Kazuhiro Kushida

Risk factors for vertebral fractures in renal osteodystrophy.

We determined the prevalence of vertebral fractures in hemodialysis (HD) patients, investigated whether low bone mineral density (BMD) is predictive of vertebral fracture, and evaluated the effect of serum intact parathyroid hormone (iPTH) and alkaline phosphatase (ALP) levels on vertebral fracture. One hundred eighty-seven male HD patients were assessed for vertebral fractures, and lumbar-spine and total-body BMD were measured by dual-energy x-ray absorptiometory. Thirty-nine patients (20.9%) had vertebral fractures. Each standard deviation (SD) decrease in lumbar-spine BMD increased the age-adjusted odds ratio of vertebral fracture 2.0 times (95% confidence interval [CI], 1.4 to 2.0) and 1.6 times (95% CI, 1.1 to 1.6) for total-body BMD. The area under the receiver operating characteristic curve for lumbar-spine BMD was significantly greater than that for total-body BMD (P < 0.05). Patients with serum iPTH levels in the lowest tertile had a 2.4-fold greater risk for vertebral fracture than those in the middle tertile and a 1.6-fold greater risk than those in the highest tertile (P < 0.05). When the two criteria of lowest tertile of serum iPTH level and highest tertile of serum ALP level were combined, the prevalence of vertebral fractures was the greatest. Similarly, when the lowest tertile of serum iPTH level and lowest tertile of serum ALP level were combined, the prevalence was the second greatest among the combined groups according to tertiles of serum iPTH and ALP levels. We conclude that low lumbar-spine BMD might be a sensitive predictor of vertebral fracture in HD patients, and patients with relatively low iPTH levels would have a greater risk for vertebral fracture than those with hyperparathyroidism.

Diagnostic criteria of primary osteoporosis

New diagnostic criteria of primary osteoporosis (2000 version) was presented. The basic concepts are as follows. Firstly, estimation of low bone mass should be made by lumbar BMD by DXA. However, when measurement of lumbar BMD is not appropriate due to fracture or deformities of the spine, hip, radial, calcaneal, or metacarpal BMD should be used. X ray picture of the spine should be used when DXA is not available. Secondary, in cases with fragility fractures, or in cases with BMD below 70% of young adult mean, differential diagnosis should be made in order to rule out other diseases with low BMD than primary osteoporosis.

Metacarpal bone mass in normal and osteoporotic Japanese women using computed X-ray densitometry

The metacarpal bone mineral density (BMD) and metacarpal index (MCI) of the second metacarpal bone were measured by computed X-ray densitometry (CXD) (Teijin Ltd., Tokyo), which we have established with the development of microdensitometry of radiographs. In this study, we evaluated the basic attributes of this CXD method and determined the age-related changes in both metacarpal measurements in normal Japanese women. The precision in vivo was measured in eight subjects. The precision errors [coefficient of variation (CV)] were 0.2–1.2% CV for metacarpal BMD and 0.4–2.0% CV for MCI, respectively. We have obtained low precision error and more rapid analysis, within 3 minutes respectively, compared with the previous methods. Age-related changes in the metacarpal measurements were evaluated in 1438 normal women. Both measurements showed the most significant decrease in the sixth decade of life. The rate of decrease in the sixth decade was 1.6%/year for metacarpal BMD and 1.5%/year for MCI. On comparison between metacarpal BMD by CXD and spine BMD using dual energy X-ray absorptiometry (DXA) in 248 normal women with and without menstruation, the two measurements were found to be similarly decreased in the subjects within 5 years after menopause. There was also no significant difference in the Z-score between metacarpal BMD and spine BMD within 5 years after menopause. These results indicate that early postmenopausal bone loss occurs not only in the spine but also in the metacarpal bone. The metacarpal BMD for patients with osteoporosis was significantly lower than that for age-matched normal controls, although the Z-score for spine BMD (-1.46) was significantly better than that for metacarpal BMD (-0.82). In conclusion, because CXD has excellent low precision error and is widely available at relatively low cost, it appears potentially to be applicable to problems in the diagnosis and management of osteoporosis, when used in association with DXA.

Ultrasound bone densitometry of the os calcis in Japanese women

The velocity (SOS), attenuation slope (BUA) and stiffness index in the os calcis were measured using the ‘Achilles’ ultrasound bone densitometer (Lunar, Madison, WI). We evaluated the basic attributes of this ultrasound bone densitometer, and showed the age-related changes in ultrasound values in normal Japanese women. The precision was measured in vivo on ten occasions over a 2-week period in 5 subjects. The short-term precision errors (CVs) in vivo were 0.6% for stiffness index, 0.3% for SOS and 1.0% for BUA. Spine, femur neck and total body BMD using dual X-ray absorptiometry (DXA) were highly correlated with stiffness index (r=0.80, 0.77 and 0.78, respectively) in 194 subjects. Ultrasound values for patients with osteoporosis were significantly lower than those for the normal controls. TheZ-score compared with young normals was significantly higher for spine bone mineral density (−4.4) than for stiffness index (−3.5); BUA and SOS gave significantly lowerZ-scores −2.9 and −3.0, respectively). Ultrasound values were also lower compared with age-matched normal controls. TheZ-score for stiffness index (−2.1) was significantly superior to that for either SOS or BUA (−1.5). Age-related change in ultrasound values was evaluated in 842 normal women. There was a decline in stiffness index of about 24% from the values in young adulthood to those of women in their seventies, about 75% of which occurred from age 44–49 years onward. These findings seem to indicate that the menopause affected the change in ultrasound values. In conclusion, ultrasound bone densitometry may not be as useful as DXA of the spine for screening for osteoporosis, since theZ-score for DXA is excellent. However, ultrasound bone densitometry appears potentially to be applicable to problems in the diagnosis and management of osteoporosis when used in association with DXA.

Bone mineral density of the spine in normal Japanese subjects using dual-energy X-ray absorptiometry effect of obesity and menopausal status

SummaryBone mineral density (BMD) of the lumbar spine was measured to determine normal Japanese values and to examine the effect of obesity and menopausal status on BMD. Normal Japanese subjects (N=1,296, 1,048 women and 248 men) were examined using dual-energy X-ray absorptiometry. BMD for men peaked between age 20 and 29. For women, there was abrupt bone loss after age 50. Obese women within the same age bracket had a higher BMD than thin women after age 40–49. We determined that BMD began to decline during the irregular menstruation period before the onset of menopause. We conclude that there is a positive correlation between obesity and BMD, particularly in postmenopausal women. In addition, we found that bone loss related to menopause begins during the irregular menstruation period before menopause.

Guidelines for the use of biochemical markers of bone turnover in osteoporosis (2004)

A definition of osteoporosis was agreed upon at the 1993 consensus conference held in Hong Kong. It states that osteoporosis is “characterized by low bone mass and the microarchitectural deterioration of bony tissue, with a consequent increase in bone fragility and susceptibility to fracture.” This definition had been internationally used without revision until recently, when the definition was significantly changed at a National Institutes of Health (NIH) consensus conference in 2000 [1]. According to the consensus statement, osteoporosis is defined as “a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture.” Bone strength is determined by integrating bone mineral density (BMD) and bone quality. BMD is expressed as grams of mineral per area or volume, and, currently, BMD is defined by the individual peak bone density and the resorption rate from the peak. Bone quality is determined by characteristics of the bone matrix, such as microarchitecture, bone turnover, microdamage accumulation, the degree of calcification, and collagen [2,3]. Currently, it is thought that bone quality may not be clinically assessed by measures other than the determination of bone metabolism with biochemical markers of bone turnover. The change in definition may be the result of more recent findings [4], one that demonstrates bone fractures routinely occur despite patients having modest BMD levels, and another that has shown no significant reduction in the risk of a fracture occurring in patients taking one of the two standard medications, one that significantly increases BMD and the other that moderately increases it.

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.

Circadian Variation of Urinary Type I Collagen Crosslinked C-Telopeptide and Free and Peptide-Bound Forms of Pyridinium Crosslinks

This study was performed to investigate the circadian variation of urinary CrossLaps (CTx), which was the type I collagen peptide released during bone matrix degradation, and peptide-bound and free forms of urinary pyridinium crosslinks. Urine was obtained during the 24 h of the study in seven separate collections as follows: from 23:00 h to the first void (FV) followed by FV at 11:00, 11:00-14:00, 14:00-17:00, 17:00-20:00, 20:00-23:00, and 23:00 h to FV the next morning. Total, free, and peptide-bound pyridinoline (Pyr) and deoxypyridinoline (Dpyr) excretion measured by high-performance liquid chromatography (HPLC) and CTx measured by enzyme-linked immunosorbent assay in nine premenopausal women aged 22-40 years and nine osteoporotic women aged 65-83 years was analyzed. Among three parameters of Pyr measured by HPLC, a significant day and night difference was found only in total Pyr (21.9% higher at night than during the day in premenopausal women and 24.0% in osteoporotic women, whereas no significant day and night variation was found in free and peptide-bound Pyr in either group. In contrast, total and peptide-bound Dpyr were significantly (37.9% and 66.9%) higher at night than those during the day in premenopausal women (38.0%) and osteoporotic women (48.8%). For free Dpyr, there were no day and night differences in the two groups. The day and night variances were significantly greater in peptide-bound Dpyr than with total Dpyr in both groups. In urinary CTx, a significant circadian variation with a peak at night and a nadir at 17:00 h was found (p < 0.0001) (premenopausal was 54.0% higher at night than during the day; osteoporotic was 38.4%. In conclusion, urinary CTx represented remarkable circadian variation compared with urinary pyridinium crosslinks measured by HPLC. Furthermore, free pyridinium crosslinks did not undergo a circadian variation. Peptide-bound crosslinks might contribute mostly to the circadian variation of total excretion of pyridinium crosslinks.

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.