Efficacy of combined treatment with alendronate (ALN) and eldecalcitol, a new active vitamin D analog, compared to that of concomitant ALN, vitamin D plus calcium treatment in Japanese patients with primary osteoporosis.

UNLABELLED: Combined treatment with alendronate and eldecalcitol was found to be more effective in reducing the bone turnover markers and increasing bone mineral density than alendronate treatment with vitamin D3 and calcium supplementation in the osteoporotic patients. INTRODUCTION: We compared the clinical efficacy and safety of combined treatment with alendronate plus eldecalcitol (ALN + ELD) with those of treatment with ALN plus vitamin D and calcium (ALN + VitD). METHODS: Osteoporotic 219 patients were randomly assigned to the ALN + ELD, or the ALN + VitD group. Primary endpoint was the inter-group differences in lumbar spine BMD (L-BMD) at patient's last visit. Secondary endpoints included the differences in BMD at other sites and the bone turnover marker (BTM) levels. RESULTS: L-BMD, total hip BMD and femoral neck (FN-BMD) increased from baseline by 7.30, 2.41, and 2.70 % in the ALN + ELD group, and by 6.52, 2.27, and 1.18% in the ALN + VitD group, respectively. Inter-group differences of the L-BMD and total hip BMD values were not significant. The increase of the FN-BMD was larger in the ALN + ELD group than the ALN + VitD group. Reductions of the BTMs were greater in the ALN + ELD group than the ALN + VitD group. Interaction of the percent increase of the L-BMD with the baseline values of the BTMs was observed in the ALN + VitD group only. The increases of the FN-BMD in patients with lower baseline values of type-I-collagen C-telopeptide (sCTX) and serum 25(OH) D levels <20 ng/mL were significantly larger in the ALN + ELD group than the other group. CONCLUSION: Combination treatment of ALN plus ELD was more effective in reducing the BTMs and increasing the FN-BMD than ALN treatment with vitamin D3 and calcium.

Effect of the cathepsin K inhibitor odanacatib administered once weekly on bone mineral density in Japanese patients with osteoporosis--a double-blind, randomized, dose-finding study.

UNLABELLED: The efficacy and safety of oral placebo or odanacatib 10, 25, or 50 mg once weekly for 52 weeks were evaluated in a double-blind, randomized, multi-center study in Japanese female and male patients with osteoporosis. INTRODUCTION: Odanacatib is a selective and reversible cathepsin K inhibitor that decreases bone resorption and increases bone mineral density (BMD). METHODS: The primary efficacy endpoint was percent change from baseline to week 52 in lumbar spine BMD. Secondary endpoints included percent change in total hip, femoral neck, and trochanter BMD and in bone biomarkers after treatment for 52 weeks. RESULTS: In this study, 286 patients [94% female, mean age (SD) 68.2 (7.1) years] were included in the analysis. The least-squares mean percent changes from baseline to week 52 in the groups receiving placebo, 10, 25 and 50 mg of odanacatib for lumbar spine (L1~L4) BMD were 0.5, 4.1, 5.7, and 5.9% and for total hip BMD were -0.4, 1.3, 1.8, and 2.7%, respectively. The changes in femoral neck and trochanter BMD were similar to those at the total hip. Bone turnover markers were reduced in a dose-dependent manner. However, the effects of odanacatib on bone formation markers were less compared with the effects on bone resorption markers. Tolerability and safety profiles were similar among all treatment groups with no dose-related trends in any adverse events. CONCLUSIONS: Weekly odanacatib treatment for 52 weeks increased BMD at the lumbar spine and at all hip sites in a dose-dependent manner and was well tolerated in Japanese patients with osteoporosis.

Biochemical markers for the detection of bone metastasis in patients with prostate cancer: diagnostic efficacy and the effect of hormonal therapy.

In the present study, we investigated the diagnostic effectiveness of biochemical markers of bone turnover for the detection of bone metastasis from prostate cancer and changes in the levels of these markers caused by hormonal therapy. Ninety-five patients with prostate cancer were divided into one of three groups: 26 patients with bone metastasis (BM(+)), 35 patients without bone metastasis on nonhormonal therapy (BM(-)HT(-)) and 34 patients without bone metastasis on hormonal therapy (BM(-)HT(+)). All patients in the BM(+) group had received hormonal therapy. Serum or urinary levels of the following biochemical markers of bone turnover were examined: bone-specific alkaline phosphatase (B-ALP), osteocalcin (OC), type I procoIlagen C-propeptide (PICP), type I collagen cross-linked C-telopeptide (ICTP), C-telopeptide fragment (CTx), N-telopeptide fragment (NTx), total pyridinoline (T-Pyr), total deoxypyridinoline (T-D-Pyr) and free deoxypyridinoline (F-D-Pyr). The BM(+) group showed significantly higher values than the BM(-)HT(-) group for B-ALP, PICP, NTx, CTx, T-Pyr, T-D-Pyr, and F-D-Pyr. Compared with the BM(-)HT(+) group, the BM(-) group showed significantly higher values for B-ALP, ICTP, NTx, T-Pyr and T-D-Pyr. The levels of B-ALP, NTx, CTx, T-D-Pyr and F-D-Pyr were significantly different between the BM(-)HT(-) and BM(-)HT(+) groups. All markers, except OC and CTx, significantly were correlated with the extent of bone metastasis on bone scintigraphy. Of all markers, receiver operating characteristic (ROC) analyses revealed B-ALP and F-D-Pyr to be the most sensitive and specific for differentiation between the BM(+) and BM(-)HT(-) groups with regard to bone formation and resorption. respectively. In contrast, B-ALP and ICTP were most sensitive and specific for differentiation between the BM(+) and BM(-)HT(+) groups. The results suggest that hormonal therapy greatly affects the efficacy of PICP, CTx and F-D-Pyr in the diagnosis of bone metastasis, whereas its effects on ICTP are small. Although bone metabolic markers would be useful in the diagnosis of bone metastasis from prostate cancer, the effects of hormonal therapy on bone metabolism should be kept in mind in their evaluation.

[Diagnosis with bone mass].

In diagnostic criteria of osteoporosis proposed by WHO, the severe osteoporosis is defined as a patient with a value for BMD or BMC more than 2.5SD below the young adult mean value in the presence of one or more fragility fractures. When severe fragility fracture occurs from the second to forth lumbar vertebra, the lumbar BMD could be over-estimated. On the other hand, when the lumbar BMD is markedly low, the demarcation of bone contour is incomplete, and the precision of the BMD measurement decreases. Thus, in the severe osteoporosis it is necessary to be careful in the diagnosis with bone mass using DXA.

[Chronological study for solitary bone metastasis in the sternum from breast cancer with bone scintigraphy].

Since breast cancer is frequently associated with bone metastasis, bone scintigraphies have been performed to determine pre-operative staging and to survey postoperative bone metastasis. The sternum, in particular, is a site at which is difficult to differentiate between benign bone disease and bone metastasis, because of varied uptake and wide individual variations. In this study, chronological bone images were scintigraphied in six cases with solitary sternal metastasis and three cases with benign bone disease including two fracture cases and one arthritis case. On bone scintigrams in which solitary sternal metastasis appeared, increased uptake was found in five cases, and photon deficiency was observed in one case. During follow-up scintigraphies, abnormal accumulations, such as hot spots and cold lesions, increased in the bone metastasis while abnormal uptake disappeared or was unchanged in the benign bone disease cases. On CT, four cases showed osteolytic change, and one exhibited osteosclerotic change. These findings indicate that sternal metastasis usually shows osteolytic change, even if a hot lesion is recognized on bone scintigraphy. In solitary sternal metastasis, for which early diagnosis is difficult, both an integrated diagnosis using other imaging techniques and chronological bone scintigraphy are important.

[Usefulness of 67Ga scintigraphy in deciding surgical indication in secondary hyperparathyroidism].

In order to evaluate the usefulness in deciding surgical indication in secondary hyperparathyroidism (SHP), 67Ga scintigraphy was performed in 37 patients of SHP before parathyroidectomy (PTx). The radionuclide accumulation in skull and submandible was classified into 4 patterns (skull-submandibular pattern, skull pattern, submandibular pattern and normal pattern). Serum alkaline phosphatase levels were significantly elevated in patients of skull-submandibular pattern (13 cases) compared with skull pattern (6 cases), submandibular pattern (6 cases) and normal pattern (12 cases). Serum intact parathyroid hormone levels were significantly elevated in patients of skull-submandibular and skull patterns compared with normal pattern. No significant difference was observed among the weight of resected parathyroid glands. In 4 of 6 patients of normal pattern on 67Ga scintigram, bone scintigraphy showed a characteristic pattern of SHP including an increased accumulation in the skull and submandible. Bone mineral density (BMD) in the distal radius was increased within six to twelve months after PTx in 10 of 11 patients of skull-submandibular pattern on 67Ga scintigram, whereas only one patient showed an increase in BMD in 9 patients of normal pattern. In summary, it was concluded that 67Ga scintigraphy could provide a useful information in deciding the indication for PTx in secondary hyperparathyroidism.

[Development of a simple method for the washout correction of 123I-IMP SPECT and its application to a quantitative rCBF method].

We have developed a simple method to correct the washout of tracer from the brain based on the two-compartment model in brain early SPECT using N-isopropyl-p-[123I]iodoamphetamine (123I-IMP). This correction was applied to a new quantitative method of regional cerebral blood flow (rCBF) in combination with the microsphere method by continuous arterial sampling previously reported. Data acquisition of 123I-IMP early SPECT was started from 35 min after 123I-IMP i.v. injection, and the time activity curve of whole brain on anterior head planar images was monitored immediately after 123I-IMP i.v. injection for the correction of washout of tracer from the brain. The usefulness of this method was evaluated in 12 patients with various brain diseases by comparison with the results obtained from the super-early SPECT at 7-10 min after 123I-IMP i.v. injection. The washout rates in cases of early SPECT corrected by this method ranged from 16.91% to 39.34% with a mean +/- SD of 27.72 +/- 5.44%. The contrast of hypo- to hyperperfusion regions on early SPECT was improved by the correction of the washout, and its intracerebral distribution was similar to the simultaneously obtained super-early SPECT images. These results indicated that the present correction method for the washout was useful for more correct quantification of rCBF.

Rates of change in spinal bone density among Japanese women.

To determine the rates of change in bone mineral density (BMD) at the spine in healthy Japanese women, longitudinal measurements of spinal BMD using dual X-ray absorptiometry were collected from 984 women over 17 years of age (mean age 51.6) at eight medical research centers. They were followed up for 20.9 months on average without any treatment influencing bone and calcium metabolism. Measurements of BMD obtained by two different scanners were converted into standardized BMD (sBMD) values. The multiple linear regression model predicts that spinal sBMD increases up to about 23 years of age: the estimated average rates of increases were 0.13%/year for women aged 20 years. After the age of 23, the sBMD began decreasing: the rates of loss increased by 0.045%/year for each year increase in age among premenopausal women. In perimenopausal women, the rate of loss was 2. 1%/year. In postnatural menopausal women, the rates of loss decreased exponentially with increasing years since menopause. The rates of loss increased by 0.04%/year for 1 kg decrease in body weight or by 0.1%/year for 1 kg/m2 decrease in body mass index. No significant differences in changes in sBMD were found between scanners and between centers after multiple adjustment. We conclude that the rates of change in spinal sBMD are associated with age in premenopausal women, and with years since menopause and weight or BMI in postmenopausal women. Caution is needed, however, when using data from different densitometers to evaluate rates in bone loss in multicenter trials.

Calcaneus as a site for the assessment of bone mass.

The calcaneus is a skeletal site frequently used for monitoring bone loss after spaceflight, because it is sensitive to microgravity-induced bone mineral loss and reflects the degree of demineralization in the vertebra and the femoral neck. In this article, methods for assessing the calcaneus are reviewed, and their potential applications and limitations as the monitoring site for bone loss in weightlessness are discussed. Currently, single or dual energy X-ray absorptiometry appears to be most sensitive for monitoring bone mineral loss in weightlessness. The results of recent studies suggest two- to threefold longer follow-up times required for ultrasound techniques. However, ultrasound devices can be designed to be portable, making them attractive for inflight use, and ultrasound techniques are expected to provide information related to bone quality. Additional investigations that assess new ultrasound techniques would be important to determine and utilize the full potential of this technology for monitoring bone loss in weightlessness.

[Comparative study on the tumor accumulation of 99mTc-tetrofosmin and 99mTc-MIBI in rabbits bearing VX-2 cancer].

Each of myocardial blood flow imaging agents has a potential usefulness as an agent for tumor scintigraphy. The tumor accumulation and washout of 99mTc-tetrofosmin and 99mTc-MIBI were comparatively studied using rabbits bearing VX-2 cancer. From seventeen to twenty days after the implantation of VX-2 cancer into the femoral region of seven rabbits, tumor to soft tissue accumulation ratio (T/S ratio) of each agent was calculated in early images (5 min after injection) and in late images (50 min after injection). Compared with 99mTc-tetrofosmin, the T/S ratio of 99mTc-MIBI was higher and, moreover, the washout was delayed. These results suggest that there is a difference in tumor accumulation property between these two agents.

[Compartment analysis of 123I-iomazenil brain on early and delayed SPECT].

We investigated the characteristics of 123I-Iomazenil (IMZ) SPECT images in 12 adults (six males and six females, with a mean age of 56.1 years). The washout rate of 123I-IMZ from the brain was estimated from two SPECTs done 15 min and 3 hr after injection. Although the washout was relatively slow, the rates differed in each intracerebral region, suggesting that the distribution of 123I-IMZ was gradually changing. Furthermore, assuming 123I-IMZ kinetics in the brain for the three-compartment, two-parameter model, the transition rate constant (K1) from the blood to the brain and the binding potentials (BP) of benzodiazepine to the receptor were calculated. The BP and K1 values were compared with 123I-IMZ SPECT counts and CBF values by 123I-IMP. The BP values correlated more closely with the counts on the delayed SPECT than those on the early SPECT. It was confirmed that delayed SPECT images reflect better the distribution of the benzodiazepine receptor than early images do. On the other hand, the K1 values correlated highly with CBF obtained by 123I-IMP, and this finding suggested that super-early SPECT images might be remarkably influenced by the distribution of CBF.

Age-related changes in vertebral height ratios and vertebral fracture.

Because no gold standard for the definition of vertebral fracture exists, there has been controversy about whether mild vertebral deformities are truly fractures or simply normal variation in vertebral size and shape. The aim of this study was to assess the associations of mild variations of vertebral height ratios to definite vertebral fractures. In 479 Japanese women (aged 53.9 +/- 9.1 years) who visited our institute for a medical checkup, we performed lateral lumbar radiographs and morphometric parameters were derived by measuring the anterior (Ha), middle (Hm) and posterior (Hp) height of each vertebral body from T12 to L4. Vertebral height ratios, Ha/Hp, Hm/Hp or Hp/Hp' of adjacent vertebrae that were more than 3 SD different from vertebra-specific means of normative data were considered to indicate fractures. Forty-five women were diagnosed with at least one fracture. After excluding the subjects with vertebral fracture, we examined the associations of the variations in vertebral height ratios with age, anthropometric parameters and lumbar bone mineral density (BMD) measured by dual-energy X-ray absorptiometry. Vertebral height ratios, especially Hm/Hp in postmenopausal women, tended to decrease with age and were positively associated with BMD. No significant correlation was observed between anthropometric parameters and vertebral height ratios. Aged-related decrease in vertebral height ratios (Ha/Hp and Hm/Hp, each averaged from T12 to L4) was significant even after the correction for BMD. Mean values of height ratios of non-fractured vertebrae adjusted for age and BMD were significantly lower in postmenopausal women with vertebral fracture than in those without vertebral fracture. Logistic regression analysis showed that BMD and height ratios of non-fractured vertebrae were independent predictors of vertebral fracture risk. The results suggest that older women, and women with at least one obvious (3 SD) fracture, tend to have mild deformities which do not qualify using the 3 SD definition. These mild deformities may represent real consequences of osteoporosis, because they are more pronounced among women with obvious fracture.

Bone mineral measurement in Japan.

Various methods for evaluating bone mineral in appendicular, and axial bone or in the whole skeleton have recently become available. As bone mineral is one of the major determinants of bone strength, its exact measurement should be useful for the diagnosis of osteoporosis, as well as for the prediction of fracture risk and monitoring of therapeutical response. The aims of this paper are to review the fundamental performance of bone mineral measurements, the improvements in DXA systems, and the progress in site-specific bone mineral instruments for the radius and calcaneus used in Japan, and to introduce diagnostic criteria for primary osteoporosis, and report on annual rates of bone loss in Japanese females.

Sex and age patterns of quantitative ultrasound densitometry of the calcaneus in normal Japanese subjects.

: The speed of sound (SOS), broadband ultrasound attenuation (BUA), and the stiffness index (stiffness), which was derived from SOS and BUA, were measured on the calcaneus using the Achilles ultrasound densitometer (Lunar) in normal Japanese woman (n = 473) and men (n = 218). Sex differences and age-related changes in these variables were investigated. In addition, the bone mineral density (BMD) of the lumbar vertebrae measured by dual X-ray absorptiometry (QDR-2000, Hologic) was compared with SOS, BUA, and stiffness. There were some decreases of ultrasound variables in both young adult men and women. BMD values were similar in young adults of both sexes. BMD was relatively stable in women from 20 to 49 years, then decreased at about 1.5%/year. Ultrasound variables were higher in males than females at all ages, and they decreased from age 20 onward in both sexes with an annual loss of about 0.6%. Age-related changes in SOS, BUA, and stiffness were different from those in BMD in normal Japanese subjects. The correlations between BMD and SOS and BUA and stiffness were higher in women (r = 0.51-0.64) than in men (r = 0. 43-0.49).

Influence of exercise and degenerative vertebral changes on BMD: a cross-sectional study in Japanese men.

The effects of recreational exercise and milk intake on BMD were assessed in Japanese men using analysis of covariance with significant predictor variables, selected from age, height, body weight and body mass index (BMI), as covariates. The influence of degenerative vertebral changes on these effects was also evaluated. Recreational exercise was found to be positively associated with BMD at the lumbar spine and the femoral neck, whereas milk intake, a possible indicator of calcium intake in the Japanese, was positively associated with BMD at the radius and the lumbar spine. Not only vertebral BMD but also radial and femoral neck BMD was higher in the subjects with osteophytosis or sclerosis in the lumbar vertebrae. Neither exercise nor lumbar pain was significantly related to these vertebral changes. These data suggest a protective effect of regular recreational exercise and milk intake on bone health in Japanese men.

[Study on tumor accumulation property of 99mTc-HM-PAO and 99mTc-MIBI in rabbits bearing VX-2 cancer].

Each of blood flow imaging agents has a potential usefulness as an agent for tumor scintigraphy. The usefulness for tumor scintigraphy of two agents, i.e. cerebral blood flow scintigraphy agent 99mTc-HM-PAO and myocardial blood flow scintigraphy agent 99mTc-MIBI, was comparatively studied using rabbits bearing VX-2 cancer. From then to twenty days after the implantation of VX-2 cancer into the femoral region of five rabbits, tumor to soft tissue accumulation ratio (T/S ratio) of each agent was calculated in early images (5 min after injection) and in late images (50 min after injection). Compared with 99mTc-MIBI, the T/S ratio of 99mTc-HM-PAO was higher and, moreover, the washout was delayed. These results suggest that there is a difference in tumor accumulation property between these two agents.

A fundamental study of a computed X-ray densitometry system for bone mineral measurement in the second metacarpal bone.

The effect of radiographic exposure factors such as the photographic film density, X-ray tube voltage, and focus-film distance on the indices of bone mineral obtained by computed X-ray densitometry (CXD), a newly developed X-ray microdensitometric system, was investigated. sigma GS/D, which corresponded to the bone mineral density divided the integrated bone mineral by the bone width of the second metacarpal bone, was influenced by these exposure factors, whereas MCI, which represented the ratio of the cortical bone to whole bone, was independent of them. Present results indicated that the focus-film distance between 85 and 115 cm, the X-ray tube voltage in 45-60 kV, and a photographic density of lower than 1.82-1.86 of the screen-film combination should be used to assess quantitatively bone mineral of the second metacarpal bone using the CXD system.

[Usefulness of 99mTc-ECD SPECT in diseases of the central nerve system: special reference to a comparison with 123I-IMP and 99mTc-HM-PAO SPECT].

The usefulness of a new cerebral perfusion imaging radiopharmaceutical, 99mTc-ethyl cysteinate dimer (ECD), was clinically evaluated. The subjects of this study were 14 patients with neurological disorders including 10 patients with cerebral infarction and 4 patients with other diseases. A total of 15 examinations was performed. 99mTc-HM-PAO or 123I-IMP SPECTs were performed simultaneously, and the findings from those examinations were compared with 99mTc-ECD. As to the count ratio of lesions to normal area (L/N), the L/N ratio in severe ischemic patients was lower in 99mTc-ECD than in 99mTc-HM-PAO or 123I-IMP. In mild ischemic patients, on the other hand, the L/N ratio was the lowest in 123I-IMP. When the relationship between rCBFs obtained from 123I-IMP and the values of L/N in 99mTc-ECD or 99mTc-HM-PAO was compared, the values of L/N in 99mTc-ECD or 99mTc-HM-PAO were found to have decreased linearity with increasing rCBF. In a patient showing luxury perfusion, the accumulation pattern of 99mTc-ECD was different from that of the other two radiopharmaceuticals, and focal defect was revealed in 99mTc-ECD SPECT. On the dynamic SPECT of 99mTc-ECD in a patient with meningioma, the tumor showed a change from high to low perfusion with the passage of time. This finding indicated that care should be taken in the evaluation of accumulation of 99mTc-ECD. Therefore, 99mTc-ECD was found to be useful as a cerebral perfusion agent. In addition, as accumulation of 99mTc-ECD might somehow reflect metabolism in some cases, further careful investigation of many cases should be carried out.

Confirmation of dialysate leakage by intraperitoneal administration of radioactive colloid.

A 29-year-old man who had been on continuous ambulatory peritoneal dialysis (CAPD) was admitted to our hospital because of pleural effusion. Radioactive colloid studies with intraperitoneal administration revealed a pleuroperitoneal communication. After pleurodesis by the administration of fibrin glue and antiplasmin into the thoracic cavity, the pleural effusion did not reaccumulate and there was no evidence of pleuroperitoneal communication by radioactive colloid study.