Effects of recombinant human growth hormone and insulin‐like growth factor‐I, with or without 17β‐estradiol, on bone and mineral homeostasis of aged ovariectomized rats

This study aimed to evaluate whether recombinant human growth hormone (rhGH) or insulin-like growth factor-I (rhIGF-I) can reverse or prevent further bone loss in aged osteopenic ovariectomized (OVX) rats and to compare their effects with those of 17β-estradiol (E 2 ). Twelve-month-old rats were OVX, remained untreated for 8 weeks, and subsequently received daily subcutaneous (SC) injections of rhGH (75 μg/day), rhIGF-I (250 μg/day), E 2 (1.5 μg/day), and their respective combinations during 8 weeks, and were then compared with sham-operated, pretreatment OVX, and saline-treated OVX rats. A single sc injection of rhGH resulted in peak hGH concentrations after 90 minutes, with a half-life of 124 minutes ; the highest plasma IGF-I concentrations were reached 45 minutes after rhIGF-I injection (+57% vs. baseline) with a gradual decline thereafter. Measurements included : biochemical parameters of bone remodeling (plasma osteocalcin and urinary pyridinolines) ; histomorphometry of proximal tibial metaphysis ; DXA of femur ; biomechanical analysis of femur and fifth lumbar vertebra (L5) ; plasma 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), and calbindin-D 9K in duodenal mucosa. Whereas all E 2 -treated OVX rats had much suppressed bone remodeling, rhGH or rhIGF-I had no effect on any biochemical or histomorphometrical parameter of remodeling. The bone mineral density (BMD) at the distal femoral metaphysis as well as parameters of strength at L5 were maintained at pretreatment values in OVX rats treated with E 2 , GH, or IGF-I, but not in saline-treated OVX rats ; their effects were not additive, however. Trabecular bone volume in the tibial metaphysis was also higher in rats treated with these agents than in saline-treated rats, but this was more apparent at the primary than at the secondary spongiosa, suggesting that their mechanism of action is on primary spongiosa formation or breakdown. E 2 alone was ineffective to augment the BMD at the femoral diaphysis ; however, the diaphyseal BMD was 12-14% higher (p < 0.01) after 8 weeks of GH treatment than in pretreatment or saline-treated OVX rats and sham-operated rats, while IGF-I was less effective than GH. GH or IGF-I treatment had no effect on plasma 1,25(OH) 2 D 3 or duodenal calbindin-D 9K concentrations, but the combination of GH or IGF-I with E 2 potentiated the effect of E 2 to stimulate calbindin-D 9K concentrations and urinary calcium excretion, indicating hyperabsorption hypercalciuria. In conclusion, the administration of rhGH and rhIGF-I, like that of E 2 , into aged OVX rats prevents further loss of bone mass and strength at sites containing trabecular bone. In addition, rhGH increases cortical bone mass above pretreatment values.