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Combination/sequential therapies for anabolic and antiresorptive skeletal agents for osteoporosis

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Abstract

In this paper, we focus upon the use of anabolic skeletal therapy for the treatment of postmenopausal and other forms of osteoporosis. The only anabolic skeletal agent currently available is a recombinant bioactive fragment of parathyroid hormone, PTH(1-34), known as teriparatide. The full length molecule, human PTH(1-84) is being investigated at this time as are other PTH molecules. Teriparatide improves bone quality by actions on bone turnover, bone density, bone size, and microarchitecture. In postmenopausal women with osteoporosis, teriparatide reduces the incidence for vertebral and nonvertebral fractures. In individuals who have been treated previously with an antiresorptive agent, the subsequent actions of teriparatide on bone density are delayed transiently if bone turnover is markedly suppressed. Combination therapy with teriparatide or PTH(1-84) and an antiresorptive does not appear, at this time, to offer advantages over the use of PTH or an antiresorptive alone. To maintain the gains in bone density with PTH, it is important to follow its use with an antiresorptive agent.

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References and Recommended Reading

  1. Hauselmann HJ, Rizzoli R: A comprehensive review of treatments for postmenopausal osteoporosis. Osteoporos Int 2003, 14:2–12.

    Article  PubMed  CAS  Google Scholar 

  2. Rosen CJ: Postmenopausal osteoporosis. N Engl J Med 2005, 353:595–603.

    Article  PubMed  CAS  Google Scholar 

  3. Dempster DW, Cosman F, Kurland ES, et al.: Effects of daily treatment with parathyroid hormone on bone microarchitecture and turnover in patients with osteoporosis: a paired biopsy study. J Bone Miner Res 2001, 16:1846–1853.

    Article  PubMed  CAS  Google Scholar 

  4. Hodsman AB, Bauer DC, Dempster DW, et al.: Parathyroid hormone and teriparatide for the treatment of osteoporosis; a review of the evidence and suggested guidelines for its use. Endocr Rev 2005, 26:688–703.

    Article  PubMed  CAS  Google Scholar 

  5. Lindsay R, Silverman SL, Cooper C, et al.: Risk of new vertebral fracture in the year following a fracture. JAMA 2001, 285:320–323.

    Article  PubMed  CAS  Google Scholar 

  6. Neer RM, Arnaud CD, Zanchetta JR, et al.: Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001, 344:1434–1441. This pivotal clinical trial establishes the efficacy of teriparatide in reducing vertebral and nonvertebral fracture incidence in postmenopausal women with osteoporosis.

    Article  PubMed  CAS  Google Scholar 

  7. Body JJ, Gaich GA, Scheele WH, et al.: A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1-34)] with alendronate in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2002, 87:4528–4535.

    Article  PubMed  CAS  Google Scholar 

  8. Prince R, Sipos A, Hossain A, et al.: Sustained nonvertebral fragility fracture risk reduction after discontinuation of teriparatide treatment. J Bone Miner Res 2005, 20:1507–1513.

    Article  PubMed  CAS  Google Scholar 

  9. Gallagher JC, Genant HK, Crans GG, et al.: Teriparatide reduces the fracture risk associated with increasing number and severity of osteoporotic fractures. J Clin Endocrinol Metab 2005, 90:1583–1587.

    Article  PubMed  CAS  Google Scholar 

  10. Marcus R, Wang O, Satterwhite J, Mitlak B: The skeletal response to teriparatide is largely independent of age, initial bone mineral density, and prevalent vertebral fractures in postmenopausal women with osteoporosis. J Bone Miner Res 2003, 18:18–23.

    Article  PubMed  CAS  Google Scholar 

  11. Kurland ES, Cosman F, McMahon DJ, et al.: Parathyroid hormone as a therapy for idiopathic osteoporosis in men: effects on bone mineral density and bone markers. J Clin Endocrinol Metab 2000, 85:3069–3076. This publication represents the first clinical trial of teriparatide in men with osteoporosis demonstrating its actions to increase bone density and providing an experimental basis to the concept of the anabolic window.

    Article  PubMed  CAS  Google Scholar 

  12. Orwoll ES, Scheele WH, Paul S, et al.: The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis. J Bone Miner Res 2003, 18:9–17. The largest clinical trial to date on the use of teriparatide in men with osteoporosis. With a larger number of subjects than employed in the report of Kurland et al. [11•], this paper helps to document the efficacy of teriparatide in men with idiopathic osteoporosis or in those with hypogonadism.

    Article  PubMed  CAS  Google Scholar 

  13. Kaufman JM, Orwoll E, Goemaere S, et al.: Teriparatide effects on vertebral fractures and bone mineral density in men with osteoporosis: treatment and discontinuation of therapy. Osteoporos Int 2005, 16:510–516.

    Article  PubMed  CAS  Google Scholar 

  14. Rubin MR, Bilezikian JP: Parathyroid hormone as an anabolic skeletal therapy. Drugs 2005, 65:2481–2498.

    Article  PubMed  CAS  Google Scholar 

  15. Chen P, Satterwhite JH, Licata AA, et al.: Early changes in biochemical markers of bone formation predict BMD response to teriparatide in postmenopausal women with osteoporosis. J Bone Miner Res 2005, 20:962–970.

    Article  PubMed  CAS  Google Scholar 

  16. Dobnig H, Sipos A, Jiang Y, et al.: Early changes in biochemical markers of bone formation correlate with improvements in bone structure during teriparatide therapy. J Clin Endocrinol Metab 2005, 90:3970–3977.

    Article  PubMed  CAS  Google Scholar 

  17. Hodsman AB, Hanley DA, Ettinger MP, et al.: Efficacy and safety of human parathyroid hormone-(1-84) in increasing bone mineral density in postmenopausal osteoporosis. J Clin Endocrinol Metab 2003, 88:5212–5220.

    Article  PubMed  CAS  Google Scholar 

  18. Greenspan SL, Bone HG, Marriott TB, et al.: Preventing the first vertebral fracture in postmenopausal women with low bone mass using PTH(1-84): results from the TOP Study. J Bone Miner Res 2005, 20(Suppl1):S56.

    Google Scholar 

  19. Jiang Y, Zhao JJ, Mitlak BH, et al.: Recombinant human parathyroid hormone (1-34) [teriparatide] improves both cortical and cancellous bone structure. J Bone Miner Res 2003, 18:1932–1941.

    Article  PubMed  CAS  Google Scholar 

  20. Recker R, Bare S, Miller M, et al.: Treatment of osteoporotic women with parathyroid hormone 1–84 for 18 months improves cancellous bone formation and structure; a bone biopsy study. J Bone Miner Res 2004, 19(Supp1):S97.

    Google Scholar 

  21. Burr DB, Hirano T, Turner CH, et al.: Intermittently administered human parathyroid hormone(1-34) treatment increases intracortical bone turnover and porosity without reducing bone strength in the humerus of ovariectomized cynomolgus monkeys. J Bone Miner Res 2001, 16:157–165.

    Article  PubMed  CAS  Google Scholar 

  22. Zanchetta JR, Bogado CE, Ferretti JL, et al.: Effects of teriparatide [recombinant human parathyroid hormone (1-34)] on cortical bone in postmenopausal women with osteoporosis. J Bone Miner Res 2003, 18:539–543.

    Article  PubMed  CAS  Google Scholar 

  23. Hodsman AB, Kisiel M, Adachi JD, et al.: Histomorphometric evidence for increased bone turnover without change in cortical thickness or porosity after 2 years of cyclical hPTH(1-34) therapy in women with severe osteoporosis. Bone 2000, 27:311–318.

    Article  PubMed  CAS  Google Scholar 

  24. Mashiba T, Burr DB, Turner CH, et al.: 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, 28:538–547.

    Article  PubMed  CAS  Google Scholar 

  25. Lindsay R, Nieves J, Formica C, 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, 350:550–555.

    Article  PubMed  CAS  Google Scholar 

  26. Cosman F, Nieves J, Woelfert L, et al.: Parathyroid hormone added to established hormone therapy: effects on vertebral fracture and maintenance of bone mass after parathyroid hormone withdrawal. J Bone Miner Res 2001, 16:925–931.

    Article  PubMed  CAS  Google Scholar 

  27. Roe E, Sanchez S, del Puerto G, et al.: trogen produce dramatic bone density increases in postmenopausal osteoporosis-results from a placebo-controlled randomized trial. J Bone Miner Res 1999, 14(Suppl1):S137.

    Google Scholar 

  28. Ettinger B, San Martin J, Crans G, Pavo I: Differential effects of teriparatide on BMD after treatment with raloxifene or alendronate. J Bone Miner Res 2004, 19:745–751. A widely quoted article addressing an important issue, namely whether previous antiresorptive therapy affects the subsequent densitometric response to teriparatide. This paper led to the concept that marked suppression of bone turnover by antiresorptive therapy can lead to a delay in the densitometric response to teriparatide.

    Article  PubMed  CAS  Google Scholar 

  29. Cosman F, Nieves J, Zion M, et al.: Daily and cyclic parathyroid hormone in women receiving alendronate. N Engl J Med 2005, 353:566–575. In this paper, the authors present an interesting new way to administer teriparatide. They compared the effects of a cyclical 3-month regimen with continuous teriparatide therapy over a 15 month period. In addition to showing that bone density improves to the same extent with either approach, they provide intriguing new possibility that this approach expands the anabolic window.

    Article  PubMed  CAS  Google Scholar 

  30. Rubin MR, Bilezikian JP: Clinical review 151: the role of parathyroid hormone in the pathogenesis of glucocorticoid-induced osteoporosis: a re-examination of the evidence. J Clin Endocrinol Metab 2002, 87:4033–4041.

    Article  PubMed  CAS  Google Scholar 

  31. Lane NE, Sanchez S, Modin GW, et al.: Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial. J Clin Invest 1998, 102:1627–1633.

    Article  PubMed  CAS  Google Scholar 

  32. Black DM, Greenspan SL, Ensrud KE, et al.: The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 2003, 349:1207–1215. A seminal paper showing that combination therapy with PTH and alendronate does not provide for greater gains in bone density than PTH alone.

    Article  PubMed  CAS  Google Scholar 

  33. Finkelstein JS, Hayes A, Hunzelman JL, et al.: The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med 2003, 349:1216–1226. Similar to the results of Black et al. [32••], this paper shows similar results when a group of men with osteoporosis were studied with combination antiresorptive and anabolic therapy.

    Article  PubMed  CAS  Google Scholar 

  34. Deal C, Omizo M, Schwartz EN, et al.: Combination teriparatide and raloxifene therapy for postmenopausal osteoporosis; results from a 6-month double-blind placebo-controlled trial. J Bone Miner Res, 2004 19(Supp1):1169.

    Google Scholar 

  35. Lindsay R, Scheele WH, Neer R, et al.: Sustained vertebral fracture risk reduction after withdrawal of teriparatide in postmenopasual women with osteoporosis. Arch Intern Med 2004, 164:2024–2030.

    Article  PubMed  Google Scholar 

  36. Rittmaster RS, Bolognese M, Ettinger MP, et al.: Enhancement of bone mass in osteoporotic women with parathyroid hormone followed by alendronate [see comments]. J Clin Endocrinol Metab 2000, 85:2129–2134.

    Article  PubMed  CAS  Google Scholar 

  37. Lane NE, Sanchez S, Modin GW, et al.: Bone mass continues to increase at the hip after parathyroid hormone treatment is discontinued in glucocorticoid-induced osteoporosis: results of a randomized controlled clinical trial. J Bone Miner Res 2000, 15:944–951.

    Article  PubMed  CAS  Google Scholar 

  38. Kurland ES, Heller SL, Diamond B, et al.: The importance of bisphosphonate therapy in maintaining bone mass in men after therapy with teriparatide [human parathyroid hormone(1-34)]. Osteoporos Int 2004, 15:992–997.

    Article  PubMed  CAS  Google Scholar 

  39. Black DM, Bilezikian JP, Rosen C, et al.: The effect of one year of alendronate following one year of PTH1-84: second year results from the PTH and alendronate (PaTH) trial. N Engl J Med 2005, 353:555–566. This second PaTH paper provides data in a rigorously controlled trial that argues for the importance of antiresorptive therapy after anabolic skeletal therapy. The results show that when PTH is not followed up by alendronate, major losses in bone density, as measured by DXA or by QCT, are experienced. When alendronate is used after PTH, the gains in bone density are maintained or further enhanced.

    Article  PubMed  CAS  Google Scholar 

  40. Misof BM, Roschger P, Cosman F, et al.: Effects of intermittent parathyroid hormone administration on bone mineralization density in iliac crest biopsies from patients with osteoporosis: a paired study before and after treatment. J Clin Endocrinol Metab 2003, 88:1150–1156.

    Article  PubMed  CAS  Google Scholar 

  41. Dempster DW, Parisien M, Silverberg SJ, et al.: On the mechanism of cancellous bone preservation in postmenopausal women with mild primary hyperparathyroidism. J Clin Endocrinol Metab 1999, 84:1562–1566.

    Article  PubMed  CAS  Google Scholar 

  42. Vahle JL, Long GG, Sandusky G, et al.: Bone neoplasms in F344 rats given teriparatide [rhPTH(1-34)] are dependent on duration of treatment and dose. Toxicol Pathol 2004, 32:426–438.

    Article  PubMed  CAS  Google Scholar 

  43. Wilker C, Jolette J, Smith S, et al.: No observable carcinogenic effect dose level identified in Fischer 344 rats following daily treatment with PTH(1-84) for 2 years: role of the C-terminal PTH receptor? J Bone Miner Res 2004, 19(Supp1):SA435.

    Google Scholar 

  44. Tashjian AH, Chabner BA: Commentary on clinical safety of recombinant human parathyroid hormone 1–34 in the treatment of osteoporosis in men and postmenopausal women. J Bone Miner Res 2002, 17:1151–1161.

    Article  PubMed  CAS  Google Scholar 

  45. Betancourt M, Wirfel KL, Raymond AK, et al.: Vassilopoulousellin, osteosarcoma of bone in apatient with primary hyperparathyroidism: a case report. J Bone Miner Res 2003, 18:163–166.

    Article  PubMed  CAS  Google Scholar 

  46. Wiig JN, Bakken TS: Hyperparathyroidism with multiple malignant tumours of bone with giant-cells. A case report. Acta Chir Scand 1971, 137:391–393.

    PubMed  CAS  Google Scholar 

  47. Smith J, Huvos AG, Chapman M, et al.: Hyperparathyroidism associated with sarcoma of bone. Skeletal Radiol 1997, 26:107–112.

    Article  PubMed  CAS  Google Scholar 

  48. Palmer M, Adami HO, Krusemo UB, Ljunghall S: Increased risk of malignant diseases after surgery for primary hyperparathyroidism. A nationwide cohort study. Am J Epidemiol 1988, 127:1031–1040.

    PubMed  CAS  Google Scholar 

  49. Jiminez C, Yang Y, Kim HW, et al.: Primary hyperparathyroidism and osteosarcoma: examination of a large cohort identifies three cases of fibroblastic osteosarcoma. J Bone Miner Res 2005, 20:1562–1568.

    Article  Google Scholar 

  50. Gopalakrishnan V, Hwang S, Loughre H, et al.: Administration of ThPTH to humans using Macroflux transdermal technology reults in the rapid delivery of biologically active PTH. J Bone Miner Res 2004, 19(Supp1):M484.

    Google Scholar 

  51. Leone-Bay A, Sato M, Paton D, et al.: Oral delivery of biologically active parathyroid hormone. Pharm Res 2001, 18:964–970.

    Article  PubMed  CAS  Google Scholar 

  52. Fraher LJ, Avram R, Watson PH, et al.: Comparison of the biochemical responses to human parathyroid hormone-(1–31)NH2 and hPTH-(1-34) in healthy humans. J Clin Endocrinol Metab 1999, 84:2739–2743.

    Article  PubMed  CAS  Google Scholar 

  53. Horwitz MJ, Tedesco MB, Gundberg C, et al.: Short-term, high-dose parathyroid hormone-related protein as a skeletal anabolic agent for the treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab 2003, 88:569–575.

    Article  PubMed  CAS  Google Scholar 

  54. Black DM, Rosen CJ: Parsimony with PTH: Is a single weekly injection of PTH superior to a larger cumulative dose given daily? J Bone Miner Res 2002, 17(Suppl1):SA367.

    Google Scholar 

  55. Heaney RP, Recker RR: Combination and sequential therapy for osteoporosis. N Engl J Med 2005, 353:624–625.

    Article  PubMed  CAS  Google Scholar 

  56. Gowen M, Stroup GB, Dodds RA, et al.: Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats. J Clin Invest 2000, 105:1595–1604.

    PubMed  CAS  Google Scholar 

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Correspondence to John P. Bilezikian MD.

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Bilezikian, J.P., Rubin, M.R. Combination/sequential therapies for anabolic and antiresorptive skeletal agents for osteoporosis. Curr Osteoporos Rep 4, 5–13 (2006). https://doi.org/10.1007/s11914-006-0009-2

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