Yasuo Imanishi

Serum Levels of TRAP5b, a New Bone Resorption Marker Unaffected by Renal Dysfunction, as a Useful Marker of Cortical Bone Loss in Hemodialysis Patients

Tartrate-resistant acid phosphatase (TRAP) 5b is a new marker of bone resorption that is unaffected by renal dysfunction. The significance of TRAP5b was assessed in hemodialysis (HD) patients. Serum concentrations of TRAP5b and cross-linked N-telopeptide of type I collagen (NTX) were determined as bone resorption markers, and those of bone alkaline phosphatase (BAP) and intact osteocalcin (OC) were measured as bone formation markers in 58 HD patients. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry twice in the distal third of the radius, with a 2-year interval between measurements. Serum TRAP5b correlated significantly with BAP, intact OC, intact parathyroid hormone (PTH), and especially serum NTX. TRAP5b, NTX, BAP, and intact OC all correlated significantly with BMD at the time of the second measurement; and TRAP5b, NTX, and intact OC, but not BAP and intact PTH, correlated significantly with the annual change in BMD during the 2-year period. Among the bone markers, patients in the highest tertile for serum TRAP5b and intact OC showed the fastest rate of cortical bone loss. The sensitivity and specificity for detection of rapid bone loss were 57.9% and 76.9%, respectively, for serum TRAP5b. Measurement of serum TRAP5b, as well as intact OC, may be a clinically relevant assay for estimation of bone metabolic status in HD patients, although serum intact OC accumulates in uremic serum.

Utility of serum tartrate‐resistant acid phosphatase (TRACP5b) as a bone resorption marker in patients with chronic kidney disease: independence from renal dysfunction

Backgroundu2002 Serum tartrate‐resistant acid phosphatase (TRACP) 5b levels were assessed in predialysis patients with chronic kidney disease (CKD). The aim of the study was to establish the usefulness of a new assay for TRACP5b in assessing bone turnover in these patients.

Add-on combination therapy with adefovir dipivoxil induces renal impairment in patients with lamivudine-refractory hepatitis B virus.

Summary.u2002 Combination therapy with adefovir dipivoxil (ADV) and lamivudine (LAM) is recommended for patients infected with LAM‐refractory hepatitis B virus (HBV). However, the effects of such therapy on renal function and serum phosphorus levels have not been fully evaluated. Combination therapy with ADV and LAM was given to 37 patients infected with LAM‐refractory HBV, including 17 with hepatic cirrhosis. Serum HBV DNA levels decreased to below 2.6 log10u2003copies/mL in 23 (62%) of 37 patients at 12u2003months, 25 (78%) of 32 patients at 24u2003months, and 16 (84%) of 19 patients at 36u2003months. Except for one cirrhotic patient, serum alanine aminotransferase levels were below 50u2003IU/L in all patients during combination therapy. Serum creatinine levels increased in 14 (38%) of 37 patients, and serum phosphate levels decreased to below 2.5u2003mg/mL in 6 (16%) of 37 patients during combination therapy. Patients who received combination therapy for 36u2003months or longer had a significantly incidence of elevated serum creatinine levels. Fanconi syndrome occurred in a 57‐year‐old woman with cirrhosis after ADV was added to LAM. Combination therapy with ADV and LAM can maintain biochemical remission in patients with LAM‐refractory HBV. However, the dosing interval of ADV should be adjusted according to renal function and serum phosphate levels in patients receiving long‐term treatment.

Association of increased active PTH(1–84) fraction with decreased GFR and serum Ca in predialysis CRF patients: modulation by serum 25-OH-D

SummaryAs the serum calcium and glomerular filtration rate decreased, the proportion of active PTH(1–84) molecules in PTH immunoreactivity increased in serum from predialysis uremic patients, particularly those with vitamin D insufficiency.IntroductionThe PTH(1–84) fraction was altered in predialysis patients with chronic renal failure (CRF).MethodsSerum PTH in predialysis CRF patients without any medication was measured by PTH(1–84)-specific whole PTH assay and intact PTH assay cross-reacting with N-truncated PTH.ResultsIn CRF patients, the glomerular filtration rate (GFR) correlated positively with serum Ca and 1,25-dihydroxyvitamin D (1,25(OH)2D), and inversely with serum Pi, log intact PTH, and log whole PTH. In multiple regression analysis, including age, gender, body mass index, GFR, Ca, and Pi and 1,25(OH)2D as independent variables, serum Ca and GFR associated significantly with serum log whole PTH and intact PTH. Serum log whole PTH/intact PTH ratio, which increased as serum Ca and GFR decreased, retained a negative correlation in those with serum 25-hydroxyvitamin D levels below 20xa0ng/ml, but not in those above 20xa0ng/ml. The ratio also correlated positively with serum log tartrate-resistant acid-phosphatase-5b, log cross-linked N-telopeptide of type-I collagen, and log bone alkaline-phosphatase.ConclusionAs GFR declined with suppression of serum Ca, the proportion of active PTH molecules increased in predialysis CRF patients, particularly those with vitamin D insufficiency.

Cinacalcet HCl Suppresses Cyclin D1 Oncogene-Derived Parathyroid Cell Proliferation in a Murine Model for Primary Hyperparathyroidism

Cinacalcet HCl (cinacalcet) is a calcimimetic compound, which suppresses parathyroid (PTH) hormone secretion from parathyroid glands in both primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism (SHPT). We previously reported the suppressive effect of cinacalcet on PTH secretion in vivo in a PHPT model mouse, in which parathyroid-targeted overexpression of the cyclinD1 oncogene caused chronic biochemical hyperparathyroidism and parathyroid cell hyperplasia. Although cinacalcet suppressed parathyroid cell proliferation in SHPT in 5/6-nephrectomized uremic rats, its effect on PHPT has not yet been determined. In this study, the effect of cinacalcet on parathyroid cell proliferation was analyzed in PHPT mice. Cinacalcet (1xa0mg/g) was mixed into the rodent diet and orally administrated to 80-week-old PHPT mice for 10xa0days before death. 5-Bromo-2′-deoxyuridine (BrdU, 6xa0mg/day) was infused by an osmotic pump for 5xa0days before death, followed by immunostaining of the thyroid–parathyroid complex using an anti-BrdU antibody to estimate parathyroid cell proliferation. Compared to untreated PHPT mice, cinacalcet significantly suppressed both serum calcium and PTH. The proportion of BrdU-positive cells to the total cell number in the parathyroid glands increased considerably in untreated PHPT mice (9.5xa0±xa03.1%) compared to wild-type mice (0.7xa0±xa00.1%) and was significantly suppressed by cinacalcet (1.2xa0±xa00.2%). Cinacalcet did not affect apoptosis in the parathyroid cells of PHPT mice. These data suggest that cinacalcet suppressed both serum PTH levels and parathyroid cell proliferation in vivo in PHPT.

Beneficial effect of risedronate on arterial thickening and stiffening with a reciprocal relationship to its effect on bone mass in female osteoporosis patients: A longitudinal study

AIMSnA longitudinal study was performed to examine the effect of risedronate on arterial thickening and stiffening in postmenopausal female osteoporosis patients.nnnMAIN METHODSnPatients treated with risedronate (2.5mg/day) (n=33) and those that did not receive risedronate (n=30, control group) were monitored over a 1-year period. Bone metabolic markers, bone mineral density (BMD) of the femur neck (FN), brachial-ankle pulse wave velocity (baPWV), and intima-media thickness at the carotid artery (CA-IMT) were measured.nnnKEY FINDINGSnAt baseline, there was no significant difference in blood pressure, serum lipid profiles, FN BMD, baPWV and CA-IMT between the risedronate-treated patients and the controls. Baseline levels of FN BMD were significantly negatively correlated with those of CA-IMT and baPWV. During the study, FN BMD increased significantly in the risedronate group (p=0.0097), but decreased significantly in the control group (p=0.0013). BaPWV and CA-IMT did not change significantly in the risedronate group, but both increased significantly in the control group. The percentage change in FN BMD over the study period showed a significant negative correlation with those for baPWV (r=-0.294, p=0.0262) and CA-IMT (r=-0.305, p=0.0234) in all subjects (risedronate-treated patients and controls).nnnSIGNIFICANCEnIn addition to increasing BMD, risedronate significantly suppressed the progression of arterial thickening and stiffening in postmenopausal osteoporotic patients over one year. These changes may indirectly be due to the effect of risedronate on bone.

Effects of raloxifene treatment on the structural geometry of the proximal femur in Japanese women with osteoporosis

The purpose of this study was to clarify the effects of 2-year treatment with raloxifene on the proximal femoral geometry among Japanese patients with osteoporosis by hip structure analysis. One hundred ninety-eight community-dwelling postmenopausal women with osteoporosis were enrolled. The structural variables were areal bone mineral density (BMD), cross-sectional area (CSA), section modulus (index of resistance to bending forces), and buckling ratio (index of cortical instability). BMD, CSA, and section modulus at the narrow neck significantly increased by 1.27, 2.67, and 3.90% at 2xa0years, respectively. BMD, CSA, and section modulus at the intertrochanter significantly increased by 2.55, 4.49, and 6.60% at study termination, respectively. The buckling ratio at the intertrochanter decreased by 2.36% at 1xa0year, but differences at 2xa0years became non-significant. Parameters at the shaft were qualitatively similar to those of the narrow neck and intertrochanter. The percent change of the section modulus was significantly higher than that of BMD at 2xa0years in all three regions. The percent changes of the section modulus is strongly correlated with the percent changes of BMD and CSA, and negative correlated with the percent changes of buckling ratio in all regions. In conclusion, Japanese osteoporotic women on raloxifene therapy have significant improvements of both BMD and geometry in the proximal femur.

The Levels of Somatostatin Receptors in Causative Tumors of Oncogenic Osteomalacia Are Insufficient for Their Agonist to Normalize Serum Phosphate Levels

Oncogenic osteomalacia (OOM) is a rare disease characterized by renal phosphate wasting and osteomalacia and is caused by the secretion of fibroblast growth factor 23 (FGF-23) from causative tumors. Scintigraphy with octreotide, which binds to somatostatin receptors (SSTRs), is a useful way to locate causative tumors in OOM patients. However, the therapeutic effects of octreotide acetate are still controversial. Two OOM patients were administered octreotide acetate intramuscularly. Ten causative OOM tumors, including two resected from the patients participating in the octreotide administration study, were examined for expression of genes encoding SSTRs by quantitative real-time RT-PCR and immunohistochemistry. Octreotide therapy did not improve hypophosphatemia in either case, despite temporal decreases in FGF-23 levels in one patient. The mean expression levels of SSTR1, SSTR3, and SSTR5 were similar in the OOM and non-OOM tumors. Expression of SSTR2 was significantly higher in the OOM tumors than in the non-OOM tumors. Immunohistochemical examinations revealed the presence of SSTR2A, SSTR2B, and SSTR5 in both the OOM and non-OOM tumors. The expression of SSTR genes in OOM tumors contributes to positive imaging using octreotide scintigraphy. However, the levels of SSTRs seem to be insufficient for the octreotide therapy to improve hypophosphatemia. Further studies are needed to clarify the mechanisms by which FGF-23 secretion from OOM tumors is suppressed by octreotide acetate.

Animal models of hyperfunctioning parathyroid diseases for drug development

Background: Disorders of mineral and bone metabolism have been implicated as a risk factor in the high mortality in patients with chronic kidney disease (CKD). Hyperphosphatemia, disorders of vitamin D metabolism and secondary hyperparathyroidism of uremia (SHPT) are therapeutic targets in these patients to improve the mortality. Animal models for CKD are indispensable and uremic rats produced by 5/6-nephrectomies are one of the most useful animal models for the development of new therapeutic agents. As there are limitations of uremic rats such as short lifespan and less severity of secondary hyperparathyroidism distinct from CKD patients on maintenance hemodialysis, the development of new model animals is expected. Objective: This review discusses the molecular pathogenesis of hyperfunctioning parathyroid diseases and the applications of animal models exhibiting hyperparathyroidisms in the aspect of the development of new therapeutics. Conclusion: PTH–cyclin D1 transgenic mice, with parathyroid-targeted overexpression of cyclin D1 oncogene, not only developed abnormal parathyroid cell proliferation but, notably, also developed biochemical hyperparathyroidism with characteristic abnormalities in bone. The mice exhibit age-dependent development of biochemical hyperparathyroidism, which enables testing of the drug precisely. In addition, the mice develop parathyroid cell hyperplasia, followed by monoclonal expansion, which is observed in refractory SHPT patients.

Clinical and Biochemical Response of TNFRSF11A-Mediated Early-Onset Familial Paget Disease to Bisphosphonate Therapy

Early-onset familial Paget disease of bone (EoPDB) is a rare condition caused by a 27-bp insertion mutation affecting the signal peptide of TNFRSF11A, which encodes RANK. EoPDB shows phenotypic overlap to both familial expansile osteolysis and expansile skeletal hyperphosphatasia, which are caused by similar mutations in TNFRSF11A. Although EoPDB is characterized by elevated bone turnover, there is no published information on the response of this condition to antiresorptive therapy. Here, we describe the clinical and biochemical response to bisphosphonate therapy in three patients with EoPDB. In all cases, treatment with the first-generation bisphosphonate etidronate at high doses reduced biochemical markers of bone turnover but the response was incomplete and short-lived. In contrast, treatment with aminobisphosphonates resulted in greater suppression of biochemical markers of bone turnover with an extended duration of response. From a clinical perspective, the results were less impressive and there was no clear benefit from antiresorptive treatment in terms of bone deformity, deafness, and tooth loss, although bone pain improved in one patient. We conclude that intravenous aminobisphosphonate therapy may be the preferred mode of treatment for EoPDB to provide long-term suppression of bone turnover. The long-term clinical effects of treatment on the natural history of the bone disease remain uncertain however, and this will require further study.