Hideaki Kishimoto

Changing incidence of hip, distal radius, and proximal humerus fractures in Tottori Prefecture, Japan

A survey of all fractures in patients > or =35 years of age for hip, distal radius, and proximal humerus was performed in Tottori Prefecture, Japan. Hip fracture survey was done for the years 1986-1988, and also 1992-1994. A distal radius and proximal humerus fracture survey was done for the years 1986-1988, 1992, and 1995. The age- and gender-specific incidence rates of these three types of fracture among Japanese were substantially lower than those of whites living in North America or northern Europe. The age-adjusted incidence rates of hip fracture (per 100,000 person-years) were 40.7 and 114.1 in 1986 and 57.1 and 145.2 in 1994 for men and women, respectively, showing a significant increase with time for women. Upon examination of individual fracture types, there was no significant increase in cervical fractures, whereas a significant increase was observed in trochanteric fractures for women. The age-adjusted incidence rates of distal radius fractures for women were 164.9 in 1986 and 211.4 in 1995, showing a significant increase with time; however, no increase was observed among men. Incidence of proximal humerus fractures was 10.3 and 42.0 in 1986 and 17.1 and 47.9 in 1995 for men and women, respectively, and these increases were significant for both genders.

Randomized Teriparatide [Human Parathyroid Hormone (PTH) 1–34] Once-Weekly Efficacy Research (TOWER) Trial for Examining the Reduction in New Vertebral Fractures in Subjects with Primary Osteoporosis and High Fracture Risk

CONTEXT Weekly teriparatide injection at a dose of 56.5 μg has been shown to increase bone mineral density. OBJECTIVE A phase 3 study was conducted to determine the efficacy of once-weekly teriparatide injection for reducing the incidence of vertebral fractures in patients with osteoporosis. DESIGN AND SETTING In this randomized, multicenter, double-blind, placebo-controlled trial conducted in Japan, the incidence of morphological vertebral fractures by radiographs was assessed. PATIENTS Subjects were 578 Japanese patients between the ages of 65 and 95 yr who had prevalent vertebral fracture. INTERVENTION Subjects were randomly assigned to receive once-weekly s.c. injections of teriparatide (56.5 μg) or placebo for 72 wk. MAIN OUTCOME MEASURE The primary endpoint was the incidence of new vertebral fracture. RESULTS Once-weekly injections of teriparatide reduced the risk of new vertebral fracture with a cumulative incidence of 3.1% in the teriparatide group, compared with 14.5% in the placebo group (P < 0.01), and a relative risk of 0.20 (95% confidence interval, 0.09 to 0.45). At 72 wk, teriparatide administration increased bone mineral density by 6.4, 3.0, and 2.3% at the lumbar spine, the total hip, and the femoral neck, respectively, compared with the placebo (P < 0.01). Adverse events (AE) and the dropout rates by AE were more frequently experienced in the teriparatide group, but AE were generally mild and tolerable. CONCLUSION Weekly s.c. administration of teriparatide at a dose of 56.5 μg may provide another option of anabolic treatments in patients with osteoporosis at higher fracture risk.

A Double-Masked Multicenter Comparative Study Between Alendronate and Alfacalcidol in Japanese Patients with Osteoporosis

Abstract: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 μg/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.

The incidence of fractures of the proximal femur and the distal radius in Tottori prefecture, Japan

SummaryWe report the incidence of proximal femur and distal radius fractures in Tottori prefecture, Japan. In 1986 and 1987, 573 proximal femoral fractures and 1576 distal radial fractures were registered in this district. The age- and sex-specific incidence rates of these two fractures are lower among Japanese than among European or North American whites, according to previous reports. Thus, it was concluded that the incidence rates of these two fractures are lower in Japanese than in Caucasians.

A comparison of incidences of vertebral fracture in Japanese patients with involutional osteoporosis treated with risedronate and etidronate: a randomized, double-masked trial

To demonstrate the clinical benefit of risedronate at 2.5 mg daily in the treatment of involutional osteoporosis, the effect of risedronate on incidence of vertebral fracture was compared with that of etidronate. A total of 547 patients with one to four vertebral fractures were randomized to receive either treatment with 2.5 mg/day of risedronate or intermittent treatment (treatment of 2 weeks and off period of 10 weeks) with 200 mg/day of etidronate for 96 weeks in a double-masked fashion. All patients received 200 mg calcium supplement daily. Lateral and anteroposterior thoracic and lumbar spine radiographs were obtained at baseline and at 24, 48, 72, and 96 weeks. Cumulative incidence rates of patients who had at least one new or worsening vertebral fracture during the 96-week period were 12.3% for risedronate and 14.2% for etidronate, and it was verified that the fracture prevention effect of risedronate was not inferior to that of etidronate. The incidence rates of fracture during the initial 24-week period were 8.8% for risedronate and 6.0% for etidronate, but the cumulative incidence rate of fracture from 24 to 96 weeks was lower in the risedronate group (3.9%) as compared to the etidronate group (8.7%). Height loss was significantly less in the risedronate group (−0.28 cm) than in the etidronate group (−0.70 cm) after 96 weeks. Decreases in bone resorption markers including urinary total deoxypyridinoline and NTX were significantly greater in the risedronate group than in the etidronate group throughout the treatment period. An improvement of patient QOL was observed in both groups. No significant difference in the incidence of adverse events was observed between the two treatments. Daily oral risedronate (2.5 mg) was shown to provide an effective therapy for involutional osteoporosis in Japanese patients with good tolerability.

Alendronate reduced vertebral fracture risk in postmenopausal Japanese women with osteoporosis: a 3-year follow-up study.

The risk-reducing effect of alendronate on vertebral fractures has been consistently reported. In a 2-year, randomized, double-blind, active drug-controlled (1 µg alfacalcidol) double-dummy study, we also reported that alendronate (5.0 mg) had a fracture-reducing effect in Japanese patients with preexisting vertebral fractures. The present report describes the risk-reducing effect of alendronate (5.0 mg) for 3 years in postmenopausal osteoporotic patients. The 3-year treatment period consisted of the original 2-year double-blind study followed by a 1-year extension. A total of 170 postmenopausal female patients were involved in the third year; 90 received alendronate and 80 received alfacalcidol. Both efficacy and safety were analyzed in these 170 patients. Vertebral fracture was determined by quantitative morphometry, and vertebral bone mineral density (BMD) was measured by the DXA method (dual-energy X-ray absorptiometry). The primary efficacy endpoint was the incidence of vertebral fracture, excluding fracture cases that occurred in the first 6 months after treatment initiation. The cumulative incidence of vertebral fracture at 3 years was 7.8% (7/90) in the alendronate group and 18.8% (15/80) in the alfacalcidol group, indicating a significantly reduced risk of fractures in the alendronate group (relative risk = 0.41, 95% CI = 0.18–0.97). Lumbar spine BMD increased by 9.2% in the alendronate group (n = 26) and by 1.4% in the alfacalcidol group (n = 22) at 3 years. The safety profile of alendronate during 3 years of treatment was similar to that of alfacalcidol. The present study thus demonstrated that treatment with alendronate 5.0 mg for 3 years increased vertebral BMD and reduced the risk of vertebral fractures in Japanese, postmenopausal women with osteoporosis.

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

Abstract: 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.

Efficacy and tolerability of once-weekly administration of 17.5 mg risedronate in Japanese patients with involutional osteoporosis: a comparison with 2.5-mg once-daily dosage regimen.

In this multicenter, randomized, double-blind controlled trial, the efficacy and safety of once-weekly dosing with 17.5 mg risedronate was compared with once-daily dosing with 2.5 mg risedronate in Japanese patients with involutional osteoporosis. A total of 496 patients were randomized to receive either once-weekly (n = 249) or once-daily (n = 247) treatment. All patients were supplemented with 200 mg/day calcium. Following 48 weeks of treatment, the mean (±SD) percent changes, from baseline, in the bone mineral density of the lumbar spine (L2-L4 BMD) in the once-weekly and once-daily treatment groups were 5.36 ± 4.27% and 5.87 ± 4.47%, respectively. The difference between the groups was −0.5% (95% confidence interval: −1.35% to 0.35%), demonstrating that the effect on BMD of once-weekly treatment was not inferior to that of once-daily treatment. The time-course reductions in biochemical markers of bone resorption (urinary N- and C-telopeptide of type I collagen) and bone formation (bone-specific alkaline phosphatase) were similar for the two dosing regimens. There were no differences in the incidence of new vertebral fractures or the worsening of existing fractures between the once-weekly (2.2%) and once-daily (2.7%) dosing regimens. No significant differences were observed between the two dosing regimens in the incidence or the type of adverse events. However, 10.1% of the patients in the once-daily group withdrew due to adverse events as compared to 5.2% in the once-weekly group. Moreover, drug-related adverse events, including upper gastrointestinal disorders and abnormal changes in laboratory parameters, tended to be less in the once-weekly dosing regimen than in the once-daily dosing regimen. In conclusion, once-weekly oral dosing with 17.5 mg risedronate was well tolerated in Japanese osteoporotic patients, and showed equivalent efficacy to once-daily oral dosing with 2.5 mg risedronate. This once-weekly regimen is expected to provide a more convenient therapeutic option as an alternative to daily dosing and to enhance patient compliance in long-term therapy for osteoporosis.

Effect of ED-71 on modeling of bone in distraction osteogenesis

We investigated the effect of 2-beta-(3-hydroxypropoxy)-1alpha,25-dihydroxyvitamin D3 (ED-71) on the modeling of bone in distraction osteogenesis. The tibiae of 30 rabbits were lengthened by 10 mm in 10 days. Following osteotomy, ED-71 (0.05 microg/kg) was administered subcutaneously twice a week to the ED-71 group until necropsy. The bone mineral content (BMC) of the lengthened callus was measured by dual-energy X-ray absorptiometry (DXA). Five rabbits per group were killed at 1, 3, and 8 weeks after completion of lengthening, and the lengthened callus was examined histologically and histomorphometrically. Bone volume of the lengthened callus was measured by peripheral quantitative computed tomography (pQCT) at 8 weeks after the completion of lengthening. At all timepoints the BMC in the ED-71 group was significantly higher than that in the untreated group. The mineral apposition rate and bone formation rate were higher in the ED-71 group than in the untreated group at 1 and 3 weeks after the completion of lengthening on the coronal section. In cross sections, the cortical area and width in the ED-71 group showed significantly higher values than in the untreated group at 8 weeks after the completion of lengthening. Both the endosteal osteoid surface and endosteal eroded surface showed no differences between groups. However, the endosteal mineral apposition rate and endosteal bone formation rate were significantly higher in the ED-71 group. At 8 weeks after completion of lengthening, the intracortical area and intracortical BMC were significantly greater in the ED-71 group than in the untreated group, but no significant difference was noted in intracortical BMD. These findings indicate that ED-71 increases callus volume during the early period after the completion of lengthening, resulting in thick cortical bone formation.

Bone Responses at Various Skeletal Sites to Human Parathyroid Hormone in Ovariectomized Rats: Effects of Long-term Administration, Withdrawal, and Readministration

This study was undertaken to examine bone responses to human parathyroid hormone (hPTH) at various skeletal sites. Forty 6-month-old female Wistar rats were divided into four groups, and bilateral ovariectomy (ovx) was performed in three of the four groups (n=30). The other group (n=10) received sham surgery (sham). Four weeks after the ovx, hPTH(1-34) administration was started. The ovx rats received 5 microg/kg per day of PTH (PTH-5; n=10), 10 microg/kg per day of PTH (PTH-10; n=10), or vehicle (PTH-v; n=10), three times a week for 24 weeks. Thereafter, PTH was withdrawn for 16 weeks followed by readministration at the same dosage for 8 weeks. The bone mineral content (BMC) at the whole skeleton and the bone mineral density (BMD) at the lumbar vertebrae, caudal vertebrae, distal femur, diaphysis of the femur, proximal tibia, and skull were longitudinally measured by dual-energy x-ray absorptiometry (DXA) at 4-week intervals during the experimental period. Thirteen rats that died during the experimental period were excluded from the analysis. As a result, the whole skeleton showed an increase in BMC during the PTH administration, whereas no withdrawal or readministration effects were observed. The metaphysis showed a highly sensitive bone response, while the lumbar vertebrae and diaphysis showed a moderate magnitude of changes in bone mass during the PTH administration. The skull and the caudal vertebrae did not show sensitive responses to PTH. After withdrawal, the BMD was markedly decreased at the sites that showed marked increases in BMD after PTH administration. The PTH readministration increased the BMD again at the sites that showed sensitive responses after the initial administration. Strength tests were also performed when the readministration was completed. The ultimate loads for the femur and vertebral body in the PTH-treated groups were significantly higher than those in the vehicle-treated group. In conclusion, the response to PTH in ovx rats varied among skeletal sites; withdrawal-related decreases were marked at the sites showing marked increases in bone mass related to PTH administration, and PTH readministration may be sufficiently effective.