Effects of cyclic vs. daily treatment with human parathyroid hormone (1–34) on murine bone structure and cellular activity (original) (raw)

Abstract

Previously, we demonstrated that the human parathyroid hormone (1-34) fragment (hPTH(1-34)) increased bone strength in proportion to its effects on BMD and cortical bone structure in the murine femur by comparing cyclic vs. daily administration of hPTH(1-34). Both cyclic and daily regimens increased vertebral BMD similarly at 7 weeks. Here, we have examined the effects of daily and cyclic PTH regimens on bone structure and cellular activity by static and dynamic histomorphometry. Twenty-week-old, intact female C57BL/J6 mice were treated with the following regimens (n = 7 for each group): daily injection with vehicle for 7 weeks [control]; daily injection with hPTH(1-34) (40 μg/kg/day) for 7 weeks [daily PTH]; and daily injection with hPTH(1-34) (40 μg/kg/ day) and vehicle alternating weekly for 7 weeks [cyclic PTH]. At days 9 and 10, and 2 and 3 prior to euthanasia, calcein (10 mg/kg) was injected subcutaneously. At the end of study, the lumbar vertebrae 1-3 and the left femora were excised, cleaned, and processed for histomorphometry. In the lumbar vertebrae, daily and cyclic PTH regimens significantly increased cancellous bone volume (BV/TV), trabecular number, trabecular osteoclast and osteoblast perimeters, trabecular mineral apposition rate (MAR) and bone formation rate (BFR), and periosteal MAR and BFR compared to control, with no significant difference between the two PTH-treated groups. Increased trabecular tunneling was observed in both PTHtreated groups. Both regimens tended to increase vertebral cortical bone formation parameters with the effects at the periosteum site being more marked than those at the endosteum site, resulting in a significant increase in cortical width. In the femur, the effects of cyclic PTH on BV/TV, trabecular width and number, trabecular and endocortical osteoblast and osteoclast perimeters, cortical width, and trabecular and periosteal BFR were less marked than those of daily PTH. A cyclic PTH regimen was as effective as a daily regimen in improving cancellous and cortical bone microarchitecture and cellular activity in the murine vertebra.

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References (46)

  1. Lindsay R, Nieves J, Formica C, Henneman E, Woelfert L, Shen V, et al. Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis. Lancet 1997;350:550-5.
  2. Cosman F, Nieves J, Woelfert L, Formica C, Gordon S, Shen V, et al. Parathyroid hormone added to established hormone therapy: effects on vertebral fracture and maintenance of bone mass after PTH withdrawal. J Bone Miner Res 2001;16:925-31.
  3. Finkelstein JS, Hayes A, Hunzelman JL, Wyland JJ. The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med 2003;349:1216-26.
  4. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-41.
  5. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. Results from a 3-year randomized clinical trial. JAMA 1999;282:637-45.
  6. Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures. JAMA 1998; 280:2077-82.
  7. Iida-Klein A, Zhou H, Lu SS, Levine L, Ducayen-Knowles M, Dempster DW, et al. Anabolic action of human parathyroid hormone is skeletal site specific at the tissue and cellular levels in mice. J Bone Miner Res 2002;17:808-16.
  8. Cosman F, Nieves JW, Lucky MM, Zion M, Woelfert L, Lindsay R. Daily versus cyclic PTH combined with alendronate versus alendronate alone for treatment of osteoporosis. N Engl J Med 2005;353:566-75.
  9. Iida-Klein A, Hughes C, Shen V, Moreno A, Lu SS, Dempster DW, et al. Effects of cyclic vs. daily PTH regimens on bone strength in association with bone density, biochemical markers and bone structure in mice. J Bone Miner Res 2006;21:274-83.
  10. Iida-Klein A, Lu SS, Kapadia R, Burkhart M, Moreno A, Dempster DW, et al. Short-term continuous infusion of human PTH1-34 fragment is catabolic with decreased trabecular connectivity density accompanied by hypercalcemia in C57BL/J6 mice. J Endocrinol 2005;186:549-57.
  11. Cefalu CA. Is bone mineral density predictive of fracture risk reduction? Curr Med Res Opin 2004;20:341-9.
  12. Small RE. Uses and limitations of bone mineral density measurements in the management of osteoporosis. MedGenMed 2005;7:3-9.
  13. Ammann P, Rizzoli R. Bone strength and its determinants. Osteoporosis Int 2003;14(suppl3):S13-8.
  14. Zhou H, Iida-Klein A, Lu SS, Levine L, Ducayen-Knowles M, Dempster DW, et al. The anabolic action of PTH on cortical and cancellous bone differs between axial and appendicular skeletal sites in mice. Bone 2003; 32:513-20.
  15. Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, et al. Bone histomorphometry: standardization of nomenclature, symbols, and units. J Bone Miner Res 1987;2:595-610.
  16. Jerome CP, Burr DB, Van Bibber T, Hock JM, Brommage R. Treatment with human parathyroid hormone (1-34) for 18 months increases cancellous bone volume and improves trabecular architecture in ovariecto- mized cynomolgus monkeys (Macaca fascicularis). Bone 2001;28:150-9.
  17. Sato M, Westmore M, Ma YL, Schmidt A, Zeng QQ, Glass EV, et al. Teriparatide [PTH(1-34)] strengthens the proximal femur of ovariecto- mized nonhuman primates despite increasing porosity. J Bone Miner Res 2004;19:623-9.
  18. Boyce RW, Paddock CL, Franks AF, Jankowsky ML, Eriksen EF. Effects of intermittent hPTH(1-34) alone and in combination with 1,25(OH) 2 D 3 or risedronate on endosteal bone remodeling in canine cancellous and cortical bone. J Bone Miner Res 1999;11:600-13.
  19. Turner RT, Evans GL, Cavolina JM, Halloran B, Morey-Holton E. Programmed administration of parathyroid hormone increases bone formation and reduces bone loss in hindlimb-unloaded ovariectomized rats. Endocrinology 1998;139:4086-91.
  20. Kasukawa Y, Miyakoshi N, Itoi E, Tsuchida T, Tamua Y, Kudo T, et al. Effects of h-PTH on cancellous bone mass, connectivity, and bone strength in ovariectomized rats with and without sciatic-neurectomy. J Orthop Res 2004;22:457-64.
  21. Miyakoshi N. Effects of parathyroid hormone on cancellous bone mass and structure in osteoporosis. Curr Pharmacol Des 2004;10:2615-27.
  22. Schipani E, Ryan HE, Didrickson S, Kobayashi T, Knight M, Johnson RS. Hypoxia in cartilage: HIF-1α is essential for chondrocyte growth arrest and survival. Genes Dev 2001;15:2865-76.
  23. Schipani E. Hypoxia and HIF-1a in chondrogenesis. Semin Cell Dev Biol 2005;16:539-46.
  24. Gross TS, Akeno N, Clemens TL, Komarova S, Srinivasan S, Weimer DA, et al. Physiological and genomic consequences of intermittent hypoxia selected contribution: osteocytes upregulate HIF-1 in response to acute disuse and oxygen deprivation. J Appl Physiol 2001;90:2514-9.
  25. Gross TS, King KA, Brabaia NA, Pathare P, Srinivasan S. Upregulation of osteopontin by osteocytes deprived of mechanical loading or oxygen. J Bone Miner Res 2005;20:250-6.
  26. Arnett TR, Gibbons DC, Utting JC, Orriss IR, Hoebertz A, Rosendaal M, et al. Hypoxia is a major stimulator of osteoclast formation and bone resorption. J Cell Physiol 2003;196:2-8.
  27. Fukuoka H, Aoyama M, Miyasawa K, Asai K, Goto S. Hypoxic stress enhances osteoclast differentiation via increasing IGF2 production by non- osteoclastic cells. Biochem Biophys Res Commun 2005;328:885-94.
  28. Ham AW. Some histophysiological problems peculiar to calcified tissues. J Bone Joint Surg 1952;34A:701-28.
  29. Aaron JE, de Vernejoul M-C, Kanis JA. Bone hypertrophy and trabecular generation in Paget's disease and in fluoride-treated osteoporosis. Bone Miner 1992;17:399-413.
  30. Seeman E. Periosteal bone formation-A neglected determinant of bone strength. N Engl J Med 2003;349:320-3.
  31. Ahlborg HG, Johnell O, Turner CH, Rannevik G, Karlsson MK. Bone loss and bone size after menopause. N Engl J Med 2003;349:327-34.
  32. Samnegard E, Iwaniec UT, Cullen DM, Kimmel DB, Recker RR. Maintenance of cortical bone in human parathyroid hormone(1-84)- treated ovariectomized rats. Bone 2001;28:251-60.
  33. Kneissel M, Boyde A, Gasser JA. Bone tissue and its mineralization in aged estrogen-depleted rats after long-term intermittent treatment with parathyroid hormone (PTH) analog STZ PTS 893 or human PTH(1-34). Bone 2001;28:237-50.
  34. Mashiba T, Burr DB, Turner CH, Sato M, Cain RL, Hock JM. Effects of human parathyroid hormone (1-34), LY333334, on bone mass, remodeling, and mechanical properties of cortical bone during the first remodeling cycle in rabbits. Bone 2001;28:538-47.
  35. Zanchetta JR, Boado CE, Ferretti JL, Wang O, Sato Wilson MG, Gaich GA, et al. Effects of teriparatide [recombinant human parathyroid hormone (1-34)] on cortical bone in postmenopausal women with osteoporosis. J Bone Miner Res 2003;18:539-43.
  36. Uusi-Rasi K, Semanick LM, Zanchetta JR, Bogado CE, Eriksen EF, Sato M, et al. Effects of teriparatide [rhPTH (1-34)] treatment on structural geometry of the proximal femur in elderly osteoporotic women. Bone 2005;36:948-58.
  37. Chen Q, Kaji H, Iu M-F, Nomura R, Sowa H, Yamauchi M, et al. Effects of an excess and a deficiency of endogenous parathyroid hormone on volu- metric bone mineral density and bone geometry determined by peripheral quantitative computed tomography in female subjects. J Clin Endocrinol Metab 2003;88:4655-8.
  38. Calvi LM, Sims NA, Hunzelman JL, Knight MC, Giovannetti A, Saxton JM, et al. Activated parathyroid hormone/parathyroid hormone-related protein receptor in osteoblastic cells differentially affects cortical and trabecular bone. J Clin Invest 2001;107:277-86.
  39. Chiusaroli R, Maier A, Knight MC, Byrne M, Calvi LM, Baron R, et al. Collagenase cleavage of type I collagen is essential for both basal and parathyroid hormone (PTH)/PTH-related peptide receptor-induced osteo- clast activation and has differential effects on discrete bone compartments. Endocrinology 2003;144:4106-16.
  40. Kitahara K, Ishijima M, Rittling SR, Tsuji K, Kurosawa H, Nifuji A, et al. Osteopontin deficiency induces parathyroid hormone enhancement of cortical bone formation. Endocrinology 2003;144:2132-40.
  41. Bouxsein ML, Pierroz DD, Glatt V, Goddard DS, Cavat F, Rizzoli R, et al. β-arrestin2 regulates the differential response of cortical and trabecular bone to intermittent PTH in female mice. J Bone Miner Res 2005;20:635-43.
  42. Li J, Duncan RL, Burr DB, Gattone VH, Turner CH. Parathyroid hormone enhances mechanically induced bone formation, possibly involving L-type voltage-sensitive calcium channels. Endocrinology 2003;144:1226-33.
  43. Komarova SV. Mathematical model of paracrine interaction between osteoclasts and osteoblasts predicts anabolic action of parathyroid hormone on bone. Endocrinology 2005;146:3589-95.
  44. Guinness-Hey M, Hock JM. Loss of the anabolic effect of parathyroid hormone on bone after discontinuation of hormone in rats. Bone 1989; 10:447-52.
  45. Qi H, Li M, Wronski TJ. A comparison of the anabolic effects of parathyroid hormone at skeletal sites with moderate and severe osteopenia in aged ovariectomized rats. J Bone Miner Res 1995;10:948-55.
  46. Li M, Wronski TJ. Response of femoral neck to estrogen depletion and parathyroid hormone in aged rats. Bone 1995;16:551-7.