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Raloxifene and teriparatide (hPTH 1-34) have complementary effects on the osteopenic skeleton of ovariectomized rats

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Abstract

The skeletal efficacy of raloxifene (Ral) plus weekly teriparatide [recombinant human parathyroid hormone (1-34), TPTD] combinations relative to each treatment alone or sequentially were evaluated in osteopenic, ovariectomized rats. In the first study, 6-month-old Sprague-Dawley rats were ovariectomized (Ovx) and permitted to lose bone for 1 month before treatment for the following 3 months. Raloxifene (Ral, 1 mg/kg/day orally) was evaluated alone and in combination with TPTD (10 or 30 μg/kg/week) administered weekly by subcutaneous injection. QCT, biomechanical testing, and histomorphometry were used to quantitate skeletal effects. Weekly TPTD alone at either dose had no skeletal effect relative to Ovx. Daily Ral prevented further loss of vertebral bone mineral density (BMD), resulting in BMD that was significantly greater than Ovx, but significantly less than age-matched, sham-Ovx, vehicle controls (sham). The raloxifene plus 30μg/kg/week TPTD group had vertebral BMD that was significantly greater than Ovx, Ral alone, and both TPTD dose-alone groups. Therefore, the Ral plus TPTD group completely restored bone mass to sham levels. Compression testing of lumbar vertebra L5 confirmed increased strength for both Ral plus TPTD combinations relative to Ovx, with strength not different from sham. Histomorphometry of the proximal tibial metaphysis showed that Ovx significantly increased eroded surface and bone formation compared to sham. Raloxifene treatment restored eroded surface and bone formation rate back to sham levels. Raloxifene plus TPTD at 30μg/kg/week resulted in a significantly higher mineral appositional rate compared to Ral and sham, which was not different from Ovx and TPTD alone. Raloxifene plus TPTD at both doses had eroded surfaces that were significantly less than Ovx but not different from sham or Ral alone. In a sequential study, 6-month-old Ovx rats were permitted to develop osteopenia for 2 months before a daily TPTD 80μg/kg/day subcutaneous injection was initiated. Following 2 months of TPTD treatment, animals were either (1) continued on TPTD, (2) discontinued from TPTD, (3) switched to Ral 3 mg/kg/day, oral, or 17α-ethynyl estradiol (EE2) 0.1mg/kg/day, oral, for another 2 months. Raloxifene and EE2 maintained most of TPTD-induced new bone in Ovx rats by preventing the increase in bone turnover rate after withdrawal of TPTD. Raloxifene also restored the elevated bone formation activity induced by TPTD to the level of sham. These data suggest that Ral and TPTD have complementary interactions in osteopenic, Ovx rats. Raloxifene inhibited bone resorption, and reduced high bone turnover without significantly retarding TPTD stimulation of bone formation activity.

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References

  1. Maricic M, Adachi JD, Sarkar S, Wu W, Wong M, Harper KD (2002) Early effects of raloxifene on clinical vertebral fractures at 12 months in postmenopausal women with osteoporosis. Arch Intern Med 162: 1140–1143

    Article  PubMed  CAS  Google Scholar 

  2. Delmas PD, Ensrud KE, Adachi JD, Harper KD, Sarkar S, Gennari C, Reginster JY, Pols HA, Recker RR, Harris ST, Wu W, Genant HK, Black DM, Eastell R (2002) Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. Mulitple Outcomes of Raloxifene Evaluation Investigators. J Clin Endocrinol Metab 87: 3609–3617

    Article  PubMed  CAS  Google Scholar 

  3. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, Christiansen C, Delmas PD, Zanchetta JR, Stakkestad J, Gluer CC, Krueger K, Cohen FJ, Eckert S, Ensrud KE, Avioli LV, Lips P, Cummings SR (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 282: 637–645

    Article  PubMed  CAS  Google Scholar 

  4. Turner CH, Sato M, Bryant HU (1994) Raloxifene preserves bone strength and bone mass in ovariectomized rats. Endocrinology 135: 2001–2005

    Article  PubMed  CAS  Google Scholar 

  5. Black L, Sato M, Rowley ER, Magee D, Bekele A, Williams D, Cullinan GJ, Bendele R, Kauffman RF, Bensch WR, Frolik CA, Termine JD, Bryant HU (1994) Raloxifene (LY139481 HCI) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats. J Clin Invest 93: 63–69

    Article  PubMed  CAS  Google Scholar 

  6. Sato M, Bryant HU, Iversen P, Helterbrand J, Smietana F, Bemis K, Higgs R, Turner CH, Owan I, Takano Y, Burr DB (1996) Advantages of raloxifene over alendronate or estrogen on nonreproductive and reproductive tissues in the long-term dosing of ovariectomized rats. J Pharmacol Exp Ther 279: 298–305

    PubMed  CAS  Google Scholar 

  7. Evens G, Brynat HU, Magee D, Sato M, Turner RT (1994) The effects of raloxifene on tibial histomorphometry in ovariectomized rats. Endocrinology 134: 2283–2288

    Article  Google Scholar 

  8. Lindsay R, Nieves J, Formica C, Henneman E, Woelfert L, Shen V, Dempster D, Cosman F (1997) Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis. Lancet 350(9077): 550–555

    Article  PubMed  CAS  Google Scholar 

  9. 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

    Article  PubMed  CAS  Google Scholar 

  10. Gasser JA, Jerome CP (1992) Parathyroid hormone: a cure for osteoporosis? Triangle 31: 111–121

    Google Scholar 

  11. Dempster DW, Cosman F, Parisien M, Shen V, Lindsay R (1993) Anabolic actions of parathyroid hormone on bone. Endocr Rev 14: 690–709

    Article  PubMed  CAS  Google Scholar 

  12. Sato M, Zeng GQ, Turner CH (1997) Biosynthetic human parathyroid hormone (1-34) effects on bone quality in aged ovariectomized rats. Endocrinology 138: 4330–4337

    Article  PubMed  CAS  Google Scholar 

  13. Ma YF, Jee WS, Ke HZ, Lin BY, Liang XG, Li M, Yamamoto N (1995) Human parathyroid hormone-(l-38) restores cancellous bone to the immobilized, osteopenic proximal tibial metaphysis in rats. J Bone Miner Res 10: 496–505

    PubMed  CAS  Google Scholar 

  14. Jerome CP, Johnson CS, Vafai HT. Kaplan KC, Bailey J, Capwell B, Fraser F, Hansen L, Ramsay H, Shadoan M, Lees CJ, Thomsen JS, Mosekilde L (1999) Effect of treatment for 6 months with human parathyroid hormone (1-34) peptide in ovariectomized cynomolgus monkeys (Macaca fascicularis). Bone 25: 301–309

    Article  PubMed  CAS  Google Scholar 

  15. Jerome CP, Burr DB, Van Bibber T, Hock JM, Brommage R (2001) Treatment with human parathyroid hormone (1-34) for 18 months increases cancellous bone volume and improves trabecular architecture in ovariectomized cynomolgus monkeys (Macaca fascicularis). Bone 28: 150–159

    Article  PubMed  CAS  Google Scholar 

  16. Sato M, Westmore M, Clendenon J, Smith S, Hannum B, Zeng GQ, Brommage R, Turner CH (2000) Three-dimensional modeling of the effects of parathyroid hormone on bone distribution in lumbar vertebrae of ovariectomized cynomolgus macaques. Osteoporosis Int 11: 871–880

    Article  CAS  Google Scholar 

  17. Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR (1987) Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 2: 595–610

    PubMed  CAS  Google Scholar 

  18. Turner CH, Burr DB (1993) Basic biomechanical measurements of bone: a tutorial. Bone 14: 595–608

    Article  PubMed  CAS  Google Scholar 

  19. Bryant HU, Glasebrook AL, Yang NN, Sato M (1996) A pharmacological review of raloxifene. J Bone Miner Metab 14: 1–9

    Article  CAS  Google Scholar 

  20. Ma YL, Bryant HU, Zeng QQ, Schmidt A, Hoover J, Cole HW, Yao W, Jee WSS, Sato M (2003) New bone formation with teriparatide (hPTH (1-34)) is not retarded by long-term pretreatment with alendronate, estrogen or raloxifene in ovariectomized rats. Endocrinology 144: 2008–2015

    Article  PubMed  CAS  Google Scholar 

  21. Fujita T, Inoue T, Morii H, Morita R, Norimatsu H, Orimo H, Takahashi H, Yamamoto K, Fukunaga M (1999) Effect of an intermittent weekly dose of human parathyroid hormone (1-34) on osteoporosis: a randomized double-masked prospective study using 3 dose levels. Osteoporosis Int 9: 296–306

    Article  CAS  Google Scholar 

  22. Frolik CA, Black EC, Cain RL, Satterwhite JH, Brown-Augsburger, Sato M, Hock JM (2003) Anabolic and catabolic effects of human parathyroid hormone (1-34) are predicted by duration of hormone exposure. Bone 33: 372–379

    Article  PubMed  CAS  Google Scholar 

  23. Lindsay R, Nieves J, Henneman E, Shen V, Cosman F (1993) Subcutaneous administration of amino-terminal fragment of human parathyroid hormone-(l-34): kinetics and biochemical response in estrogenized osteoporosis patients. J Clin Endocrinol Metab 77: 1535–1537

    Article  PubMed  CAS  Google Scholar 

  24. Dobnig H, Turner RT (1995) Evidence that intermittent treatment with parathyroid hormone increases bone formation in adult rats by activation of bone lining cells. Endocrinology 136: 3632–3638

    Article  PubMed  CAS  Google Scholar 

  25. Onyia JE, Bidwell J, Herring J, Hulman J, Hock JM (1995) In vivo, human parathyroid hormone fragment (hPTH 1-34) transiently stimulates immediate early response gene expression, but not proliferation, in trabecular bone cells of young rats. Bone 17: 479–484

    Article  PubMed  CAS  Google Scholar 

  26. Stanislaus D, Yang X, Liang JD, Wolfe J, Cain RL, Onyia JE, Falla N, Marder P, Bidwell JP, Queener SW, Hock JM (2000) In vivo regulation of apoptosis in metaphyseal trabecular bone of young rats by synthetic human parathyroid hormone (1-34) fragment. Bone 27: 209–218

    Article  PubMed  CAS  Google Scholar 

  27. Jilka RL, Weinstein RS, Bellido T, Roberson P, Parfitt AM, Manolagas SC (1999) Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J Clin Invest 104: 439–446

    Article  PubMed  CAS  Google Scholar 

  28. Ma YL, Cain RL, Halladay DL, Yang X, Zeng Q, Miles RR, Chandrasekhar S, Martin TJ, Onyia JE (2001) Catabolic effects of continuous parathyroid hormone (hPTH 1-38) in vivo is associated with sustained stimulation of RANK ligand and inhibition ofosteoprotegerin and genes associated bone formation. Endocrinology 142: 4047–4054

    Article  PubMed  CAS  Google Scholar 

  29. Sato M, Bryant HU (1996) Raloxifene efficacy in nonreproductive and reproductive tissues in rat models in vivo and in vitro. In: Kuramoto H, Gurpide E (eds) In Vitro Biology of Sex Steroid Hormone Action. Churchill Livingstone, Tokyo, pp 406–421

    Google Scholar 

  30. Gunness-Hey M, Hock JM (1989) Loss of the anabolic effect of parathyroid hormone on bone after discontinuation of hormone in rats. Bone 10: 447–452

    Article  PubMed  CAS  Google Scholar 

  31. Ma YF, Jee WSS, Chen YY, Gasser J, Ke HZ, Li XJ, Kimmel DB (1995) Partial maintenance of extra cancellous bone mass by antiresorptive agents after discontinuation of human parathyroid hormone (1-38) in right hindlimb immobilization rats. J Bone Miner Res 10: 1726–1734

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Lilly Research Laboratories, Lilly Corporate Center, Bldg. 98C/B, DC 0403, 46285, Indianapolis, IN, USA

    Yanfei L. Ma, Henry U. Bryant, Qingqiang Zeng, Allen Schmidt & Masahiko Sato

  2. Radiobiology Division, University of Utah, Salt Lake City, UT, USA

    Webster S. S. Jee

Authors
  1. Yanfei L. Ma
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  2. Henry U. Bryant
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  3. Qingqiang Zeng
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  4. Allen Schmidt
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  5. Webster S. S. Jee
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  6. Masahiko Sato
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Correspondence to Yanfei L. Ma.

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Ma, Y.L., Bryant, H.U., Zeng, Q. et al. Raloxifene and teriparatide (hPTH 1-34) have complementary effects on the osteopenic skeleton of ovariectomized rats. J Bone Miner Metab 23 (Suppl 1), 62–68 (2005). https://doi.org/10.1007/BF03026325

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  • DOI: https://doi.org/10.1007/BF03026325

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