A double-blind dose-ranging study of risedronate in Japanese patients with osteoporosis (a study by the Risedronate Late Phase II Research Group).

To determine the clinical recommended dosage regimen of risedronate for the treatment of involutional osteoporosis in Japanese patients, dose-response relationships for the efficacy and safety of this drug were investigated using a multi-center, randomized, double-blind, parallel group comparative design with four dose levels of risedronate (placebo, 1 mg, 2.5 mg and 5 mg per day). A total of 211 patients diagnosed with involutional osteoporosis according to the criteria proposed by the Japanese Society for Bone and Mineral Research were randomized and received one of the four doses once daily for 36 weeks. All patients were supplemented with 200 mg of calcium daily in the form of calcium lactate. The primary efficacy endpoint was the percent change in bone mineral density of the lumbar spine (L2-L4 BMD) determined by dual-energy X-ray absorptiometry (DXA) from baseline to the time of final evaluation. Changes in biochemical markers of bone turnover and safety profile were also compared. Percent changes in L2-L4 BMD at final evaluation in the placebo, and 1-, 2.5-, and 5-mg risedronate groups were 0.79+/-5.30, 2.71+/-4.93, 5.29+/-3.96, and 5.15+/-4.25% (mean+/-SD), respectively. A linear dose-response relationship was obtained up to a dose of 2.5 mg, whereas no further increase in BMD was observed at 5 mg. The decrease in bone turnover markers, including N-terminal osteocalcin, phosphorus, and urinary deoxypyridinoline, also showed a linear dose-response relationship up to a dose of 2.5 mg. Alkaline phosphatase level decreased linearly up to a dose of 5 mg. Risedronate was well tolerated in this 36-week study with 1- to 5-mg doses. Neither the overall incidence of adverse events nor the percentage of patients without problem in overall safety assessment differed significantly among the dose groups including the placebo group. Based on these results, a once-daily dose of 2.5 mg of risedronate, which is half that used in Caucasians, is recommended for the treatment of involutional osteoporosis in Japanese patients.

A comparison of the effect of risedronate and etidronate on lumbar bone mineral density in Japanese patients with osteoporosis: a randomized controlled trial.

To demonstrate the clinical benefit of 2.5 mg daily risedronate in the treatment of involutional osteoporosis, the effect of risedronate on bone mineral density (BMD) of the lumbar spine was compared with that of etidronate, selected as a representative of the bisphosphonates currently marketed in Japan. In this multicenter, randomized, double-masked, active (etidronate) controlled comparative study, a total of 235 Japanese patients with involutional osteoporosis were randomized to receive either treatment with 2.5 mg/day of risedronate for 48 weeks or intermittent treatment with etidronate (4 cycles of 2 weeks of treatment with 200 mg/day followed by 10-week medication-free periods). All patients received 200 mg of calcium supplement daily in the form of the calcium lactate. Bone mineral density of the lumbar spine (L2-L4 BMD) was determined at 12, 24, 36 and 48 weeks by dual-energy X-ray absorptiometry. The primary endpoint was the percent change in L2-L4 BMD from baseline to the time of final evaluation. Changes in biochemical markers of bone turnover and safety profiles were also compared. A significant increase in L2-L4 BMD was observed at 12 weeks after initiation of therapy in both the risedronate (2.8%) and etidronate (1.8%) groups. The increase in L2-L4 BMD at the time of final evaluation in the risedronate group (4.9%) was significantly greater ( p = 0.002) than that in the etidronate group (3.1%). The changes in bone resorption markers (urinary total deoxypyridinoline and N-terminal telopeptide of type I collagen) from baseline to 48 weeks were -37.6% and -41.3% for risedronate and -22.5% and -26.6% for etidronate, respectively. New vertebral fractures or deterioration of existing fractures were observed in 2.8% (3/106) of the patients in the etidronate group, while no such cases (0/101) were observed in the risedronate group. No significant difference in the incidence of adverse events was found between two treatments. Daily oral risedronate (2.5 mg) exhibited efficacy superior to that of intermittent cyclical etidronate (200 mg) in increasing L2-L4 BMD, and was well tolerated by Japanese patients with involutional osteoporosis.

Early postmenopausal bone loss is prevented by estrogen and partially by 1alpha-OH-vitamin D3: therapeutic effects of estrogen and/or 1alpha-OH-vitamin D3.

A total of 79 Japanese women who were within 5 years of menopause were randomly assigned 1alpha-hydroxyvitamin D3 [1alpha(OH)D3] 1.0 microg/day, conjugated estrogens 0.625 mg/day, a combination of both, or control (no treatment). Lumbar spine and proximal femur bone mineral density (BMD) and biochemical indices were monitored over 2 years. In the 1alpha(OH)D3-treated group, there was a nonsignificant decrease in lumbar spine BMD compared with controls, and no significant loss in the femoral neck compared with controls. In the estrogen-treated group, there was a nonsignificant increase in spine BMD (+2.17% in the first year and +1.71% in the second year), and no loss in femoral neck BMD. The combination of conjugated estrogens +1alpha(OH)D3 was more effective in increasing BMD in the spine (+3. 68% in the first year and +3.63% in the second year) and femur (+2. 56% in the first year and +4.44% in the second year) BMD. There was a significant difference in lumbar spine BMD in both the first and second years between the combination-treated group and the 1alpha(OH)D3-treated and control groups (P < 0.01). Serum osteocalcin (OC) significantly decreased in the combination-treated group (-23.8% in the first year) and the estrogen-treated group (-37. 6% and -41.2% at 6 and 18 months, respectively), and serum alkaline phosphatase (Alp) decreased significantly in the first year in the combination-treated (-31.5%), estrogen-treated (-27.3%), and 1alpha(OH)D3-treated (-7.9%) groups, whereas serum OC increased (+45. 4% in the first year) in women without treatment. The results of this study indicate that early postmenopausal bone loss in the femoral neck is prevented by conjugated estrogens, 1alpha(OH)D3, or both, whereas bone loss in the spine is not prevented by 1alpha(OH)D3. Estrogen proves effective in preventing early postmenopausal bone loss by markedly inhibiting bone turnover. Moreover, a synergistic bone-sparing effect can be expected when estrogen is administered concomitantly with 1alpha(OH)D3 rather than when used alone.

A placebo-controlled, single-blind study to determine the appropriate alendronate dosage in postmenopausal Japanese patients with osteoporosis. The Alendronate Research Group.

Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is a potent inhibitor of bone resorption. The efficacy and safety of 36 weeks of treatment with alendronate were evaluated in Japanese women with osteoporosis, osteoporotic osteopenia or artificial menopause. The bone mineral density (BMD) of the lumbar vertebrae, markers of bone and calcium metabolism and clinical symptoms were monitored. A total of 113 randomly selected patients with osteoporosis or osteopenia were enrolled in the study, of whom 12 were excluded from the analyses because of lack of data. As a result, 101 patients were evaluated for the safety of the drug. Since eight patients were excluded from the efficacy analysis, 93 were evaluated. The incidence of adverse effects in the placebo (P), alendronate 2.5 mg/day (L) and alendronate 10 mg/day (H) groups increased with increasing dose of alendronate, being 6.1, 14.3 and 18.2%, respectively. The most common adverse effects were gastrointestinal symptoms, none of which was serious. Lumbar BMD increased after 36 weeks of drug administration to 5.21%, 5.64% and -0.90% in the L, H and P groups, respectively (P < 0.001, L vs. P and H vs. P). Serum alkaline phosphatase activity, serum osteocalcin and urinary deoxypyridinoline excretion were significantly decreased in a dose-related manner. Serum calcium and phosphorus were also significantly decreased after alendronate administration. Serum intact PTH was transiently increased. The present results indicate that alendronate effectively decreases bone turnover in a dose-related manner and increases lumbar BMD at a dosage of 2.5 mg/day, the lowest dose used in this study, in Japanese patients with osteoporosis.

Classification of hypothalamic progestin-nonresponsive amenorrhea by secretion pattern of serum LH.

The pathogenesis of hypothalamic progestin-nonresponsive amenorrhea is unclear and this disease often fails to respond to treatment. The pulsatile patterns of diurnal and nocturnal secretion of serum LH as well as serum levels of melatonin were examined to improve the understanding of the pathogenesis and to develop strategies for the management of a severe type of hypothalamic amenorrhea. Four types of LH pulsatile patterns were observed: a) no pulse during the day or night (Group 1); b) more than 1 pulse only at night (Group 2); c) only 1 pulse during the day and more than 2 pulses at night (Group 3); and d) more than 2 pulses during the day and at night (Group 4). Serum estradiol was less than 30 pg/mL, and the serum PRL and PRL response to TRH did not differ among the four groups. The basal level and the pulse amplitude of LH increased successively from Group 1 to Group 4. The serum level of melatonin at night was noticeably increased in Group 1 and correlated negatively with the LH pulse frequency at night. After 6-month hormone replacement therapy with estrogen and progesterone, the rate of improvement in ovarian function were 0%, 33.3%, 57.1% and 67.0% in Groups 1, 2, 3, and 4, respectively. In 5 patients, the LH pulse pattern was re-examined at 6 months, the LH pulsatile pattern was changed from that of Group 1 to that of Group 4, with a decrease in serum concentrations of nocturnal melatonin, indicating improved ovarian function. In conclusion, classification of patients according to the LH secretion pattern is useful in establishing the severity of hypothalamic disturbance in hypothalamic progestin-nonresponsive amenorrhea and in predicting its prognosis; in addition nocturnal melatonin can be used as a marker for severer cases of hypothalamic amenorrhea.

Effects of noradrenaline on GnRH-secreting immortalized hypothalamic (GT1-7) neurons.

Noradrenaline (NA) is one of the most important neurotransmitters involved in the regulation of gonadotropin-releasing hormone (GnRH) secretion. In this study, the effects of NA on GnRH secretion, intracellular Ca2+ concentrations ([Ca2+]i), and membrane potentials were investigated in immortalized hypothalamic neurons (GT1-7) to determine the direct effects of NA on GnRH cells. Cells were perfused in a plastic minicolumn, and GnRH concentrations of the effluents were measured. NA increased the release of GnRH in a dose-dependent manner. Cells were loaded with a 4 microM Fura 2-AM, and the ratio of the intensities of fluorescent emission at 510 nm with excitation at 340 and 380 nm was calculated at 100-ms intervals. NA increased the [Ca2+]i responses of single GnRH cells dose-dependently. The NA-induced [Ca2+]i increase was attenuated in the absence of extracellular calcium and was blocked by the beta-adrenergic antagonist propranolol, but not by the alpha-adrenergic antagonist phentolamine. The cell membrane potential was recorded with a whole-cell patch clamp amplifier with glass-electrodes. NA induced membrane depolarization under current-clamp conditions. The depolarization was also inhibited by propranolol, but not by phentolamine. The results show that NA directly affects the membrane potential of GT1-7 cells via beta-adrenergic receptors and induces Ca2+ mobilization; these effects stimulate GnRH secretion.

Pure ovarian ependymoma: report of a case treated with surgery, chemotherapy, irradiation and hyperthermotherapy.

Ependymomas usually develop from neuroectodermal organs. Pure ovarian ependymoma is an extremely rare tumor. We report a patient with ovarian ependymoma who died at the age of 28, 9 years after initial surgery and subsequent intensive combination therapy (chemotherapy, irradiation and hyperthermotherapy) for repeated relapses and metastatic tumors. The diagnosis was confirmed by histopathological and immunohistochemical studies. For recurrent and persistent ependymoma, a combination of the treatment modalities described above is suggested to be beneficial in attenuating the rapid progress and spread of this disease.

[Endocrinological analysis of hypothalamic primary amenorrhea (author's transl)].

Primary amenorrhea, in which serum concentrations of gonadotropins are low or normal, has been considered to be relatively rare. Recent analysis in our outpatient clinic revealed that the incidence of hypothalamic primary amenorrhea is higher than previously appreciated, comprising 26.7% of the total primary amenorrheas. Endocrinological functions of the hypothalamo-hypophyseo-ovarian axis in these patients were therefore investigated. Studies on gonadotropin secretion indicated that a disturbance in LH-RH secretion and a lack of estrogen positive feedback were principle features of this disease. In addition to the dysfunction of gonadotropin secretion, the control of PRL secretion was disturbed in this disease since there was a poor PRL response to chlorpromazine in spite of normal responsiveness to TRH. Thus, "isolated gonadotropin deficiency" hitherto used to describe this disease is not pertinent. Furthermore, these results suggest that PRL might be involved in the onset of puberty in humans. Clinically, the induction of ovulation with HMG (Human Menopausal Gonadotropin) is possible in hypothalamic primary amenorrhea, although the ovarian responsiveness to gonadotropin is poor. Therefore, an endocrinologically precise diagnosis of hypothalamic primary amenorrhea is important in the gynecological clinic because fertility has been considered to be almost impossible in primary amenorrhea.

Effect of hypothalamic deafferentation on the distribution of luteinizing hormone-releasing hormone (LHRH) in the rat brain.

Anterior (AHD) and complete hypothalamic deafferentation (CHD) were performed in female rats to ascertain the origin of LHRH detected in the external layer of ME. Deafferented brains were serially sectioned in a cryostat in the frontal plane. LHRH activity in each section was determined by RIA. While AHD, using a knife with a small radius caused no change in the distribution of LHRH in the brain, AHD, using a knife with a large radius resulted in a significant decrease in LHRH content in the ARC-ME. CHD caused a more marked decrease in the ARC-ME LHRH than AHD. The decrease was more marked in the anterior and posterior portions of the ARC-ME than in the middle one. These effects of CHD on the distribution of LHRH in the ME were ascertained by immunohistochemical studies. In contrast, LHRH content in the POA showed no significant change after AHD and CHD. However, a few LHRH containing fibers were observed in the area lying just proximal to the cut by immunohistochemistry. These results strongly suggest that a part of the LHRH detected in the external layer of ME is derived from that synthesized outside the MBH, possibly in the POA and another part is derived from that synthesized inside the MBH, possibly in the ARC.