Brand Name¹
Forteo^®

- For the treatment of postmenopausal women with osteoporosis who are at high risk for fracture

- To increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture

- For the treatment of corticosteroid-induced osteoporosis

- For the treatment of hypoparathyroidism

Effect of Parathyroid Hormone (1-34) of Fractures and Bone Mineral Density in Postmenopausal Women with Osteoporosis⁴

This was a randomized, placebo-controlled, multi-center study. Inclusion criteria consisted of women being ambulatory, a period of at least 5 years had elapsed since menopause, and at least one moderate or two mild atraumatic vertebral fractures on radiographs of the thoracic and lumbar spine. In women with fewer than two moderate fractures, an additional criteria for enrollment was a value for bone mineral density (BMD) of the hip or lumbar spine that was at lest 1 SD below the mean value in normal premenopausal women. Sixteen hundred and thirty seven subjects were randomly assigned to receive placebo (n=544) or parathyroid hormone (1-34) at a dose of 20 mcg daily (n=541) or 40 mcg daily (n=552) via self-administered injections. Participants were also given supplements of calcium 1000 mg and vitamin D 400 to 1200 IU daily. All participants had serum calcium measurements before and 4 to 6 hours after injection at baseline and after 1, 3, 6, 12, 18, and 24 months of treatment. Calcium and creatinine excretion were also measured via a 24-hour urine specimen at baseline and after 1, 6, 12, and 24 months of treatment. All participants underwent anteroposterior and lateral radiography of the thoracic and lumbar spine at base line and at the end of the study.

This study was expected to be 24 months, but was terminated early by the study’s sponsor. The mean treatment length for all treatment groups was approximately 18 months. Results of the study showed that teriparatide reduced the risk of one or more new vertebral fractures by 65% for the 20 mcg dose (p<0.001) and 69% for the 40 mcg dose (p<0.001) as compared to placebo. The risk of developing two or more fractures was reduced by 77% (p<0.001) and 86% (p<0.001) in the two teriparatide groups, while the risk of developing at least one moderate or severe vertebral fracture was reduced by 90% (p<0.001) and 78% (p<0.001) in the two groups. Bone Mineral Density (BMD) measurements showed a significant increase in the teriparatide groups as compared to placebo at the lumbar spine (p<0.001), femoral neck (p<0.001), trochanter (p<0.001), intertrochanter (p<0.001), and hip (p<0.001). The differences in BMD in the two teriparatide groups were not statistically significantly different. A total of 126 patients withdrew from the study due to adverse effects. Of these 32 were in the placebo group, 35 in the 20 mcg teriparatide group, and 59 in the 40 mcg teriparatide group. Nausea was reported in 18% of the women taking the 40 mcg dose of teriparatide, while 13% reported headache occurring. Only 8% of the women in the placebo group experienced these adverse effects (p<0.001for nausea, p=0.01 for headache). The incidence was similar to placebo in the group taking the 20 mcg dose of teriparatide. Dizziness was reported in 9% of the women taking the 20 mcg dose of teriparatide, and 3% reported leg cramps, but these symptoms were only reported in 6% and 1% in the placebo group (p=0.05,p=0.02). The 40 mcg group also had adverse effects similar to the placebo group.

Limitations to this study include sponsorship by Eli Lilly and Co., manufacturer of the study drug. Another limitation is the short duration. This study demonstrated that teriparatide is more effective than placebo for the first 18 to 24 months. It is unclear if it remains effective if treatment is continued long-term.

Based on the study’s results, it may be concluded that teriparatide is more effective than placebo for initial treatment of osteoporosis. A 20 mcg daily dose of teriparatide may be appropriate due to the risk of osteosarcoma and increased adverse effects noted with the higher dose.

A Randomized Double-Blind Trial to Compare the Efficacy of Teriparatide [Recombinant Human Parathyroid Hormone (1-34)] with Alendronate in Postmenopausal Women with Osteoporosis⁵

This randomized, double-blind, parallel-group, active control study was conducted at 12 sites within the United States, Austria, Belgium, Canada, Israel, and Mexico from May 1997 through April 1999. The protocol for this study consisted of two phases: a screening and run-in phase of 2 months and a planned treatment phase of 24 months. The run-in phase included at least one month of daily supplementation with 1000 mg of calcium and 400 –1200 IU of vitamin D, that was to be continued throughout the study. During this time, patients were also instructed on the proper technique for self-injection, using a placebo material. After completion of this phase, study participants, 146 postmenopausal women, were randomly assigned to either once-daily 40 mcg teriparatide subcutaneous injection and oral placebo (n=73) or once-daily placebo injection and 10 mg oral Alendronate (n=73). All participants were instructed to take the oral capsule with a glass of water on an empty stomach 30 minutes before breakfast and to remain upright for 30 minutes after ingestion. Injections were given without restriction regarding meals or activity.

Patients randomized in the study had follow-up visits at 1, 3, 6, and 12 months, and at the conclusion of the study. At these visits, patients’ adverse effects were evaluated and they rated their severity as mild, moderate, or severe. Patients had BMD measurement of the lumbar spine at baseline, 3, 6, and 12 months, and at the study’s end. BMD measurements were also taken of the proximal femur, radius, and total body at baseline, 12 months, and end of the study. Biochemical markers and serum calcium measurements were assessed at each follow-up measurement. Twenty-four hour urinary calcium, phosphorus, and creatinine excretion were measured at baseline, 1, 6, and 12 months, and at the end of the study.

The intended duration of this study was 24 months. After a median of 14 months of treatment, the study was brought to an end to evaluate the clinical relevance in humans of the observations of osteosarcoma made in rats. Percentage increase in BMD at the lumbar spine showed that teriparatide was 2.7% greater than alendronate at 3 months (p<0.001), 5.4% at 6 months, and 8.3% at 12 months (p<0.001). The total increase in BMD at 12 months of alendronate therapy was 5.9% while at 3 months teriparatide treatment showed an increase of 5.2%. Other BMD measurements showed statistically significant improvement from baseline in all treatment groups; however, there was significantly greater improvement seen in the teriparatide group compared to the alendronate group. Nonvertebral fractures were seen at a rate of 4.1% in the teriparatide group and 13.7% in the alendronate group(p=0.042). A total of 21 patients withdrew due to adverse effects, 7 in the alendronate group and 14 that received teriparatide. Adverse effects included new or worsened back pain 5.5% in the teriparatide group vs. 19.2% in the alendronate group (p=0.012). Leg cramps were reported by 8.2% of patients in the teriparatide 0.0% in the alendronate group (p=0.012).

Limitations include the study being supported by a grant from Eli Lilly and Co. who is also the manufacturer of one of the study drugs, teriparatide. Other limitations include the length of duration and small number of subjects.

Teriparatide appears to be more effective than alendronate for osteoporosis treatment during the first year. The long-term effectiveness of teriparatide has yet to be studied. Therefore, the results of this study cannot be extrapolated to include long-term effectiveness over alendronate.

The Effect of Teriparatide [Human Parathyroid Hormone (1-34)] Therapy on Bone Density in Men with Oseteoporosis⁶

Four hundred and thirty seven patients were enrolled in this randomized, double-blind, placebo-controlled study conducted at 37 centers in 11 countries. Patients were randomized to receive placebo (n=147), 20 mcg of teriparatide (n=151), or 40 mcg of teriparatide (n=139). Patients also received daily oral supplements of 1000 mg of calcium and 400 – 1200 IU of vitamin D beginning at least one month prior to randomization. Lumbar spine BMDs were measured at baseline, 3, 6, and 12 months and at the end of the study. Hip, whole body, and radial BMDs were also measured at baseline, 12 months, and at study’s end. Biochemical markers of bone formation were measured at baseline, 1, 3, 6, and 12 months. Serum calcium was measured 4 – 6 hours after injection at 1, 3, 6, and 12 months. Calcium and creatinine excretion in a 24-hour urine specimen was measured at baseline and after 1, 6, and 12 months. If these measurements were elevated, dosages of the calcium supplement and study drug were modified.

This study was expected to be 24 months; however, due to the development of osteosarcoma in animal toxicity trials, the study was stopped early. Length of treatment ranged for 2 months to 15 months, with the median length of treatment at 11 months. Results at the end of the study showed that both treatment groups that received teriparatide had dose-dependent increased lumbar spine (20mcg vs. placebo p<0.001, 40 mcg vs. placebo p<0.001, 20 mcg vs. 40 mcg P<0.001) and femoral neck (20mcg vs. placebo p=0.029, 40 mcg vs. placebo p<0.001, 20 mcg vs. 40 mcg p=0.023) BMDs. Nearly 40% of the patients in the placebo-treated group had a net decrease in their lumbar spine BMD at the end of the study, while only 7.1% and 6.2% in the teriparatide-treated groups had a decrease. Increases of greater than 5% were seen in 9.8% of placebo-treated patients compared to 55% and 71% in the teriparatide groups. Results of the biochemical markers also showed significant improvement in both teriparatide groups as compared to the placebo-treated groups (p<0.001). Thirty-nine patients withdrew from the study due to adverse effects, 7 of these patients were in the placebo group, 14 in the 20 mcg teriparatide group, and 18 in the 40 mcg teriparatide group. Nausea was reported in 18.7% of the patient in the 40 mcg teriparatide group (p<0.001), 5.3% in the 20 mcg group, and 3.4% in the placebo group. Headache occurred more frequently in the 40 mcg group at 10.8% (p=0.053), but was not more severe than in the other treatment groups.

Limitations seen in this study included the sponsorship by Eli Lilly and Co., manufacturer of the study drug. Additionally one of the contributing authors of the study was an employee of Eli Lilly and Co.

Based on the results of this study, it would appear that teriparatide is more effective than placebo in increasing BMD during the first year of treatment. While efficacy appears to be similar between doses, the rate of adverse effects and risk of osteosarcoma are higher with the 40 mcg dose.

- For the treatment of postmenopausal women with osteoporosis who are at high risk for fracture

o Recommended dosage for this patient population is 20 mcg injected subcutaneously once daily for up to 2 years. In addition, a calcium and vitamin D supplement are also suggested in this patient population.

- To increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture

o Recommended dosage for this patient population is 20 mcg injected subcutaneously once daily for up to 2 years.

- There is no need for dosage adjustments of teriparatide in the geriatric population.

- Teriparatide has not been studied in this patient population for safety and efficacy; therefore, its use should be avoided in this patient population.

- There is no data available to suggest that the teriparatide dose would need to be adjusted in patients with renal impairment.

- There is no data available to suggest that the teriparatide dose would need to be adjusted in this patient population.

1. Eli Lilly and Company. Prescribing information for Forteo^®. November 2002.

2. Anon. Teriparatide (Forteo) for Osteoporosis. Med Lett Drugs Ther 2003;45:9-10.

3. Clinical Pharmacology. Forteo. Available from: http://cp.hsc.wvu.edu. Accessed May 2, 2003.

4. Neer RM, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. New Engl J Med 2001;344:1434-41.

5. Body JJ, et al. A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1-34)] with alendronate in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2002;87:4528-35.

6. Orwoll ES, et al. The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis. J Bone Min Res 2003;18:9-17.

Emily Judy, PharmD Candidate