title: Deficiency in androgens and upregulation of insulin-like growth factor-1 are involved in high bone turnover in men receiving androgen deprivation therapy for prostate cancer.
abstract: OBJECTIVE
  This study was performed to elucidate the mechanism of high bone turnover during androgen deprivation therapy (ADT) in terms of osteogenic endocrine activity by testosterone, adrenal androgens, and insulin-like growth factor-1 (IGF-I), and to identify markers reflecting the bone mineral density (BMD) during ADT.
  
  
  METHODS
  BMD and samples of blood and urine were studied before and after 6months of ADT in 70 patients with localized prostate cancer.
  
  
  RESULTS
  Before ADT, serum free-testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, and IGF-I levels were correlated with BMD (rs=0.344, p=0.004; rs=0.264, p=0.027; rs=0.329, p=0.005; rs=0.300, p=0.012, respectively). The serum IGF-I level was independently correlated with the pretreatment BMD (Multivariate p=0.001). These relationships disappeared after ADT (p=0.519, 0.316, 0.116, and 0.597, respectively). After ADT, serum levels of free-testosterone decreased (7.9 to 0.2pg/mL), and DHEA-S and androstenedione were also reduced (3.6 to 2.3μmol/L and 5.6 to 2.9nmol/L, respectively) (p<0.001 in all). In contrast, IGF-I levels were elevated after ADT by 11.6% (19.9 to 22.3nmol/L, p<0.001). Delta-values of IGF-I (post- minus pretreatment levels, mean: +2.2, ranged between -7.1 and +15.3) were inversely correlated with the pretreatment (rs=-0.333 p=0.005) and post-treatment (rs=-0.408, p=0.001) BMD. After ADT, the serum IGF-I level was closely correlated with the serum level of the bone formation marker bone-specific alkaline phosphatase (BAP) (rs=0.328, p=0.006), and delta-IGF-I and delta-BAP showed a close positive correlation (rs=0.388, p=0.001). The post-treatment BMD was correlated only with the urine deoxypyridinoline (DPD) concentration (rs=-0.302, p=0.024) among the bone formation/resorption markers including serum/urine N-telopeptide.
  
  
  CONCLUSIONS
  Serum IGF-I levels increased during ADT in men with a low BMD. Coupled with reduced androgen levels, elevated IGF-I levels, which were positively correlated with BAP during ADT, possibly explain the mechanism of ADT-related high bone turnover. The increase of IGF-I is more prominent in men whose BMD is already low at the baseline, and urine DPD might be a marker that reflects BMD during ADT.
authors.affiliation: Division of Urology, Department of Regenerative and Transplant Medicine, Graduate School of Medical and Dental Sciences, Niigata University, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Ishizaki
authors.forename: Noboru
authors.initials: N
authors.lastname: Hara
authors.forename: Itsuhiro
authors.initials: I
authors.lastname: Takizawa
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nishiyama
authors.forename: Etsuko
authors.initials: E
authors.lastname: Isahaya
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Kota
authors.initials: K
authors.lastname: Takahashi
mesh_terms: D000368:Aged; D000726:Androgen Antagonists / Q000627:therapeutic use; D000728:Androgens / Q000172:deficiency / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D015519:Bone Density; D001862:Bone Resorption; D001842:Bone and Bones / Q000502:physiology*; D019314:Dehydroepiandrosterone Sulfate / Q000097:blood; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013739:Testosterone / Q000097:blood; D015854:Up-Regulation
chemical_list: D000726:Androgen Antagonists; D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; D013739:Testosterone; D019314:Dehydroepiandrosterone Sulfate; D007334:Insulin-Like Growth Factor I