title: Prevention of chemotherapy-induced osteoporosis by cyclophosphamide with a long-acting form of parathyroid hormone.
abstract: BACKGROUND
  Most chemotherapeutics reduce bone mineral density (BMD) and increase risk for fractures by causing gonadal suppression, which in turn increases bone removal. Cyclophosphamide (CYP) also has a direct effect of inhibiting bone formation and removal, making the resulting bone loss particularly difficult to treat with antiresorptive therapy.
  
  
  OBJECTIVE
  We tested whether a single dose of the anabolic agent PTH linked to a collagen binding domain (PTHCBD) could prevent the effects of CYP-induced bone loss.
  
  
  METHODS
  Mice received either buffer alone, CYP, or CYP+ PTH-CBD. BMD and alkaline phosphatase were measured every 2 weeks for a total of 8 weeks.
  
  
  RESULTS
  After 6 weeks, mice treated with CYP showed expected reductions in BMD (increase from baseline: 7.4 ± 6.9 vs 24.35 ± 4.86% in mice without chemotherapy, p<0.05) and decrease in alkaline phosphatase levels (42.78 ± 6.06 vs 60.62 ± 6.23 IU/l in mice without chemotherapy, p<0.05), consistent with osteoporosis from impaired bone formation. Administration of a single dose of PTH-CBD (320 μg/kg ip) prior to CYP treatment improved BMD (change from baseline: 23.4 ± 5.4 vs 7.4 ± 6.9%, CYP treatment alone, p<0.05) and increased alkaline phosphatase levels (50.14 ± 4.86 vs 42.78 ± 6.06 IU/l in CYP treatment alone, p<0.05). BMD values and alkaline phosphatase levels were restored to those seen in mice not receiving chemotherapy.
  
  
  CONCLUSIONS
  A single dose of PTHCBD prior to chemotherapy reversed CYP-induced suppression of bone formation and prevented CYP-induced bone loss in mice.
authors.affiliation: Department of Pediatric Endocrinology, Children's Hospital at Montefiore and Albert Einstein College of Medicine, Bronx, NY, USA. tponnapa@montefiore.org
authors.forename: T
authors.initials: T
authors.lastname: Ponnapakkam
authors.forename: R
authors.initials: R
authors.lastname: Katikaneni
authors.forename: T
authors.initials: T
authors.lastname: Nichols
authors.forename: G
authors.initials: G
authors.lastname: Tobin
authors.forename: J
authors.initials: J
authors.lastname: Sakon
authors.forename: O
authors.initials: O
authors.lastname: Matsushita
authors.forename: R C
authors.initials: RC
authors.lastname: Gensure
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000037:antagonists & inhibitors / Q000633:toxicity*; D015519:Bone Density / Q000187:drug effects / Q000502:physiology; D003520:Cyclophosphamide / Q000037:antagonists & inhibitors / Q000633:toxicity*; D003692:Delayed-Action Preparations; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010024:Osteoporosis / Q000139:chemically induced* / Q000517:prevention & control*; D010281:Parathyroid Hormone / Q000008:administration & dosage* / Q000235:genetics; D013997:Time Factors
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003692:Delayed-Action Preparations; D010281:Parathyroid Hormone; D003520:Cyclophosphamide