title: Effects of cyclic versus daily hPTH(1-34) regimens on bone strength in association with BMD, biochemical markers, and bone structure in mice.
abstract: We developed a cyclic PTH regimen with repeated cycles of 1-week on and off daily PTH injection and explored its effects on bone strength, BMD, bone markers, and bone structure in mice. Cyclic protocols produced 60-85% of the effects achieved by daily protocols with 57% of the total PTH given, indicating more economic use of PTH. The study supports further exploration of cyclic PTH regimens for the treatment of osteoporosis.
  
  
  BACKGROUND
  To minimize the cost and the catabolic action of hPTH(1-34), a cyclic PTH regimen with repeated 3-month cycles of on-and-off daily injection of hPTH(1-34) was developed in humans and shown to be as effective as a daily regimen in increasing vertebral BMD. However, changes in BMD may not adequately predict changes in bone strength. A murine model was developed to explore the efficacy of a cyclic PTH regimen on bone strength in association with other bone variables.
  
  
  METHODS
  Twenty-week-old, intact, female C57BL/J6 mice (n = 7/group) were treated with (1) daily injection with vehicle for 7 weeks (control); (2) daily injection with hPTH(1-34) (40 microg/kg/day) for 7 weeks (daily PTH); and (3) daily injection with hPTH(1-34) and vehicle alternating weekly for 7 weeks (cyclic PTH). BMD was measured weekly by DXA, and serum bone markers, bone structure, and strength were measured at 7 weeks.
  
  
  RESULTS
  Daily and cyclic PTH regimens increased BMD at all sites by 16-17% and 9-12%, respectively (all p < 0.01). The most dramatic effect of cyclic PTH occurred during the second week of treatment when PTH was off, with femoral and tibial BMD continuing to increase to the same extent as that produced by daily PTH. Both daily and cyclic PTH regimens significantly increased osteocalcin (daily, 330%; cyclic, 260%), mTRACP (daily, 145%; cyclic, 70%), femoral cortical width (daily, 23%; cyclic, 13%), periosteal circumference (daily, 5%; cyclic, 3.5%), and bone strength (max load: daily, 48%; cyclic, 28%; energy absorbed: daily, 103%; cyclic, 61%), respectively. Femoral bone strength was positively correlated with BMD, bone markers, and cortical structure. Neither regimen had an effect on vertebral bone strength. Although actual effects of cyclic PTH were 60-85% of those produced by daily PTH, the effects of cyclic PTH per unit amount administered were slightly greater than those of daily PTH for most measures.
  
  
  CONCLUSIONS
  PTH-enhanced femoral bone strength is positively correlated with its effects on femoral BMD, bone markers, and bone structure. Cyclic PTH regimens represent a potential economic use of PTH and warrant further study.
authors.affiliation: Regional Bone Center, Helen Hayes Hospital, West Haverstraw, New York 10993, USA. iida-kleina@helenhayeshosp.org
authors.forename: Akiko
authors.initials: A
authors.lastname: Iida-Klein
authors.forename: Christine
authors.initials: C
authors.lastname: Hughes
authors.forename: Shi Shou
authors.initials: SS
authors.lastname: Lu
authors.forename: Annette
authors.initials: A
authors.lastname: Moreno
authors.forename: Victor
authors.initials: V
authors.lastname: Shen
authors.forename: David W
authors.initials: DW
authors.lastname: Dempster
authors.forename: Felicia
authors.initials: F
authors.lastname: Cosman
authors.forename: Robert
authors.initials: R
authors.lastname: Lindsay
mesh_terms: D000135:Acid Phosphatase / Q000097:blood; D000818:Animals; D015415:Biomarkers / Q000097:blood; D015519:Bone Density / Q000187:drug effects*; D002118:Calcium / Q000097:blood; D004334:Drug Administration Schedule; D005260:Female; D005269:Femur / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000378:metabolism*; D007527:Isoenzymes / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D015675:Osteocalcin / Q000097:blood; D010024:Osteoporosis / Q000188:drug therapy*; D010446:Peptide Fragments / Q000008:administration & dosage*; D011859:Radiography; D013131:Spine / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000378:metabolism*; D000071681:Tartrate-Resistant Acid Phosphatase; D019379:Teriparatide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016474:Weight-Bearing
chemical_list: D015415:Biomarkers; D007527:Isoenzymes; D010446:Peptide Fragments; D015675:Osteocalcin; D019379:Teriparatide; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; C035748:parathyroid hormone (1-34)amide; D002118:Calcium