Calcified Tissue International

, Volume 91, Issue 3, pp 196–203 | Cite as

A Single Injection of the Anabolic Bone Agent, Parathyroid Hormone–Collagen Binding Domain (PTH–CBD), Results in Sustained Increases in Bone Mineral Density for up to 12 Months in Normal Female Mice

  • Tulasi Ponnapakkam
  • Ranjitha Katikaneni
  • Hirofumi Suda
  • Shigeru Miyata
  • Osamu Matsushita
  • Joshua Sakon
  • Robert C. Gensure
Original Research


Parathyroid hormone (PTH) is the most effective osteoporosis treatment, but it is only effective if administered by daily injections. We fused PTH(1–33) to a collagen binding domain (PTH–CBD) to extend its activity, and have shown an anabolic bone effect with monthly dosing. We tested the duration of action of this compound with different routes of administration. Normal young C57BL/6J mice received a single intraperitoneal injection of PTH–CBD (320 μg/kg). PTH–CBD treated mice showed a 22.2 % increase in bone mineral density (BMD) at 6 months and 12.8 % increase at 12 months. When administered by subcutaneous injection, PTH–CBD again caused increases in BMD, 15.2 % at 6 months and 14.3 % at 12 months. Radiolabeled PTH–CBD was concentrated in bone and skin after either route of administration. We further investigated skin effects of PTH–CBD, and histological analysis revealed an apparent increase in anagen VI hair follicles. A single dose of PTH–CBD caused sustained increases in BMD by >10 % for 1 year in normal mice, regardless of the route of administration, thus showing promise as a potential osteoporosis therapy.


Animal models Bone density technology DXA Osteoporosis therapy 


  1. 1.
    Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A (2007) Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Miner Res 22:465–475PubMedCrossRefGoogle Scholar
  2. 2.
    National Osteoporosis Foundation (2011) About osteoporosis. Bone Health Basics. Accessed 12 July 2012
  3. 3.
    Hochberg MC, Ross PD, Black D, Cummings SR, Genant HK, Nevitt MC, Barrett-Connor E, Musliner T, Thompson D (1999) Larger increases in bone mineral density during alendronate therapy are associated with a lower risk of new vertebral fractures in women with postmenopausal osteoporosis. Fracture Intervention Trial Research Group. Arthritis Rheum 42:1246–1254PubMedCrossRefGoogle Scholar
  4. 4.
    Iwamoto J, Sato Y, Takeda T, Matsumoto H (2008) Hip fracture protection by alendronate treatment in postmenopausal women with osteoporosis: a review of the literature. Clin Interv Aging 3:483–489PubMedGoogle Scholar
  5. 5.
    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 (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
  6. 6.
    Canalis E, Giustina A, Bilezikian JP (2007) Mechanisms of anabolic therapies for osteoporosis. N Engl J Med 357:905–916PubMedCrossRefGoogle Scholar
  7. 7.
    Anonymous (2002) Forteo (teriparatide) package insert. Eli Lilly, IndianapolisGoogle Scholar
  8. 8.
    Frolik CA, Black EC, Cain RL, Satterwhite JH, Brown-Augsburger PL, Sato M, Hock JM (2003) Anabolic and catabolic bone effects of human parathyroid hormone (1–34) are predicted by duration of hormone exposure. Bone 33:372–379PubMedCrossRefGoogle Scholar
  9. 9.
    Barbehenn EK, Lurie P, Wolfe SM (2001) Osteosarcoma risk in rats using PTH 1–34. Trends Endocrinol Metab 12:383PubMedGoogle Scholar
  10. 10.
    Subbiah V, Madsen VS, Raymond AK, Benjamin RS, Ludwig JA (2010) Of mice and men: divergent risks of teriparatide-induced osteosarcoma. Osteoporos Int 21:1041–1045PubMedCrossRefGoogle Scholar
  11. 11.
    Kostenuik PJ, Ferrari S, Pierroz D, Bouxsein M, Morony S, Warmington KS, Adamu S, Geng Z, Grisanti M, Shalhoub V, Martin S, Biddlecome G, Shimamoto G, Boone T, Shen V, Lacey D (2007) Infrequent delivery of a long-acting PTH-Fc fusion protein has potent anabolic effects on cortical and cancellous bone. J Bone Miner Res 22:1534–1547PubMedCrossRefGoogle Scholar
  12. 12.
    Calvi LM, Sims NA, Hunzelman JL, Knight MC, Giovannetti A, Saxton JM, Kronenberg HM, Baron R, Schipani E (2001) Activated parathyroid hormone/parathyroid hormone–related protein receptor in osteoblastic cells differentially affects cortical and trabecular bone. J Clin Invest 107:277–286PubMedCrossRefGoogle Scholar
  13. 13.
    Ponnapakkam T, Katikaneni R, Miller E, Ponnapakkam A, Hirofumi S, Miyata S, Suva LJ, Sakon J, Matsushita O, Gensure RC (2011) Monthly administration of a novel PTH–collagen binding domain fusion protein is anabolic in mice. Calcif Tissue Int 88:511–520PubMedCrossRefGoogle Scholar
  14. 14.
    Katikaneni R, Ponnapakkam A, Miller E, Ponnapakkam T, Gensure RC (2009) A new technique for precisely and accurately measuring lumbar spine bone mineral density in mice using clinical dual energy X-ray absorptiometry (DXA). Toxicol Mech Methods 19:225–231PubMedCrossRefGoogle Scholar
  15. 15.
    Tamai E, Ishida T, Miyata S, Matsushita O, Suda H, Kobayashi S, Sonobe H, Okabe A (2003) Accumulation of Clostridium perfringens epsilon-toxin in the mouse kidney and its possible biological significance. Infect Immun 71:5371–5375PubMedCrossRefGoogle Scholar
  16. 16.
    Shimamoto S, Tamai E, Matsushita O, Minami J, Okabe A, Miyata S (2005) Changes in ganglioside content affect the binding of Clostridium perfringens epsilon-toxin to detergent-resistant membranes of Madin–Darby canine kidney cells. Microbiol Immunol 49:245–253PubMedGoogle Scholar
  17. 17.
    Ponnapakkam T, Katikaneni R, Nichols T, Tobin G, Sakon J, Matsushita O, Gensure RC (2011) Prevention of chemotherapy-induced osteoporosis by cyclophosphamide with a long-acting form of parathyroid hormone. J Endocrinol Invest 34:e392–e397PubMedGoogle Scholar
  18. 18.
    Beamer WG, Donahue LR, Rosen CJ, Baylink DJ (1996) Genetic variability in adult bone density among inbred strains of mice. Bone 18:397–403PubMedCrossRefGoogle Scholar
  19. 19.
    Ahima RS, Dushay J, Flier SN, Prabakaran D, Flier JS (1997) Leptin accelerates the onset of puberty in normal female mice. J Clin Invest 99:391–395PubMedCrossRefGoogle Scholar
  20. 20.
    Ellegaard M, Jorgensen NR, Schwarz P (2010) Parathyroid hormone and bone healing. Calcif Tissue Int 87:1–13PubMedCrossRefGoogle Scholar
  21. 21.
    Katikaneni R, Ponnapakkam T, Bradford E, Pasala S, Matsushita O, Sakon J, Gensure RC (2010) A novel parathyroid hormone fusion protein causes sustained increases in bone mineral density in ovarectomized rats after monthly or single dosing. Paper presented at 32nd American Society of Bone and Mineral Research (ASBMR) annual meeting, 13–18 October, Toronto, CanadaGoogle Scholar
  22. 22.
    Tawfeek H, Bedi B, Li JY, Adams J, Kobayashi T, Weitzmann MN, Kronenberg HM, Pacifici R (2010) Disruption of PTH receptor 1 in T cells protects against PTH-induced bone loss. PLoS One 5:e12290PubMedCrossRefGoogle Scholar
  23. 23.
    Katikaneni R, Ponnapakkam T, Suda H, Miyata S, Sakon J, Matsushita O, Gensure RC (2011) Treatment for chemotherapy-induced alopecia in mice using parathyroid hormone agonists and antagonists linked to a collagen binding domain. Int J Cancer 2012 131:E813–E821CrossRefGoogle Scholar
  24. 24.
    Foley J, Dann P, Hong J, Cosgrove J, Dreyer B, Rimm D, Dunbar M, Philbrick W, Wysolmerski J (2001) Parathyroid hormone-related protein maintains mammary epithelial fate and triggers nipple skin differentiation during embryonic breast development. Development 128:513–525PubMedGoogle Scholar
  25. 25.
    Huelsken J, Vogel R, Erdmann B, Cotsarelis G, Birchmeier W (2001) Beta-catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 105:533–545PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Tulasi Ponnapakkam
    • 1
  • Ranjitha Katikaneni
    • 1
  • Hirofumi Suda
    • 2
  • Shigeru Miyata
    • 3
  • Osamu Matsushita
    • 4
  • Joshua Sakon
    • 5
  • Robert C. Gensure
    • 1
  1. 1.Department of Pediatric EndocrinologyChildren’s Hospital at Montefiore and Albert Einstein College of MedicineBronxUSA
  2. 2.Division of Radioisotope Research, Life Science Research CenterKagawa UniversityKagawaJapan
  3. 3.Department of Food and Nutritional Sciences, College of Bioscience and BiotechnologyChubu UniversityAichiJapan
  4. 4.Department of Microbiology and ParasitologyKitasato University School of MedicineKanagawaJapan
  5. 5.Department of Chemistry and BiochemistryUniversity of ArkansasFayettevilleUSA

Personalised recommendations