Abstract
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.
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References
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 22:465–475
National Osteoporosis Foundation (2011) About osteoporosis. Bone Health Basics. http://www.nof.org/aboutosteoporosis/bonebasics/whybonehealth. Accessed 12 July 2012
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 42:1246–1254
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 3:483–489
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 344:1434–1441
Canalis E, Giustina A, Bilezikian JP (2007) Mechanisms of anabolic therapies for osteoporosis. N Engl J Med 357:905–916
Anonymous (2002) Forteo (teriparatide) package insert. Eli Lilly, Indianapolis
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 33:372–379
Barbehenn EK, Lurie P, Wolfe SM (2001) Osteosarcoma risk in rats using PTH 1–34. Trends Endocrinol Metab 12:383
Subbiah V, Madsen VS, Raymond AK, Benjamin RS, Ludwig JA (2010) Of mice and men: divergent risks of teriparatide-induced osteosarcoma. Osteoporos Int 21:1041–1045
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 22:1534–1547
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 107:277–286
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 88:511–520
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 19:225–231
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 71:5371–5375
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 49:245–253
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–e397
Beamer WG, Donahue LR, Rosen CJ, Baylink DJ (1996) Genetic variability in adult bone density among inbred strains of mice. Bone 18:397–403
Ahima RS, Dushay J, Flier SN, Prabakaran D, Flier JS (1997) Leptin accelerates the onset of puberty in normal female mice. J Clin Invest 99:391–395
Ellegaard M, Jorgensen NR, Schwarz P (2010) Parathyroid hormone and bone healing. Calcif Tissue Int 87:1–13
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, Canada
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:e12290
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–E821
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 128:513–525
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 105:533–545
Acknowledgments
We thank the Ochsner Clinic Foundation for providing support for these studies. Supported in part by the National Institutes of Health Center for Protein Structure and Function grants NCRR COBRE 1 P20RR15569 and INBRE P20RR16460; AR Biosciences Institute (ABI); and a grant-in-aid for scientific research from the Japan Society for the Promotion of Science and Kagawa University Project Research Fund, 2005–2006. We thank Dr. Alan Burshell, section head, Department of Endocrinology, Ochsner Clinic Foundation, New Orleans, LA, for his support and advice.
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PTH–CBD is patented and exclusively licensed to BiologicsMD (Patent Number US 2010/0129341 A1). Robert Gensure is the chief medical officer of BiologicsMD. Joshua Sakon and Robert Gensure own stock in BiologicsMD. All other authors have nothing to disclose.
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Ponnapakkam, T., Katikaneni, R., Suda, H. et al. 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. Calcif Tissue Int 91, 196–203 (2012). https://doi.org/10.1007/s00223-012-9626-1
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DOI: https://doi.org/10.1007/s00223-012-9626-1