COMMENTARY

Initial experience with teriparatide in the United States*deborah T. Gold a, barbara s. pantos b, daniel n. Masica b, derek A. Misurski b and Robert Marcus b

a Departments of Psychiatry and Behavioral Sciences, Sociology, and Psychology, Social and Health Sciences, Duke Aging Center, Duke University Medical Center, Durham, NC, USA

b Eli Lilly and Company Indianapolis, IN, USA

Address for correspondence:  Robert Marcus, MD, Lilly Corporate Center, Indianapolis, IN 46285, USA. Tel.: +1 317 651 2261; Fax: +1 317 997 6442; email: rmarcus@lilly.com

Key words:  Osteoporosis – Patient education – Pharmacovigilance – Teriparatide

0300-7995

doi:10.1185/030079906X100159

All rights reserved: reproduction in whole or part not permitted

CuRRenT MediCAl ReseARCh And OpiniOn®

Vol. 22, No. 4, 2006, 703–708

© 2006 libRAphARM liMiTed

Paper 3250 703

Teriparatide has been commercially available in the United States (US) for over 3 years. This summary spans the early experience with this therapy. As of December 31, 2005, over 235 000 patients had filled a prescription for teriparatide world-wide. Data collected from July to December 2004, from 15 000 retail pharmacies in the US, indicated that the mean age of patients was 67.5 years, and more recent data collected from January through October 2005 indicated that 90% of patients were female. According to market research conducted with prescribing physicians from February through March of 2005, it is estimated that over 80% of patients receiving prescriptions for teriparatide had already experienced one or more prior fractures.

Since teriparatide is administered subcutaneously, it is important that patients receive training on the use of the teriparatide injection device (i.e., the pen device). Educational programs are available for those who have been

prescribed teriparatide therapy. Patients may also contact a customer care program regarding a variety of topics, including pen device use. Based on patient feedback, design changes have been implemented in the pen device to facilitate optimal use. Updates have also been made to the prescribing information to reflect the post-marketing surveillance experience.

Adverse experiences reported to date have been consistent with the current product label and with cumulative teriparatide clinical trial experience. As of December 31, 2005 no reports of pathology-confirmed osteosarcoma have been received for individuals who have been treated with teriparatide, either with the commercially available drug or in clinical trials. We are unaware of any reports of osteosarcoma in association with other preparations of teriparatide, or other peptides of parathyroid hormone, either in the setting of clinical trials or from marketed drug experience.

A B S T R A C T

Introduction

On November 26, 2002, the US Food and Drug Administration (FDA) approved teriparatide [Forteo†] to treat postmenopausal women with osteoporosis who are at high risk for fracture and to increase bone mass in men with primary or hypogonadal osteoporosis

who are at high risk for fracture1. Teriparatide requires refrigeration. It is administered by a single, daily, subcutaneous injection into the thigh or abdomen using a pre-filled injection device, at a recommended dose of 20 µg. The current prescribing information states that teriparatide not be used for longer than 2 years1.

* Content from this manuscript was presented at the Bone and Tooth Society Annual Meeting, June 29–30, 2004, Oxford, UK

† Eli Lilly and Company, Indianapolis, IN, USA

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704 Initial experience with teriparatide in the United States © 2006 libRAphARM lTd – Curr Med Res Opin 2006; 22(�)

As teriparatide has been commercially available in the United States for over 3 years, it is appropriate to summarize the experience with this therapy.

This commentary provides new information regard-ing the number of patients prescribed teriparatide, their demographics and persistency with therapy. Because the psychosocial and physical effects of osteo-porosis can be detrimental to adherence2, a summary of the program developed to help address the educational and pen device support requirements of individuals who have been prescribed teriparatide is provided. Recent pen device modifications are also summarized. Post-marketing, surveillance-based changes to the adverse event section of the prescribing information are discussed, as is the post-marketing surveillance update on the black box warning that was assigned to teriparatide on the basis of a rat carcinogenicity study3. For information regarding the clinical use of teriparatide, the reader is directed to recent reviews by Miller et al.4 and Hodsman et al.5.

Patients prescribed teriparatide

World-wide over 235 000 patients had filled a prescription for teriparatide by December 31, 20056. Examination of a US-based retail prescription database indicated that 58% of patients who filled a prescription for teriparatide between January 1, 2003 and June 30, 2003 were treatment naïve (i.e., they had no antiresorptive prescriptions filled in the 12 months prior to initiation of teriparatide)7, and data from July to December of 2004 indicated that the mean age was 67.5 years8. More recent data collected from January through October 2005 indicated that 90% of patients were female9. According to market research conducted on a sample of prescribing physicians from February through March 2005, it is estimated that over 80% of patients had already experienced one or more prior fractures10.

Patient education/support programs

Osteoporotic fractures motivate people to strive for a lifestyle without new fractures. This may include positive self-management activities, such as taking supplemental calcium and vitamin D, weight-bearing and strength-training exercise, and fall avoidance. People with disease-associated physical disabilities are also generally more likely to comply with prescribed therapy2. However, the physical attributes of high-risk fracture patients (frailty, advanced age, previous

fracture) may complicate adherence to a daily, self-administered injectable regimen. The social isolation and psychological impairment that are often associated with severe osteoporosis could further complicate adherence2. Loss of employment could restrict access to medical treatment.

Long-term adherence and persistence with oral osteoporosis therapy can be poor11. As, long-term adherence and persistence with an injectable osteo-porosis therapy might be expected to suffer equally or even more so, it is important that patients receiving teriparatide understand the importance of adherence and that they receive detailed training on the use of the injection device (i.e., the pen device). It is also important that patients be knowledgeable about osteoporosis and its treatment, as education may aid adherence12.

Multidimensional approaches to osteoporosis treat-ment should focus on appropriate pharmacotherapy with attention to adherence, improvement in overall physical condition, appropriate nutritional support, and improvement in quality of life through psycho-social interventions and pain management13. To help patients and their families better understand both osteoporosis and the real and potential risks associated with teriparatide use, an educational program has been made available for those identified by their physicians to begin teriparatide therapy. Registered nurses, dietitians, or individuals with at least a 4-year degree in a relevant field lead the educational programs. All educators are skilled in patient education and in teaching injection techniques. They are trained and certified to teach the educational program and are required to update their training quarterly. Seminar teaching sessions last approximately 1.5 h and typically involve 1–5 patients. Patients are educated about the osteoporosis disease state and lifestyle factors, including the importance of nutrition and regular exercise. Teriparatide therapy is also explained, and specific instruction on the use of the pen device is provided. Patients are given literature and sample pen devices (unless they have already filled a prescription for teriparatide) so they can administer a dose to themselves with the supervision of the educator. After the educational program, patients receive follow-up newsletters that provide continued information and education about osteoporosis.

Over 8000 seminar teaching sessions were held in the first 2 years of this program14. Of approximately 24 000 participants who completed a survey after an educational seminar, over 90% stated that the pen was easy to operate and expressed confidence in its use14. Examination of a US-based retail prescription database indicated that the 60-day persistency in patients initiating teriparatide was greater than the persistency in patients initiating alendronate during

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the same period (teriparatide, 64.6% vs. alendronate, 59.9%; Pearson χ2; p < 0.0001)7. It should be noted, however, that it was not always possible to follow patients who had subsequent prescriptions filled for the same drug at a different pharmacy. Since we do not know if patients on teriparatide are more or less likely than patients on alendronate to fill subsequent prescriptions at different pharmacies, we do not know how this may affect persistency data. Moreover, this comparison did not adjust for potential differences in patient demographics and we do not know how many of the patients in this database attended one of the educational sessions. Therefore, the influence of this program on the persistency of the patients in question cannot be assessed.

Participants who require continued support after the educational session are encouraged to contact the customer care program. This program is accessible via a toll-free number [1-866-4FORTEO (1-866-436-7836)]. It provides information related to teriparatide, the pen device, and/or financial support for patients without insurance coverage or sufficient financial resources to complete a prescribed therapy course. The toll-free number is printed on patient education materials and on the product packaging, allowing patients who did not participate in the educational program to access the customer care program. In addition, all patients prescribed teriparatide are eligible to receive a starter kit with several educational materials, including a pen device user manual, large-print, step-by-step instructions on pen device use; and a DVD (videotape on request) with an actual demonstration of techniques. Healthcare professionals may also use the toll-free number for questions about teriparatide therapy and/or the pen device, as well as for adverse event reporting. Most telephone calls concerning the pen device have been requests for information from consumers and patients who have been prescribed teriparatide, but who have not yet used it. The remainder of pen device calls has been from patients who have started use but are seeking further information.

Regarding the pen device, patient feedback-based design changes were implemented to facilitate optimal use. Two of the eight plastic components of the pen device have recently been modified to limit possible misuse. Specifically, a dialing and dosing channel and a small protrusion (called a ‘nib’) have been added. The nib is guided through the channel to ensure correct dialing and complete dosing. The modified pen device will not allow dosing from intermediate positions between the prime dose setting and the injection dose setting, and will not reset for the next dose until the current dose has been completed. In cases when the pen device has been misdialed, an ‘X’ appears in the

window and the pen device becomes inoperable15. Although some clarifying changes to wording and formatting have been made, the current instructions for use are consistent with the former instructions.

Adverse events

Double-blinded, placebo-controlled clinical trials are the standard for human drug research; however, the ability of these studies to detect adverse events is generally limited by trial size and a lack of heterogeneous study populations due to exclusion criteria16. Although spontaneous adverse events tend to be underreported during post-marketing surveillance, these data have the virtue of being generally representative of a broader population. Spontaneous reports provide information about the safety profile of a drug in real-world use. The majority of spontaneous reports for teriparatide have been communicated via the toll-free call center. The prescribing information has recently been updated to reflect the post-marketing surveillance adverse event experience with teriparatide1. The following is a summary of these updates.

Spontaneous reports of possible allergic events occurring shortly after the injection of teriparatide have been received. These included acute dyspnea, swelling of the oro/facial region, generalized urticaria, and chest pain. This information has been included under the Post-marketing Reports section of the prescribing information. The reporting frequency of these events has been less than one report for 1000 patients treated with teriparatide. The prescribing information states that teriparatide should not be given to patients with hypersensitivity to teriparatide or its excipients1.

Consistent with the known physiologic effects of parathyroid hormone, teriparatide has induced small and transient increases in serum calcium concentration in patients in clinical trials. The peak serum calcium concentration remained below 11 mg/dL in greater than 99% of women at each visit. Since teriparatide has been commercially available, spontaneous reports of elevated calcium concentrations have been received. Hypercalcemia greater than 11 mg/dL has been noted in spontaneous reports, with a reporting rate of less than 1 out of 100 patients treated. Hypercalcemia greater than 13 mg/dL has also been noted in spontaneous reports, with a reporting rate of less than 1 out of 1000 patients treated. There are several potential causes for hypercalcemia, including excessive calcium and/or vitamin D supplementation (or both), malignancy, underlying hypercalcemic disorders and concomitant use of drugs that may increase serum calcium concentration.

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Because of the nature of spontaneous adverse event reporting, the specific cause(s) of hypercalcemia in individual cases can be difficult to ascertain. Teriparatide should not be used in patients known to have underlying hypercalcemic disorders, such as hyperparathyroidism. If persistent hypercalcemia is detected, treatment with teriparatide should be discontinued pending further evaluation of the cause1. Existing evidence from clinical trials does not indicate a major risk of hypercalcemia and, therefore, the prescribing information does not mandate a serum calcium measurement. Nonetheless, some physicians may elect to assess this parameter. Miller et al.4 have suggested obtaining a serum calcium determination 1 month after initiating therapy. Because serum calcium concentrations obtained within 16 h of administration may reflect the pharmacologic effects of teriparatide, the blood sample should be obtained 16 h or more after the last dose.

Spontaneous reports have been received regarding injection site and injection technique events. Injection events reported include pain, swelling, erythema, localized bruising, pruritus, and minor bleeding at the injection site, with a reporting frequency of less than 1 in 30 patients. These events usually have been mild and transient. This information has been added under the Post-marketing Reports section of the US prescribing information.

Medication errors, in which the entire contents of the teriparatide pen device were administered as a single dose (up to 800 µg) have been rarely reported (spontaneous reports of less than 1 in 1000 patients treated). Transient events resulting from this medica-tion error have included nausea, weakness/lethargy, and hypotension. In some cases, no adverse events occurred as a result of the overdose. This information has been added under the Overdosage section of the prescribing information. In addition, the FDA has recently approved a new pen device carton label, which directs the individual administering teriparatide to consult the pen device user manual. Through December 31, 2005, no fatalities associated with overdose have been reported. The new pen device label clearly states that the contents of the pen device cartridge are not to be transferred to a syringe and that the pen device contains 28 daily subcutaneous doses.

Black box warning

Long-term carcinogenicity studies in Fischer 344 (F344) rats treated with near-lifelong, daily injections of teriparatide demonstrated a dose-related occurrence of skeletal proliferative lesions, including osteosarcoma, after approximately 17 months of treatment. Informa-tion regarding the original rat carcinogenicity studies

has been published3,17. When this carcinogenicity finding emerged, all teriparatide clinical trials were promptly and voluntarily discontinued until relevance to human risk could be determined. As a result, a pivotal clinical trial of teriparatide in postmenopausal women with osteoporosis, originally planned for 36 months, concluded at a median duration of 19 months18. The clinical trial in men, originally planned to last 24 months, concluded at a median duration of 11 months19. A black box warning is contained in the prescribing information regarding the rat preclinical osteosarcoma findings. It states that 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 external beam or implant radiation therapy involving the skeleton)1.

The original carcinogenicity study was initiated in rats that were approximately 2 months old, an age at which rapid skeletal growth is occurring. Treatment was continued for approximately 24 months or about 70–80% of the rat life span. In contrast, the US package insert states that teriparatide therapy should not exceed 2 years1, or approximately 2–3% of the human life span. Furthermore, as noted previously, the mean age of patients started on teriparatide is 67.5 years8. A follow-up study reported that there were no bone neoplasms when 6-month-old female F344 rats were treated with 5 µg/kg/day of recombinant teriparatide for either 6 or 20 months20. Notably, the serum exposure of a rat receiving a 5-µg/kg dose of teriparatide is approximately three times greater than that of a woman receiving a 20-µg dose17. A long-term study in primates was also recently completed. The objective of this study was to determine if bone tumors would develop during either an 18-month treatment period or a 3-year post treatment observation period. In this study, ovariectomized cynomolgus monkeys were treated with either a placebo or teriparatide for 18 months. No bone neoplasms were noted in any of the teriparatide-treated animals21. A full report on these data is planned.

Reports associating hyperparathyroidism with osteosarcoma in humans may provide insight into the clinical relevance of this issue. We identified seven cases of bone malignancy in patients with hyperpara-thyroidism published in five reports. The first published report, by Wiig et al.22, in 1971, described a 49-year-old woman with a parathyroid adenoma and hyperparathyroidism who had multiple osteolytic tumors of the skeleton. In 1997, Smith et al.23, reported two cases in which bone sarcomas were present at the time of hyperparathyroidism diagnosis. The first was in a 46-year-old woman who developed chondrosarcoma

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of the tibia; the second occurred in a 34-year-old woman who developed osteosarcoma of the mandible. In 2003, an osteosarcoma of the right proximal femur was reported in a 69-year-old woman with primary hyperparathyroidism24. A case report in 2004 described two females, ages 66 and 36 years, with hyperpara-thyroidism and chondrosarcoma25; and most recently, a 56-year-old woman presented with hyperparathyroid-ism and osteosarcoma of the tibia26. As primary hyper-parathyroidism has an annual incidence of 100 000 cases per year27, this very small number of bone sarcomas cases makes it unlikely that there is a causal association between these two conditions. Furthermore, a recent analysis found that hyperparathyroidism is not more prevalent in patients with osteosarcoma than in the general population28.

Through December 31, 2005 no human reports of pathology-confirmed osteosarcoma have been received for individuals treated with teriparatide, other prepara-tions of teriparatide, or other peptides of parathyroid hormone, either in the setting of clinical trials or from post-marketing drug experience. Over 1900 participants from Lilly-sponsored teriparatide trials have been observed for up to 7 years from the time of first teriparatide use.

Summary

Although people with severe osteoporosis require effective therapeutic agents that reduce fractures, they may also experience numerous co-morbid conditions and psychosocial factors. A multidimensional approach to patients with osteoporosis needs to be taken. It should focus on improvements in overall physical condition, appropriate nutritional support, improvement in quality of life, and pharmacotherapy adherence. An osteoporosis educational program has been developed for those identified by their physicians to initiate teriparatide therapy. The program focuses on many of the issues associated with osteoporosis and assists patients in the use of the teriparatide pen device. Call center support is also available to assist consumers and healthcare professionals with issues concerning teriparatide therapy, the pen device, and financial support.

Updates to the adverse events section of the US prescribing information have been made to reflect post-marketing surveillance experience. As of December 31, 2005 no reports of pathology-confirmed osteosarcoma have been received for individuals treated with teriparatide, either with the commercially available drug or in clinical trials. We are unaware of any reports of osteosarcoma in association with other preparations of teriparatide, or other peptides of parathyroid

hormone, either in the setting of clinical trials or from marketed drug experience.

Acknowledgments

The authors thank Drs Adrien Sipos, Carolyn Bugler, Rachel Wagman, John Vahle, and Matthew Rousculp for their insight and contributions to the development of this commentary. This work was supported by Eli Lilly and Company, Indianapolis, IN, USA.

References 1. US Forteo Prescribing Information: Eli Lilly and Company,

Indianapolis, IN, USA, 2004 2. McDonald HP, Garg AX, Haynes RB. Interventions to enhance

patient adherence to medication prescriptions: scientific review. J Am Med Assoc 2002;288:2868-79

3. Vahle JL, Sato M, Long GG, et al. Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety. Toxicol Pathol 2002;30:312-21

4. Miller PD, Bilezikian JP, Deal C. Clinical use of teriparatide in the real world: initial insights. Endocr Pract 2004;10:139-48

5. Hodsman AB, Bauer DC, Dempster D, et al. Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use. Endocr Rev 2005;26:688-703

6. Data on file (FOR20060222A). Eli Lilly and Company, Indianapolis, IN, USA, 2005

7. Rousculp M, Cossrow N, von Allmen H, et al. Patient utilization pattern with teriparatide: examination of a US-based retail prescription database [abstract]. Osteoporosis Int 2005;16:S82

8. Data on file (FOR20060221C). Eli Lilly and Company, Indianapolis, IN, USA, 2004

9. Data on file (FOR20060221A). Eli Lilly and Company, Indianapolis, IN, USA, 2005

10. Data on file (FOR20060221B). Eli Lilly and Company, Indianapolis, IN, USA, 2005

11. Faulkner DL, Young C, Hutchins D, et al. Patient noncompliance with hormone replacement therapy: a nationwide estimate using a large prescription claims database. Menopause 1998;5:226-9

12. Rozenberg S, Vandromme J, Kroll M, et al. Compliance to hormone replacement therapy. Int J Fertil Menopausal Stud 1995;40(Suppl 1):23-32

13. Gold DT. The nonskeletal consequences of osteoporotic fractures. Psychologic and social outcomes. Rheum Dis Clin North Am 2001;27:255-62

14. Data on file (FOR20050519D). Eli Lilly and Company, Indianapolis, IN, USA, 2005

15. Forteo (TM) [teriparatide (rDNA origin)] user manual:prefilled delivery device, 2005

16. Ajayi FO, Sun H, Perry J. Adverse drug reactions: a review of relevant factors. J Clin Pharmacol 2000;40:1093-01

17. Tashjian Jr AH, Chabner BA. Commentary on clinical safety of recombinant human parathyroid hormone 1-34 in the treatment of osteoporosis in men and postmenopausal women. J Bone Miner Res 2002;7:1151-61

18. Neer RM, Arnaud CD, Zanchetta JR, 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

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

20. Vahle JL, Long GG, Sandusky G, et al. Bone neoplasms in F344 rats given teriparatide [rhPTH(1-34)] are dependent on duration of treatment and dose. Toxicol Pathol 2004; 32:426-8

Cur

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from

info

rmah

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care

.com

by

McM

aste

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11/2

6/14

For

pers

onal

use

onl

y.

708 Initial experience with teriparatide in the United States © 2006 libRAphARM lTd – Curr Med Res Opin 2006; 22(�)

21. Data on file [1691-003]. Eli Lilly and Company, Indianapolis, IN, USA, 2005

22. Wiig JN, Bakken TS. Hyperparathyroidism with multiple malignant tumours of bone with giant-cells. A case report. Acta Chir Scand 1971;137:391-3

23. Smith J, Huvos AG, Chapman M, et al. Hyperparathyroidism associated with sarcoma of bone. Skeletal Radiol 1997;26: 107-12

24. Betancourt M, Wirfel KL, Raymond AK, et al. Osteosarcoma of bone in a patient with primary hyperparathyroidism: a case report. J Bone Miner Res 2003;18:163-6

25. Bhatia A, Cannon S, Briggs T, Keen RW. Chondrosarcoma in association with primary hyperparathyroidism. J Bone Miner Res 2004;19:1200-3

26. Jutte PC, Rosso R, de Paolis M, et al. Osteosarcoma associated with hyperparathyroidism. Skeletal Radiol 2004;33:473-6

27. Bilezikian JP, Silverberg SJ. Clinical spectrum of primary hyperparathyroidism. Rev Endocr Metab Disord 2000;1:237-45

28. Jimenez C, Yang Y, Kim HW, et al. Primary hyperpara-thyroidism and osteosarcoma: examination of a large cohort identifies three cases of fibroblastic osteosarcoma. J Bone Miner Res 2005;20:1562-8

CrossRef links are available in the online published version of this paper:http://www.cmrojournal.com

Paper CMRO-3250_3, Accepted for publication: 23 February 2006Published Online: 16 March 2006doi:10.1185/030079906X100159

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