality bone as demonstrated in the images shown from the same patient at baseline and completion of course of therapy of FORTEO® (teriparatide [rDNA origin] injection). These are microCT images of paired iliac crest bone biopsies, obtained at baseline and after 21 months of treatment with FORTEO, from a 65-year-old postmenopausal woman who had a BMD response that is representative of the treatment group.1 The lumbar spine BMD increased by 7.4%1 (group mean was 9.7 ? 7.4%2) and total hip BMD increased 5.2%1 (group mean was 2.6 ? 4.9%2). References: 1. Jiang Y, et al. Recombinant Human Parathyroid Hormone (1-34) [Teriparatide] Improves Both Cortical and Cancellous Bone Structure. J Bone Miner Res. 2003;18:1932-1941. 2. Neer RM, et al. Effect of Parathyroid Hormone (1-34) on Fractures and Bone Mineral Density in Postmenopausal Women With Osteoporosis. N Engl J Med. 2001;344:1434-1441.Main point: FORTEO forms normal-quality bone as demonstrated in the images shown from the same patient at baseline and completion of course of therapy of FORTEO® (teriparatide [rDNA origin] injection). These are microCT images of paired iliac crest bone biopsies, obtained at baseline and after 21 months of treatment with FORTEO, from a 65-year-old postmenopausal woman who had a BMD response that is representative of the treatment group.1 The lumbar spine BMD increased by 7.4%1 (group mean was 9.7 ? 7.4%2) and total hip BMD increased 5.2%1 (group mean was 2.6 ? 4.9%2). References: 1. Jiang Y, et al. Recombinant Human Parathyroid Hormone (1-34) [Teriparatide] Improves Both Cortical and Cancellous Bone Structure. J Bone Miner Res. 2003;18:1932-1941. 2. Neer RM, et al. Effect of Parathyroid Hormone (1-34) on Fractures and Bone Mineral Density in Postmenopausal Women With Osteoporosis. N Engl J Med. 2001;344:1434-1441.

135. LIMITATIONS OF DEXADEXA IS AN IMPERFECT TOOL FOR ASSESSING FRACTURE RISK, BUT IT IS THE BEST WE HAVE THUS FAR

136. FORTEO IS HUMAN PARATHYROID HORMONE 1-34 Main point: This slide contrasts naturally occurring PTH (1-84) with FORTEO® (teriparatide [rDNA origin] injection) recombinant human parathyroid hormone (1-34). Human parathyroid hormone is a single chain polypeptide with 84 amino acids and a molecular weight of 9425 daltons. 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 N-terminal region, 1-34, shown here in yellow, is biologically active and sufficient for regulation of mineral ion homeostasis. FORTEO contains recombinant human parathyroid hormone (1-34), [rhPTH (1-34)], which has an identical sequence to the 34 N-terminal amino acids (the biologically active region) of the 84-amino acid human parathyroid hormone. Teriparatide has a molecular weight of 4117.8 daltons and its amino acid sequence is shown above. Teriparatide is manufactured by Eli Lilly and Company using a strain of Escherichia coli modified by recombinant DNA technology. 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 and other tissues. Human PTH (1-84) refers to intact human PTH and teriparatide refers to human PTH (1-34). FORTEO refers to recombinant teriparatide 20mg. Reference: 1. Niall HD, et al. The Amino-acid Sequence of the Amino-terminal 37 Residues of Human Parathyroid Hormone. Proc Natl Acad Sci USA 1974;71:384-388. Main point: This slide contrasts naturally occurring PTH (1-84) with FORTEO® (teriparatide [rDNA origin] injection) recombinant human parathyroid hormone (1-34). Human parathyroid hormone is a single chain polypeptide with 84 amino acids and a molecular weight of 9425 daltons. 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 N-terminal region, 1-34, shown here in yellow, is biologically active and sufficient for regulation of mineral ion homeostasis. FORTEO contains recombinant human parathyroid hormone (1-34), [rhPTH (1-34)], which has an identical sequence to the 34 N-terminal amino acids (the biologically active region) of the 84-amino acid human parathyroid hormone. Teriparatide has a molecular weight of 4117.8 daltons and its amino acid sequence is shown above. Teriparatide is manufactured by Eli Lilly and Company using a strain of Escherichia coli modified by recombinant DNA technology. 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 and other tissues. Human PTH (1-84) refers to intact human PTH and teriparatide refers to human PTH (1-34). FORTEO refers to recombinant teriparatide 20mg. Reference: 1. Niall HD, et al. The Amino-acid Sequence of the Amino-terminal 37 Residues of Human Parathyroid Hormone. Proc Natl Acad Sci USA 1974;71:384-388.

139. FORTEO® (teriparatide [rDNA origin] injection) Important Safety Information Main point: FORTEO® (teriparatide [rDNA origin] injection) has a Black Box Warning. Please review this warning. “Because of the uncertain relevance of rat osteosarcoma finding to humans ...” Given the known frequency of osteosarcoma in the general population over 60 years of age (1 per 250,000 per year), rare cases can be anticipated irrespective of treatment with FORTEO. Lilly has maintained a safety monitoring program since approval in November 2002. The data from this program have not resulted in any change to the risk-benefit profile of FORTEO. ? Required Slide Main point: FORTEO® (teriparatide [rDNA origin] injection) has a Black Box Warning. Please review this warning. “Because of the uncertain relevance of rat osteosarcoma finding to humans ...” Given the known frequency of osteosarcoma in the general population over 60 years of age (1 per 250,000 per year), rare cases can be anticipated irrespective of treatment with FORTEO. Lilly has maintained a safety monitoring program since approval in November 2002. The data from this program have not resulted in any change to the risk-benefit profile of FORTEO. ? Required Slide

140. FORTEO® (teriparatide [rDNA origin] injection) Indications for FORTEO FORTEO is indicated for the treatment of postmenopausal women with osteoporosis who are at high risk for fracture FORTEO is indicated to increase bone mass in men with primary osteoporosis or osteoporosis associated with hypogonadism, who are at high risk for fracture Individuals at high risk for fracture include those who (based on physician assessment): Have a history of osteoporotic fracture, or Have multiple risk factors for fracture, or Failed previous osteoporosis therapy, or Are intolerant to previous osteoporosis therapy Main point: FORTEO® (teriparatide [rDNA origin] injection) is indicated for the treatment of postmenopausal women with osteoporosis and men with primary osteoporosis or osteoporosis associated with hypogonadism, who are at high risk for fracture. Those at high risk for fracture include women with a history of osteoporotic fracture, or who have multiple risk factors for fracture, or who have failed or are intolerant of previous osteoporosis therapy, based upon physician assessment (see BLACK BOX WARNING) ? Required SlideMain point: FORTEO® (teriparatide [rDNA origin] injection) is indicated for the treatment of postmenopausal women with osteoporosis and men with primary osteoporosis or osteoporosis associated with hypogonadism, who are at high risk for fracture. Those at high risk for fracture include women with a history of osteoporotic fracture, or who have multiple risk factors for fracture, or who have failed or are intolerant of previous osteoporosis therapy, based upon physician assessment (see BLACK BOX WARNING) ? Required Slide

141. FORTEO® (teriparatide [rDNA origin] injection) Important Safety Information Main point: Patients at increased baseline risk for osteosarcoma should not be treated with FORTEO® (teriparatide [rDNA origin] injection). The two adverse events associated with FORTEO are dizziness and leg cramps. The following categories of patients have increased baseline risk of osteosarcoma and therefore should not be treated with FORTEO® (teriparatide [rDNA origin] injection) Paget’s disease of bone. Unexplained elevations of alkaline phosphatase may indicate Paget’s disease of bone Pediatric populations and young adults with open epiphyses Prior external beam or implant radiation therapy involving the skeleton Patients with the any of the following conditions also should not receive FORTEO: Bone metastases or a history of skeletal malignancies Metabolic bone diseases other than osteoporosis Pre-existing hypercalcemia. These patients should be excluded from treatment with FORTEO because of the possibility of exacerbating hypercalcemia Pregnant and lactating women Adverse events associated with FORTEO usually were mild and generally did not require discontinuation of therapy. Early discontinuation due to adverse events occurred in 5.6% of patients assigned to placebo and 7.1% of patients assigned to FORTEO. Reported adverse events that appeared to be increased by FORTEO treatment were dizziness and leg cramps. ? Required Slide Main point: Patients at increased baseline risk for osteosarcoma should not be treated with FORTEO® (teriparatide [rDNA origin] injection). The two adverse events associated with FORTEO are dizziness and leg cramps. The following categories of patients have increased baseline risk of osteosarcoma and therefore should not be treated with FORTEO® (teriparatide [rDNA origin] injection) Paget’s disease of bone. Unexplained elevations of alkaline phosphatase may indicate Paget’s disease of bone Pediatric populations and young adults with open epiphyses Prior external beam or implant radiation therapy involving the skeleton Patients with the any of the following conditions also should not receive FORTEO: Bone metastases or a history of skeletal malignancies Metabolic bone diseases other than osteoporosis Pre-existing hypercalcemia. These patients should be excluded from treatment with FORTEO because of the possibility of exacerbating hypercalcemia Pregnant and lactating women Adverse events associated with FORTEO usually were mild and generally did not require discontinuation of therapy. Early discontinuation due to adverse events occurred in 5.6% of patients assigned to placebo and 7.1% of patients assigned to FORTEO. Reported adverse events that appeared to be increased by FORTEO treatment were dizziness and leg cramps. ? Required Slide

142. FORTEO® (teriparatide [rDNA origin] injection) Important Safety Information The safety and efficacy of FORTEO have not been evaluated beyond 2 years of treatment. Consequently, use of the drug for more than 2 years is not recommended. FORTEO should be used with caution in patients with active or recent urolithiasis or taking digitalis. Transient episodes of symptomatic orthostatic hypotension were observed infrequently in short-term pharmacology studies. Limited information is available to evaluate safety in patients with hepatic, renal, and cardiac disease. In laboratory tests, FORTEO transiently increases serum calcium, with the maximal effect observed at approximately 4 to 6 hours post-dose. By 16 hours post-dose, serum calcium generally has returned to, or near, baseline. Main point: Additional precaution should be taken with specific patient groups. In clinical trials, the frequency of urolithiasis was similar in patients treated with FORTEO® (teriparatide [rDNA origin] injection) and placebo. However, FORTEO has not been studied in patients with active urolithiasis. If active urolithiasis or pre-existing hypercalciuria are suspected, measurement of urinary calcium excretion should be considered. FORTEO should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition. In a study of 15 healthy people administered digoxin daily to steady state, a single FORTEO dose did not alter the effect of digoxin on the systolic time interval (from electrocardiographic Q-wave onset to aortic valve closure, a measure of digoxin's calcium-mediated cardiac effect). However, sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Because FORTEO transiently increases serum calcium, FORTEO should be used with caution in patients taking digitalis. In short-term clinical pharmacology studies with teriparatide, transient episodes of symptomatic orthostatic hypotension were infrequently observed. Typically, an event began within 4 hours of dosing and spontaneously resolved within a few minutes to a few hours. When transient orthostatic hypotension occurred, it happened within the first several doses, was relieved by placing the person in a reclining position, and did not preclude continued treatment. Orthostatic hypotension was not a clinically significant finding in the Phase 3 studies. Additional Safety Information FORTEO increased urinary calcium excretion and serum uric acid concentrations but did not result in any clinical adverse events. No clinically important adverse renal effects were observed in the clinical studies. ? Required Slide Main point: Additional precaution should be taken with specific patient groups. In clinical trials, the frequency of urolithiasis was similar in patients treated with FORTEO® (teriparatide [rDNA origin] injection) and placebo. However, FORTEO has not been studied in patients with active urolithiasis. If active urolithiasis or pre-existing hypercalciuria are suspected, measurement of urinary calcium excretion should be considered. FORTEO should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition. In a study of 15 healthy people administered digoxin daily to steady state, a single FORTEO dose did not alter the effect of digoxin on the systolic time interval (from electrocardiographic Q-wave onset to aortic valve closure, a measure of digoxin's calcium-mediated cardiac effect). However, sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Because FORTEO transiently increases serum calcium, FORTEO should be used with caution in patients taking digitalis. In short-term clinical pharmacology studies with teriparatide, transient episodes of symptomatic orthostatic hypotension were infrequently observed. Typically, an event began within 4 hours of dosing and spontaneously resolved within a few minutes to a few hours. When transient orthostatic hypotension occurred, it happened within the first several doses, was relieved by placing the person in a reclining position, and did not preclude continued treatment. Orthostatic hypotension was not a clinically significant finding in the Phase 3 studies. Additional Safety Information FORTEO increased urinary calcium excretion and serum uric acid concentrations but did not result in any clinical adverse events. No clinically important adverse renal effects were observed in the clinical studies. ? Required Slide

143. FORTEO® (teriparatide [rDNA origin] injection) Dosage and Administration The FORTEO Pen is a multidose, prefilled delivery device that can be used up to 4 weeks (28 daily doses), including the first injection from the pen Dose: 20 mcg once a day Do not transfer the contents of the pen into a syringe Needle (29- to 31-gauge) must be changed after each use Administered as a subcutaneous injection into the thigh or abdominal wall Duration of therapy: 18-24 months ? Required Slide ? Required Slide

144. WARNING IN MALE AND FEMALE RATS, TERIPARATIDE CAUSED AN INCREASE IN THE INCIDENCE OF OSTEOSARCOMA (A MALIGNANT BONE TUMOR), THAT WAS DEPENDENT ON DOSE AND TREATMENT DURATION. THE EFFECT WAS OBSERVED AT SYSTEMIC EXPOSURES TO TERIPARATIDE RANGING FROM 3 TO 60 TIMES THE EXPOSURE IN HUMANS GIVEN A 20-MCG DOSE. BECAUSE OF THE UNCERTAIN RELEVANCE OF THE RAT OSTEOSARCOMA FINDING TO HUMANS, TERIPARATIDE SHOULD BE PRESCRIBED ONLY TO PATIENTS FOR WHOM THE POTENTIAL BENEFITS ARE CONSIDERED TO OUTWEIGH THE POTENTIAL RISK. TERIPARATIDE SHOULD NOT BE PRESCRIBED FOR PATIENTS WHO ARE AT INCREASED BASELINE RISK FOR OSTEOSARCOMA (INCLUDING THOSE WITH PAGET’S DISEASE OF BONE OR UNEXPLAINED ELEVATIONS OF ALKALINE PHOSPHATASE, OPEN EPIPHYSES, OR PRIOR RADIATION THERAPY INVOLVING THE SKELETON) (SEE WARNINGS AND PRECAUTIONS, CARCINOGENESIS).

145. FORTEO® WARNINGS THE FOLLOWING CATEGORIES OF PATIENTS HAVE INCREASED BASELINE RISK OF OSTEOSARCOMA AND THEREFORE SHOULD NOT BE TREATED WITH FORTEO: PAGET’S DISEASE OF BONE PEDIATRIC POPULATIONS PRIOR RADIATION RX INVOLVING THE SKELETON PATIENTS WHO HAVE ANY OF THE FOLLOWING CONDITIONS ALSO SHOULD NOT RECEIVE FORTEO: BONE METASTASES OR A HISTORY OF SKELETAL MALIGNANCIES METABOLIC BONE DISEASES OTHER THAN OSTEOPOROSIS PRE-EXISTING HYPERCALCEMIA PREGNANCY AND LACTATION The following categories of patients have increased baseline risk of osteosarcoma and therefore should not be treated with FORTEO: Paget’s disease of bone. Unexplained elevations of alkaline phosphatase may indicate Paget’s disease of bone Pediatric populations and young adults with open epiphyses Prior radiation therapy involving the skeleton Patients with the any of the following conditions also should not receive FORTEO: Bone metastases or a history of skeletal malignancies Metabolic bone diseases other than osteoporosis Pre-existing hypercalcemia. These patients should be excluded from treatment with FORTEO because of the possibility of exacerbating hypercalcemia Pregnant and lactating women The following categories of patients have increased baseline risk of osteosarcoma and therefore should not be treated with FORTEO: Paget’s disease of bone. Unexplained elevations of alkaline phosphatase may indicate Paget’s disease of bone Pediatric populations and young adults with open epiphyses Prior radiation therapy involving the skeleton Patients with the any of the following conditions also should not receive FORTEO: Bone metastases or a history of skeletal malignancies Metabolic bone diseases other than osteoporosis Pre-existing hypercalcemia. These patients should be excluded from treatment with FORTEO because of the possibility of exacerbating hypercalcemia Pregnant and lactating women

146. (FORTEO®) TERIPARATIDE (rDNA ORIGIN) INJECTIONPRECAUTIONS: GENERAL THE SAFETY AND EFFICACY OF FORTEO HAVE NOT BEEN EVALUATED BEYOND 2 YEARS OF TREATMENT. CONSEQUENTLY, USE OF THE DRUG FOR MORE THAN 2 YEARS IS NOT RECOMMENDED. FORTEO SHOULD BE USED WITH CAUTION IN PATIENTS WITH ACTIVE OR RECENT UROLITHIASIS TAKING DIGITALIS LIMITED INFORMATION IS AVAILABLE TO EVALUATE SAFETY IN PATIENTS WITH HEPATIC, RENAL, AND CARDIAC DISEASE. The safety and efficacy of FORTEO have not been evaluated beyond 2 years of treatment. Consequently, use of the drug for more than 2 years is not recommended. In clinical trials, the frequency of urolithiasis was similar in patients treated with FORTEO and placebo. However, FORTEO has not been studied in patients with active urolithiasis. If active urolithiasis or pre-existing hypercalciuria are suspected, measurement of urinary calcium excretion should be considered. FORTEO should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition. In a study of 15 healthy people administered digoxin daily to steady state, a single FORTEO dose did not alter the effect of digoxin on the systolic time interval (from electrocardiographic Q-wave onset to aortic valve closure, a measure of digoxin's calcium-mediated cardiac effect). However, sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Because FORTEO transiently increases serum calcium, FORTEO should be used with caution in patients taking digitalis. In short-term clinical pharmacology studies with teriparatide, transient episodes of symptomatic orthostatic hypotension were observed infrequently. Typically, an event began within 4 hours of dosing and spontaneously resolved within a few minutes to a few hours. When transient orthostatic hypotension occurred, it happened within the first several doses, was relieved by placing the person in a reclining position, and did not preclude continued treatment. Orthostatic hypotension was not a clinically significant finding in the Phase 3 studies. Limited information is available to evaluate safety in patients with hepatic, renal, and cardiac disease. The safety and efficacy of FORTEO have not been evaluated beyond 2 years of treatment. Consequently, use of the drug for more than 2 years is not recommended. In clinical trials, the frequency of urolithiasis was similar in patients treated with FORTEO and placebo. However, FORTEO has not been studied in patients with active urolithiasis. If active urolithiasis or pre-existing hypercalciuria are suspected, measurement of urinary calcium excretion should be considered. FORTEO should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition. In a study of 15 healthy people administered digoxin daily to steady state, a single FORTEO dose did not alter the effect of digoxin on the systolic time interval (from electrocardiographic Q-wave onset to aortic valve closure, a measure of digoxin's calcium-mediated cardiac effect). However, sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Because FORTEO transiently increases serum calcium, FORTEO should be used with caution in patients taking digitalis. In short-term clinical pharmacology studies with teriparatide, transient episodes of symptomatic orthostatic hypotension were observed infrequently. Typically, an event began within 4 hours of dosing and spontaneously resolved within a few minutes to a few hours. When transient orthostatic hypotension occurred, it happened within the first several doses, was relieved by placing the person in a reclining position, and did not preclude continued treatment. Orthostatic hypotension was not a clinically significant finding in the Phase 3 studies. Limited information is available to evaluate safety in patients with hepatic, renal, and cardiac disease.

147. TERIPARATIDE SUMMARY OF SIDE EFFECTS-LAB SAFETY EVALUATION: 24 CLINICAL TRIALS-OVER 2800 WOMEN AND MEN HYPERCALCEMIA WAS ABSENT OR MILD AND TRANSIENT (MAX 4 TO 6 HOURS POST-DOSE NORMAL AT 24 HOURS)-NO PERSISTENT HYPERCALCEMIA MEAN 24-HR Ur CA INCREASED 30 MG/DAY MEAN SERUM URIC ACID INCREASED 13-20% (NO SEQUELAE SUCH AS ACUTE GOUT) CHANGES REVERSED AFTER FORTEO WITHDRAWAL NO CLINICAL ADVERSE EVENTS WERE ASSOCIATED WITH INCREASES IN SERUM OR URINE CALCIUM FORTEO affected calcium and phosphorus metabolism in a pattern consistent with the known actions of endogenous parathyroid hormone (e.g., increases serum calcium and decreases serum phosphorus). FORTEO transiently increased serum calcium, with the maximal effect observed at approximately 4 to 6 hours post-dose. Serum calcium measured at least 16 hours post-dose was not different from pre-treatment levels. In clinical trials, the frequency of at least 1 episode of transient hypercalcemia in the 4 to 6 hours after FORTEO administration was increased from 1.5% of women and none of the men treated with placebo to 11.1% of women and 6.0% of men treated with FORTEO. The number of patients treated with FORTEO whose transient hypercalcemia was verified on consecutive measurements was 3.0% of women and 1.3% of men. FORTEO increased urinary calcium excretion but the frequency of hypercalciuria (>7.5 mmol Ca/day or 300 mg/day) in clinical trials was similar for subjects with FORTEO and placebo. The median urinary excretion of calcium was 4.8 mmol/day (190 mg/day) at 6 months and 4.2 mmol/day (170 mg/day) at 12 months. These levels were 0.76 mmol/day (30 mg/day) and 0.30 mmol/day (12 mg/day) higher, respectively, than in placebo subjects. The incidence of hypercalciuria (>7.5 mmol Ca/day or 300 mg/day) was similar to that in placebo-treated subjects. FORTEO increased serum uric acid concentrations. In clinical trials, 2.8% of FORTEO subjects had serum uric acid concentrations above the upper limit of normal compared to 0.7% of placebo subjects. However, the hyperuricemia did not result in an increase in gout, arthralgia, or urolithiasis. The changes in serum and urine biochemical tests returned to pretreatment values after cessation of treatment. FORTEO affected calcium and phosphorus metabolism in a pattern consistent with the known actions of endogenous parathyroid hormone (e.g., increases serum calcium and decreases serum phosphorus). FORTEO transiently increased serum calcium, with the maximal effect observed at approximately 4 to 6 hours post-dose. Serum calcium measured at least 16 hours post-dose was not different from pre-treatment levels. In clinical trials, the frequency of at least 1 episode of transient hypercalcemia in the 4 to 6 hours after FORTEO administration was increased from 1.5% of women and none of the men treated with placebo to 11.1% of women and 6.0% of men treated with FORTEO. The number of patients treated with FORTEO whose transient hypercalcemia was verified on consecutive measurements was 3.0% of women and 1.3% of men. FORTEO increased urinary calcium excretion but the frequency of hypercalciuria (>7.5 mmol Ca/day or 300 mg/day) in clinical trials was similar for subjects with FORTEO and placebo. The median urinary excretion of calcium was 4.8 mmol/day (190 mg/day) at 6 months and 4.2 mmol/day (170 mg/day) at 12 months. These levels were 0.76 mmol/day (30 mg/day) and 0.30 mmol/day (12 mg/day) higher, respectively, than in placebo subjects. The incidence of hypercalciuria (>7.5 mmol Ca/day or 300 mg/day) was similar to that in placebo-treated subjects. FORTEO increased serum uric acid concentrations. In clinical trials, 2.8% of FORTEO subjects had serum uric acid concentrations above the upper limit of normal compared to 0.7% of placebo subjects. However, the hyperuricemia did not result in an increase in gout, arthralgia, or urolithiasis. The changes in serum and urine biochemical tests returned to pretreatment values after cessation of treatment.

149. TERIPARATIDE INDICATION IN POSTMENOPAUSAL WOMEN FORTEO IS INDICATED FOR THE TREATMENT OF POSTMENOPAUSAL WOMEN WITH OSTEOPOROSIS WHO ARE AT HIGH RISK FOR FRACTURE. THESE INCLUDE THOSE WHO (BASED ON PHYSICIAN ASSESSMENT) … HAVE A HISTORY OF OSTEOPOROTIC FRACTURE HAVE MULTIPLE RISK FACTORS FOR FRACTURE FAILED PREVIOUS OSTEOPOROSIS THERAPY ARE INTOLERANT TO PREVIOUS OSTEOPOROSIS THERAPY FORTEO is indicated for the treatment of postmenopausal women with osteoporosis who are at high risk for fracture. These include women with a history of osteoporotic fracture, or who have multiple risk factors for fracture, or who have failed or are intolerant of previous osteoporosis therapy, based upon physician assessment (see BLACK BOX WARNING). In postmenopausal women with osteoporosis, FORTEO increases BMD and reduces the risk of vertebral and nonvertebral fractures.FORTEO is indicated for the treatment of postmenopausal women with osteoporosis who are at high risk for fracture. These include women with a history of osteoporotic fracture, or who have multiple risk factors for fracture, or who have failed or are intolerant of previous osteoporosis therapy, based upon physician assessment (see BLACK BOX WARNING). In postmenopausal women with osteoporosis, FORTEO increases BMD and reduces the risk of vertebral and nonvertebral fractures.

150. TERIPARATIDE INDICATION IN MEN FORTEO IS INDICATED TO INCREASE BONE MASS IN MEN WITH PRIMARY OSTEOPOROSIS OR OSTEOPOROSIS ASSOCIATED WITH HYPOGONADISM, WHO ARE AT HIGH RISK FOR FRACTURE. THESE INCLUDE THOSE WHO (BASED ON PHYSICIAN ASSESSMENT) … HAVE A HISTORY OF OSTEOPOROTIC FRACTURE HAVE MULTIPLE RISK FACTORS FOR FRACTURE FAILED PREVIOUS OSTEOPOROSIS THERAPY ARE INTOLERANT TO PREVIOUS OSTEOPOROSIS THERAPY FORTEO is indicated to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture. These include men with a history of osteoporotic fracture, or who have multiple risk factors for fracture, or who have failed or are intolerant to previous osteoporosis therapy, based upon physician assessment (see BLACK BOX WARNING). In men with primary or hypogonadal osteoporosis, FORTEO increases BMD. The effects of FORTEO on risk for fracture in men have not been studied. FORTEO is indicated to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture. These include men with a history of osteoporotic fracture, or who have multiple risk factors for fracture, or who have failed or are intolerant to previous osteoporosis therapy, based upon physician assessment (see BLACK BOX WARNING). In men with primary or hypogonadal osteoporosis, FORTEO increases BMD. The effects of FORTEO on risk for fracture in men have not been studied.

153. RAT CARCINOGENICITY STUDY 2-YEAR RAT STUDY REQUIRED BY FDA RULES EXAGGERATED SKELETAL RESPONSE TO TPTD DOSE-RELATED BONE PROLIFERATIVE LESIONS INCLUDING OSTEOSARCOMA NO INCREASE IN SOFT-TISSUE NEOPLASMS FOLLOW-UP RAT STUDY DOSE AND DURATION OF TREATMENT ARE PRIMARY FACTORS IN DEVELOPMENT OF RAT BONE TUMORS ROLE OF AGE AT INITIATION OF TREATMENT IS NOT CONCLUSIVE Two carcinogenicity bioassays were conducted in Fischer 344 rats. In the first study, male and female rats were given daily subcutaneous teriparatide injections of 5, 30, or 75 mcg/kg/day for 24 months from 2 months of age. The treatment doses resulted in systemic exposures that were, respectively, 3, 20, and 60 times higher than the systemic exposure observed in humans following a subcutaneous dose of 20 mcg (based on AUC comparison). Teriparatide treatment resulted in a marked dose-related incidence of osteosarcoma, a rare malignant bone tumor, in both male and female rats. Osteosarcomas were observed at all doses and the incidence reached 40%-50% in the high-dose groups. Teriparatide also caused a dose-related increase in osteoblastoma and osteoma in both sexes. No osteosarcomas, osteoblastomas or osteomas were observed in untreated control rats. The bone tumors in rats occurred in association with a large increase in bone mass and focal osteoblast hyperplasia. The second 2-year study was carried out in order to determine the effect of treatment duration and animal age on the development of bone tumors. Female rats were treated for different periods between 2 and 26 months of age with subcutaneous doses of 5 and 30 mcg/kg (equivalent to 3 and 20 times the human exposure at the 20-mcg dose, based on AUC comparison). The study showed that the occurrence of osteosarcoma, osteoblastoma and osteoma was dependent upon dose and duration of exposure. Bone tumors were observed in both immature 2-month old animals treated with 5 or 30 mcg/kg/day for 6 or 24 months, and in full-grown 6-month old animals treated with 30 mcg/kg/day for 6 or 20 months. Tumors were not detected in mature 6-month old animals treated with 5 mcg/kg/day for 6 or 20 months. The results did not demonstrate a difference in susceptibility to bone tumor formation, associated with teriparatide treatment, between immature and full-grown animals. The relevance of these rat findings to humans is uncertain. Vahle JL, Sato M, Long GG, Young JK, Francis PC, Engelhardt JA, Westmore MS, Ma YL, Nold JB. Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety. Toxicologic Pathology 2002;30:312-321. Vahle JL, Long GG, Ma YL, Sato M. Dose and treatment duration are key factors in the development of neoplasms in F344 rats given teriparatide [rhPTH(1-34)]. J Bone Miner Res 2002;17(suppl 1). . Two carcinogenicity bioassays were conducted in Fischer 344 rats. In the first study, male and female rats were given daily subcutaneous teriparatide injections of 5, 30, or 75 mcg/kg/day for 24 months from 2 months of age. The treatment doses resulted in systemic exposures that were, respectively, 3, 20, and 60 times higher than the systemic exposure observed in humans following a subcutaneous dose of 20 mcg (based on AUC comparison). Teriparatide treatment resulted in a marked dose-related incidence of osteosarcoma, a rare malignant bone tumor, in both male and female rats. Osteosarcomas were observed at all doses and the incidence reached 40%-50% in the high-dose groups. Teriparatide also caused a dose-related increase in osteoblastoma and osteoma in both sexes. No osteosarcomas, osteoblastomas or osteomas were observed in untreated control rats. The bone tumors in rats occurred in association with a large increase in bone mass and focal osteoblast hyperplasia. The second 2-year study was carried out in order to determine the effect of treatment duration and animal age on the development of bone tumors. Female rats were treated for different periods between 2 and 26 months of age with subcutaneous doses of 5 and 30 mcg/kg (equivalent to 3 and 20 times the human exposure at the 20-mcg dose, based on AUC comparison). The study showed that the occurrence of osteosarcoma, osteoblastoma and osteoma was dependent upon dose and duration of exposure. Bone tumors were observed in both immature 2-month old animals treated with 5 or 30 mcg/kg/day for 6 or 24 months, and in full-grown 6-month old animals treated with 30 mcg/kg/day for 6 or 20 months. Tumors were not detected in mature 6-month old animals treated with 5 mcg/kg/day for 6 or 20 months. The results did not demonstrate a difference in susceptibility to bone tumor formation, associated with teriparatide treatment, between immature and full-grown animals. The relevance of these rat findings to humans is uncertain. Vahle JL, Sato M, Long GG, Young JK, Francis PC, Engelhardt JA, Westmore MS, Ma YL, Nold JB. Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety. Toxicologic Pathology 2002;30:312-321. Vahle JL, Long GG, Ma YL, Sato M. Dose and treatment duration are key factors in the development of neoplasms in F344 rats given teriparatide [rhPTH(1-34)]. J Bone Miner Res 2002;17(suppl 1). .

156. The number of women with one or more new vertebral fractures in each group is shown on each bar.* The height of the bar corresponds to the proportion of women within each group with a new vertebral fracture. In women assigned to treatment with FORTEO® (teriparatide [rDNA origin] injection), the relative risk for fracture was 0.35 (95% CI, 0.22 – 0.55, p<.001), corresponding to a statistically significant 65% reduction in the risk of having one or more new vertebral fractures. FORTEO reduced the risk of 1 or more new vertebral fractures from 14.3% in women in the placebo group to 5% in the FORTEO group. This difference was statistically significant (p<.001). The absolute risk reduction for >1 new vertebral fractures was 9.3%. *Baseline and follow-up radiographs were available for 1326 of the 1637 women. Follow-up radiographs were not available for 249 women, and 62 women had pretreatment radiographs that were inadequate for evaluation.1 1. N Engl J Med. 2001;344:1434-1441. (Neer RM, et al.) The number of women with one or more new vertebral fractures in each group is shown on each bar.* The height of the bar corresponds to the proportion of women within each group with a new vertebral fracture. In women assigned to treatment with FORTEO® (teriparatide [rDNA origin] injection), the relative risk for fracture was 0.35 (95% CI, 0.22 – 0.55, p<.001), corresponding to a statistically significant 65% reduction in the risk of having one or more new vertebral fractures. FORTEO reduced the risk of 1 or more new vertebral fractures from 14.3% in women in the placebo group to 5% in the FORTEO group. This difference was statistically significant (p<.001). The absolute risk reduction for >1 new vertebral fractures was 9.3%. *Baseline and follow-up radiographs were available for 1326 of the 1637 women. Follow-up radiographs were not available for 249 women, and 62 women had pretreatment radiographs that were inadequate for evaluation.1 1. N Engl J Med. 2001;344:1434-1441. (Neer RM, et al.)

157. FORTEO REDUCES THE RISK OF MULTIPLE NEW VERTEBRAL FRACTURES This figure shows the results for women who had 2 or more new vertebral fractures during the study. In women assigned to treatment with FORTEO® (teriparatide [rDNA origin] injection), the relative risk for multiple vertebral fractures was 0.23 (CI 0.09 – 0.60, p<0.001), corresponding to a 77% reduction in risk of having multiple vertebral fractures. FORTEO reduced the absolute risk of 2 or more new vertebral fractures from 4.9% in women in the placebo group to 1.1% in the FORTEO group. This difference was statistically significant (p<0.001). The absolute risk reduction for multiple vertebral fractures was 3.8%. 1. N Engl J Med 2001;344:1434-1441. (Neer RM, et al.) This figure shows the results for women who had 2 or more new vertebral fractures during the study. In women assigned to treatment with FORTEO® (teriparatide [rDNA origin] injection), the relative risk for multiple vertebral fractures was 0.23 (CI 0.09 – 0.60, p<0.001), corresponding to a 77% reduction in risk of having multiple vertebral fractures. FORTEO reduced the absolute risk of 2 or more new vertebral fractures from 4.9% in women in the placebo group to 1.1% in the FORTEO group. This difference was statistically significant (p<0.001). The absolute risk reduction for multiple vertebral fractures was 3.8%. 1. N Engl J Med 2001;344:1434-1441. (Neer RM, et al.)

158. FORTEO REDUCES THE RISK OF NONVERTEBRAL FRAGILITY FRACTURES1 In 58 women, nonvertebral fractures were considered to be the result of bone fragility. Fragility fractures are defined as those occurring with a degree of trauma equal to or less than that associated with falling from standing height. This figure shows the proportion of women who reported one or more nonvertebral fragility fractures. FORTEO significantly reduced the risk of any new nonvertebral fracture from 5.5% in women in the placebo group to 2.6% in the FORTEO group (p<0.05). The absolute risk of fracture was reduced by 2.9%. In women assigned to treatment with FORTEO, the relative risk for 1 or more nonvertebral fragility fractures was 0.47 (CI 0.25 – 0.88, p<0.05), corresponding to a 53% reduction in risk of one or more nonvertebral fragility fractures. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-1441. In 58 women, nonvertebral fractures were considered to be the result of bone fragility. Fragility fractures are defined as those occurring with a degree of trauma equal to or less than that associated with falling from standing height. This figure shows the proportion of women who reported one or more nonvertebral fragility fractures. FORTEO significantly reduced the risk of any new nonvertebral fracture from 5.5% in women in the placebo group to 2.6% in the FORTEO group (p<0.05). The absolute risk of fracture was reduced by 2.9%. In women assigned to treatment with FORTEO, the relative risk for 1 or more nonvertebral fragility fractures was 0.47 (CI 0.25 – 0.88, p<0.05), corresponding to a 53% reduction in risk of one or more nonvertebral fragility fractures. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-1441.

162. The skeletal effects of teriparatide depend upon the pattern of systemic exposure. Once-daily administration of teriparatide stimulates new bone formation on trabecular and cortical (periosteal and/or endosteal) bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. In monkey studies, teriparatide improved trabecular microarchitecture and increased bone mass and strength by stimulating new bone formation in both cancellous and cortical bone. In humans, the anabolic effects of teriparatide are manifest as an increase in skeletal mass, an increase in markers of bone formation and resorption, and an increase in bone strength. By contrast, continuous excess of endogenous PTH, as occurs in hyperparathyroidism, may be detrimental to the skeleton because bone resorption may be stimulated more than bone formation. The skeletal effects of teriparatide depend upon the pattern of systemic exposure. Once-daily administration of teriparatide stimulates new bone formation on trabecular and cortical (periosteal and/or endosteal) bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. In monkey studies, teriparatide improved trabecular microarchitecture and increased bone mass and strength by stimulating new bone formation in both cancellous and cortical bone. In humans, the anabolic effects of teriparatide are manifest as an increase in skeletal mass, an increase in markers of bone formation and resorption, and an increase in bone strength. By contrast, continuous excess of endogenous PTH, as occurs in hyperparathyroidism, may be detrimental to the skeleton because bone resorption may be stimulated more than bone formation.

164. Incidence of Osteoporotic Fractures in Women After Age 501 Main point: The incidence of osteoporotic vertebral and hip fractures increases with age. Shortly after menopause, the incidence of Colles' (wrist) fracture increases and continues to do so until age 60, at which point it plateaus. The incidence of hip fracture, however, increases more slowly with age until later life, when it undergoes a steep rise. The incidence of vertebral fracture clearly begins to rise shortly after menopause and continues to do so without reaching a plateau. Reference: 1. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999:257-259. Main point: The incidence of osteoporotic vertebral and hip fractures increases with age. Shortly after menopause, the incidence of Colles' (wrist) fracture increases and continues to do so until age 60, at which point it plateaus. The incidence of hip fracture, however, increases more slowly with age until later life, when it undergoes a steep rise. The incidence of vertebral fracture clearly begins to rise shortly after menopause and continues to do so without reaching a plateau. Reference: 1. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999:257-259.

165. FORTEO® (teriparatide [rDNA origin] injection) Time Effect to New Nonvertebral Fragility Fracture1 Main point: This graph is a Kaplan-Meier curve that shows the effect on time to first nonvertebral fragility fracture. Over the entire treatment period, the cumulative percentage of postmenopausal women sustaining new nonvertebral fractures was lower in women treated with FORTEO® (teriparatide [rDNA origin] injection) than with placebo. The curves for each group began to diverge after 9 months. The effect of FORTEO reached statistical significance at the end of study. Reference: 1. Neer RM, et al. Effect of Parathyroid Hormone (1-34) on Fractures and Bone Mineral Density in Postmenopausal Women With Osteoporosis. N Engl J Med. 2001;344:1434-1441. Main point: This graph is a Kaplan-Meier curve that shows the effect on time to first nonvertebral fragility fracture. Over the entire treatment period, the cumulative percentage of postmenopausal women sustaining new nonvertebral fractures was lower in women treated with FORTEO® (teriparatide [rDNA origin] injection) than with placebo. The curves for each group began to diverge after 9 months. The effect of FORTEO reached statistical significance at the end of study. Reference: 1. Neer RM, et al. Effect of Parathyroid Hormone (1-34) on Fractures and Bone Mineral Density in Postmenopausal Women With Osteoporosis. N Engl J Med. 2001;344:1434-1441.

166. FORTEO® (teriparatide [rDNA origin] injection) Increased Lumbar Spine BMD in Postmenopausal Women With Osteoporosis*,1 Main point: Significant increases in lumbar spine BMD were seen as early as 3 months and continued throughout the treatment period. FORTEO increased lumbar spine BMD in postmenopausal women with osteoporosis. Significant increases were seen as early as 3 months and continued throughout the treatment period (p<.001).1 FORTEO increased lumbar spine BMD from baseline in 96% of postmenopausal women treated for a median of 19 months. Seventy-two percent of patients treated with FORTEO achieved at least a 5% increase in spine BMD, and 44% gained 10% or more.1 Trial Characteristics:2 Designed to evaluate 1637 postmenopausal women with prior vertebral fracture. Mean age: 69. Median duration of exposure to therapy: 19 months (maximum 24 months). All received 1000 mg/day calcium and 400 to 1200 IU/day of vitamin D. Reference: 1. FORTEO [Package insert]. Indianapolis, IN: Eli Lilly and Company; 2004. 2. Neer RM, et al. Effect of Parathyroid Hormone (1-34) on Fractures and Bone Mineral Density in Postmenopausal Women With Osteoporosis. N Engl J Med. 2001;344:1434-1441. Main point: Significant increases in lumbar spine BMD were seen as early as 3 months and continued throughout the treatment period. FORTEO increased lumbar spine BMD in postmenopausal women with osteoporosis. Significant increases were seen as early as 3 months and continued throughout the treatment period (p<.001).1 FORTEO increased lumbar spine BMD from baseline in 96% of postmenopausal women treated for a median of 19 months. Seventy-two percent of patients treated with FORTEO achieved at least a 5% increase in spine BMD, and 44% gained 10% or more.1 Trial Characteristics:2 Designed to evaluate 1637 postmenopausal women with prior vertebral fracture. Mean age: 69. Median duration of exposure to therapy: 19 months (maximum 24 months). All received 1000 mg/day calcium and 400 to 1200 IU/day of vitamin D. Reference: 1. FORTEO [Package insert]. Indianapolis, IN: Eli Lilly and Company; 2004. 2. Neer RM, et al. Effect of Parathyroid Hormone (1-34) on Fractures and Bone Mineral Density in Postmenopausal Women With Osteoporosis. N Engl J Med. 2001;344:1434-1441.

167. FORTEO REDUCES THE RISK OFNEW NONVERTEBRAL FRAGILITY FRACTURES This figure shows the number of new nonvertebral fragility fractures at various skeletal sites. While the number of fractures at any specific site was low, the incidence of fractures at each skeletal site was similar or lower in the FORTEO-treated group than in the placebo group. * p<0.05 vs. placebo Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-1441.This figure shows the number of new nonvertebral fragility fractures at various skeletal sites. While the number of fractures at any specific site was low, the incidence of fractures at each skeletal site was similar or lower in the FORTEO-treated group than in the placebo group. * p<0.05 vs. placebo Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-1441.