Journal of Bone and Mineral Metabolism

, Volume 30, Issue 3, pp 326–337

Effects of teriparatide in Japanese and non-Japanese populations: bridging findings on pharmacokinetics and efficacy

  • Mika Tsujimoto
  • Kazunori Uenaka
  • Atsuko Iwata
  • Yoshihiro Higashiuchi
  • Hideaki Sowa
Original Article


Teriparatide is an anabolic therapy for osteoporosis approved in the United States since 2002 and European Union since 2003; however, approval in Japan lagged significantly. This report describes analyses based on International Conference on Harmonisation (ICH) E-5 guidelines that support bridging between Japanese studies and the large Fracture Prevention Trial (FPT). We analyzed data from single teriparatide doses in healthy Japanese and Caucasian postmenopausal women (J-PK) and from studies of 6 months [Phase 2, dose ranging (J-Ph2)] and 12 months [Phase 3, efficacy and safety (J-Ph3)] of randomized, placebo-controlled, once-daily treatment in Japanese subjects with osteoporosis. In J-PK, apparent teriparatide area-under-the-curve (AUC) and peak concentration (Cmax) were up to 40% higher in Japanese versus Caucasian women; however, body weight-adjusted values were comparable between populations; these findings were supported by population pharmacokinetic analyses. Between the FPT and Japanese studies, baseline demographic characteristics were similar but bone mineral density (BMD) at lumbar spine (L1–L4) and body weight were lower for Japanese subjects. With teriparatide 20 μg/day, significant increases in BMD were observed compared to placebo at 12 months in both the FPT and J-Ph3 study, and percent change and actual change in BMD were comparable between studies. Dose response at 6 months was also comparable across populations. No novel safety signals were identified in Japanese subjects. These analyses show that teriparatide clinical data met ICH E-5 criteria for bridging. Findings from foreign trials such as the FPT can thus be extrapolated to Japanese subjects treated with teriparatide 20 μg/day.


ICH E5 guideline Bridging Ethnic comparison Teriparatide Japan 


  1. 1.
    Chen P, Satterwhite JH, Licata AA, Lewiecki EM, Sipos AA, Misurski DM et al (2005) Early changes in biochemical markers of bone formation predict BMD response to teriparatide in postmenopausal women with osteoporosis. J Bone Miner Res 20:962–970PubMedCrossRefGoogle Scholar
  2. 2.
    Chen P, Miller PD, Recker R, Resch H, Rana A, Pavo I et al (2007) Increases in BMD correlate with improvements in bone microarchitecture with teriparatide treatment in postmenopausal women with osteoporosis. J Bone Miner Res 22:1173–1180PubMedCrossRefGoogle Scholar
  3. 3.
    Dobnig H, Sipos A, Jiang Y, Fahrleitner-Pammer A, Ste-Marie LG, Gallagher JC et al (2005) Early changes in biochemical markers of bone formation correlate with improvements in bone structure during teriparatide therapy. J Clin Endocrinol Metab 90:3970–3977PubMedCrossRefGoogle Scholar
  4. 4.
    Keaveny TM, Donley DW, Hoffmann PF, Mitlak BH, Glass EV, San Martin JA (2007) Effects of teriparatide and alendronate on vertebral strength as assessed by finite element modeling of QCT scans in women with osteoporosis. J Bone Miner Res 22:149–157PubMedCrossRefGoogle Scholar
  5. 5.
    Lindsay R, Zhou H, Cosman F, Nieves J, Dempster DW, Hodsman AB (2007) Effects of a one-month treatment with PTH(1–34) on bone formation on cancellous, endocortical, and periosteal surfaces of the human ilium. J Bone Miner Res 22:495–502PubMedCrossRefGoogle Scholar
  6. 6.
    McClung MR, San MJ, Miller PD, Civitelli R, Bandeira F, Omizo M et al (2005) Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass. Arch Intern Med 165:1762–1768PubMedCrossRefGoogle Scholar
  7. 7.
    Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY et al (2001) Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344:1434–1441PubMedCrossRefGoogle Scholar
  8. 8.
    Obermayer-Pietsch BM, Marin F, McCloskey EV, Hadji P, Farrerons J, Boonen S et al (2008) Effects of two years of daily teriparatide treatment on BMD in postmenopausal women with severe osteoporosis with and without prior antiresorptive treatment. J Bone Miner Res 23:1591–1600PubMedCrossRefGoogle Scholar
  9. 9.
    Orwoll ES, Scheele WH, Paul S, Adami S, Syversen U, Diez-Perez A et al (2003) The effect of teriparatide [human parathyroid hormone (1–34)] therapy on bone density in men with osteoporosis. J Bone Miner Res 18:9–17PubMedCrossRefGoogle Scholar
  10. 10.
    Saag KG, Shane E, Boonen S, Marin F, Donley DW, Taylor KA et al (2007) Teriparatide or Alendronate in Glucocorticoid-Induced Osteoporosis. N Engl J Med 357:2028–2039PubMedCrossRefGoogle Scholar
  11. 11.
    Hirai Y, Kinoshita H, Kusama M, Yasuda K, Sugiyama Y, Ono S (2010) Delays in new drug applications in Japan and industrial R&D strategies. Clin Pharmacol Ther 87:212–218PubMedCrossRefGoogle Scholar
  12. 12.
    (1998) Ethnic factors in the acceptability of foreign clinical data E5 (R1). International Conference on Harmonisation website. Accessed 23 June 2010 (updated)Google Scholar
  13. 13.
    Uyama Y, Shibata T, Nagai N, Hanaoka H, Toyoshima S, Mori K (2005) Successful bridging strategy based on ICH E5 guideline for drugs approved in Japan. Clin Pharmacol Ther 78:102–113PubMedCrossRefGoogle Scholar
  14. 14.
    Delmas PD, Calvo G, Boers M, Abadie E, Avouac B, Kahan A et al (2002) The use of placebo-controlled and non-inferiority trials for the evaluation of new drugs in the treatment of postmenopausal osteoporosis. Osteoporos Int 13:1–5PubMedCrossRefGoogle Scholar
  15. 15.
    Reginster JY, Abadie E, Delmas P, Rizzoli R, Dere W, der AP et al (2006) Recommendations for an update of the current (2001) regulatory requirements for registration of drugs to be used in the treatment of osteoporosis in postmenopausal women and in men. Osteoporos Int 17:1–7PubMedCrossRefGoogle Scholar
  16. 16.
    Boonen S, Marin F, Mellstrom D, Xie L, Desaiah D, Krege JH et al (2006) Safety and efficacy of teriparatide in elderly women with established osteoporosis: bone anabolic therapy from a geriatric perspective. J Am Geriatr Soc 54:782–789PubMedCrossRefGoogle Scholar
  17. 17.
    Miyauchi A, Matsumoto T, Shigeta H, Tsujimoto M, Thiebaud D, Nakamura T (2008) Effect of teriparatide on bone mineral density and biochemical markers in Japanese women with postmenopausal osteoporosis: a 6-month dose-response study. J Bone Miner Metab 26:624–634PubMedCrossRefGoogle Scholar
  18. 18.
    Miyauchi A, Matsumoto T, Sugimoto T, Tsujimoto M, Warner MR, Nakamura T (2010) Effects of teriparatide on bone mineral density and bone turnover markers in Japanese subjects with osteoporosis at high risk of fracture in a 24-month clinical study: 12-month, randomized, placebo-controlled, double-blind and 12-month open-label phases. Bone 47:493–502PubMedCrossRefGoogle Scholar
  19. 19.
    Orimo H, Sugioka Y, Fukunaga M, Muto Y, Hotokebuchi T, Gorai I et al (1998) Diagnostic criteria of primary osteoporosis. J Bone Miner Metab 16:139–150CrossRefGoogle Scholar
  20. 20.
    Chen P, Miller PD, Delmas PD, Misurski DA, Krege JH (2006) Change in lumbar spine BMD and vertebral fracture risk reduction in teriparatide-treated postmenopausal women with osteoporosis. J Bone Miner Res 21:1785–1790PubMedCrossRefGoogle Scholar
  21. 21.
    Uusi-Rasi K, Semanick LM, Zanchetta JR, Bogado CE, Eriksen EF, Sato M et al (2005) Effects of teriparatide [rhPTH (1–34)] treatment on structural geometry of the proximal femur in elderly osteoporotic women. Bone 36:948–958PubMedCrossRefGoogle Scholar
  22. 22.
    Jiang Y, Zhao JJ, Mitlak BH, Wang O, Genant HK, Eriksen EF (2003) Recombinant human parathyroid hormone (1–34) (teriparatide) improves both cortical and cancellous bone structure. J Bone Miner Res 18:1932–1941PubMedCrossRefGoogle Scholar
  23. 23.
    Saag KG, Zanchetta JR, Devogelaer JP, Adler RA, Eastell R, See K et al (2009) Effects of teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: thirty-six-month results of a randomized, double-blind, controlled trial. Arthritis Rheum 60:3346–3355PubMedCrossRefGoogle Scholar
  24. 24.
    Iki M, Kagamimori S, Kagawa Y, Matsuzaki T, Yoneshima H, Marumo F (2001) Bone mineral density of the spine, hip and distal forearm in representative samples of the Japanese female population: Japanese Population-Based Osteoporosis (JPOS) Study. Osteoporos Int 12:529–537PubMedCrossRefGoogle Scholar
  25. 25.
    Recker RR, Marin F, Ish-Shalom S, Moricke R, Hawkins F, Kapetanos G et al (2009) Comparative effects of teriparatide and strontium ranelate on bone biopsies and biochemical markers of bone turnover in postmenopausal women with osteoporosis. J Bone Miner Res 24:1358–1368PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society for Bone and Mineral Research and Springer 2011

Authors and Affiliations

  • Mika Tsujimoto
    • 1
  • Kazunori Uenaka
    • 2
  • Atsuko Iwata
    • 1
  • Yoshihiro Higashiuchi
    • 2
  • Hideaki Sowa
    • 2
  1. 1.Lilly Research Laboratories-Development Center of Excellence-Asia PacificEli Lilly Japan K.K.KobeJapan
  2. 2.Lilly Research Laboratories-Development Center of Excellence-JapanEli Lilly Japan K.K.KobeJapan

Personalised recommendations