To evaluate the efficacy and safety of alendronate, a double-masked, active (alfacalcidol) controlled comparative study for 48 weeks was carried out in a total of 210 Japanese patients with osteoporosis. The doses of alendronate and alfacalcidol were 5 mg/day and 1 microgram/day, respectively. The lumbar bone mineral density (LBMD) values observed at 12, 24, 36 and 48 weeks after the initiation of alendronate treatment were 3.53 +/- 0.53%, 5.37 +/- 0.62%, 5.87 +/- 0.74% and 6.21 +/- 0.59% (mean +/- SE), respectively, higher than the baseline value. Corresponding values in the alfacalcidol group were 1.50 +/- 0.43%, 0.69 +/- 0.63%, 1.12 +/- 0.60% and 1.36 +/- 0. 63%, respectively. There was a significant difference between the two groups at each time point (p<0.05 or p<0.001). The bone turnover markers were depressed during treatment in the alendronate group: -32.2% for alkaline phosphatase, -53.7% for N-terminal osteocalcin and -45.0% for urinary deoxypyridinoline compared with the corresponding baseline values. On the contrary, no notable changes in these parameters were observed in the alfacalcidol group. Treatment with alendronate caused a transient decrease in serum calcium concentrations associated with an increase in the serum level of intact parathyroid hormone. In contrast, treatment with alfacalcidol resulted in a tendency of these parameters to change in the opposite direction. No difference in fracture incidence between the two groups was observed. The overall safety of alendronate was comparable to that of alfacalcidol. In conclusion, although it was a relatively short-term study of 48 weeks, the results of the present study indicate that alendronate at the daily dose of 5 mg was effective in increasing LBMD and that no serious drug-related adverse events were observed in the alendronate-treated patients. Alendronate is more efficacious than alfacalcidol in increasing bone mineral density, although the mechanisms of the actions of the two drugs are apparently different.

We studied the signaling pathways coupling gonadotropin-releasing hormone (GnRH) secretion to elevations in cAMP levels in the GT1 GnRH-secreting neuronal cell line. We hypothesized that increased cAMP could be acting directly by means of cyclic nucleotide-gated (CNG) cation channels or indirectly by means of activation of cAMP-dependent protein kinase (PKA). We showed that GT1 cells express the three CNG subunits present in olfactory neurons (CNG2, -4.3, and -5) and exhibit functional cAMP-gated cation channels. Activation of PKA does not appear to be necessary for the stimulation of GnRH release by increased levels of cAMP. In fact, pharmacological inhibition of PKA activity caused an increase in the basal secretion of GnRH. Consistent with this observation activation PKA inhibited adenylyl cyclase activity, presumably by inhibiting adenylyl cyclase V expressed in the cells. Therefore, the stimulation of GnRH release by elevations in cAMP appears to be the result of depolarization of the neurons initiated by increased cation conductance by cAMP-gated cation channels. Activation of PKA may constitute a negative-feedback mechanisms for lowering cAMP levels. We hypothesize that these mechanisms could result in oscillations in cAMP levels, providing a biochemical basis for timing the pulsatile release of GnRH.G onadotropin-releasing hormone (GnRH) secretion is controlled by a variety of regulatory mechanisms intrinsic to individual neurons or networks of GnRH-secreting neurons and by extrinsic regulatory mechanisms regulated by neurotransmitters released by efferent inputs to GnRH neurons. The development of the highly differentiated GT1 GnRH-secreting neuronal cell lines has provided a model to study the signaling mechanisms involved in the complex regulation of GnRH secretion (1). The GT1 cell lines were established from a hypothalamic tumor induced by genetic targeting of the expression of the oncogene encoding simian virus 40 T antigen to GnRH neurons in a transgenic mouse. The cells are highly differentiated and express and process GnRH at high levels (1, 2). The pulsatile release of GnRH appears to be an intrinsic property of individual or networks of GnRH neurons, since cultures of the GT1 cells release GnRH with a pulse frequency identical to that seen in castrate rodents (3-5). In vivo numerous efferent inputs to GnRH neurons release neurotransmitters that stimulate GnRH secretion (6). Neurotransmitters stimulating GnRH release from GT1 cells include bradykinin, dopamine (DA), endothelin, glutamate, neuropeptide Y, and norepinephrine (NE) (7-12).The current study is focused on the role of the cAMP signaling pathway in the regulation of GnRH secretion from GT1 cells. GT1 cells express both D1-DA receptors (8) and ␤1-adrenergic receptors (12) which are positively coupled to adenylyl cyclase (AC). Treatment of GT1 cells with DA or NE increased intracellular cAMP levels and stimulated GnRH secretion in a dose-dependent fashion (8, 12). The GnRH-releasing effects of DA and NE were mimicked by pharmacologically...

We studied the signaling pathways coupling gonadotropin-releasing hormone (GnRH) secretion to elevations in cAMP levels in the GT1 GnRH-secreting neuronal cell line. We hypothesized that increased cAMP could be acting directly by means of cyclic nucleotide-gated (CNG) cation channels or indirectly by means of activation of cAMP-dependent protein kinase (PKA). We showed that GT1 cells express the three CNG subunits present in olfactory neurons (CNG2,-4.3, and-5) and exhibit functional cAMP-gated cation channels. Activation of PKA does not appear to be necessary for the stimulation of GnRH release by increased levels of cAMP. In fact, pharmacological inhibition of PKA activity caused an increase in the basal secretion of GnRH. Consistent with this observation activation PKA inhibited adenylyl cyclase activity, presumably by inhibiting adenylyl cyclase V expressed in the cells. Therefore, the stimulation of GnRH release by elevations in cAMP appears to be the result of depolarization of the neurons initiated by increased cation conductance by cAMP-gated cation channels. Activation of PKA may constitute a negative-feedback mechanisms for lowering cAMP levels. We hypothesize that these mechanisms could result in oscillations in cAMP levels, providing a biochemical basis for timing the pulsatile release of GnRH.