Kiyoshi Nakatsuka

Paget's disease of bone : Evidence for a susceptibility locus on chromosome 18q and for genetic heterogeneity

Pagets disease of bone is a common condition characterized by bone pain, deformity, pathological fracture, and an increased incidence of osteosarcoma. Genetic factors play a role in the pathogenesis of Pagets disease but the molecular basis of the disease remains unclear. Previous genetic linkage studies have mapped the rare Pagets disease‐like bone dysplasia familial expansile osteolysis (FEO) to chromosome 18q21–22, and recent work has shown evidence of linkage between this locus and Pagets disease in one family. Here we studied the relationship between the 18q21–22 locus and Pagets disease in eight large multiplex families from diverse ethnic backgrounds with inherited Pagets disease. Pagets disease was inherited as an autosomal dominant trait in all families, with high penetrance by the sixth decade. Analysis of seven highly polymorphic markers from chromosome 18q21–22 showed positive summated two‐point log10 odds ratio (lodscores) of +2.97 with the marker D18S42 at a recombination fraction (θ) = 0.05, and of +2.95 with the marker D18S60 at θ = 0.00, values which are close to the cut‐off of +3.0, which is generally accepted as evidence of linkage. Segregation analysis of the haplotypes and formal statistical analysis using the HOMOG program provided evidence for genetic heterogeneity, however, with evidence for linkage in five families and against linkage in the remaining three families (chi square 8.82; df = 2; p < 0.025). Multipoint linkage analysis in the five linked families showed lodscores of above +3.5 across the whole susceptibility region and a maximum summated lodscore of 3.89 at the marker D18S465. In the three nonlinked families, negative multipoint results were obtained for the whole region, with lodscores below –2.0 in one family, excluding this as a candidate locus for the disease. Our studies demonstrate the importance of hereditary factors in the pathogenesis of Pagets disease and confirm evidence of linkage between Pagets disease and chromosome 18q21–22 in some families. This raises the possibility that Pagets disease and FEO may share a common molecular basis, perhaps due to different mutations in the same gene or family of genes. Data from three families did not support evidence of linkage to 18q21–22 however, indicating that Pagets disease is genetically heterogeneous and suggests the presence of at least one additional locus which remains to be discovered.

Phenotypic Characterization of Early Onset Paget's Disease of Bone Caused by a 27-bp Duplication in the TNFRSF11A Gene†

Three different insertion mutations in the TNFRSF11A gene affecting the signal peptide of RANK have been described. An 18‐bp duplication at position 84 (84dup18) is associated with the clinical syndrome of familial expansile osteolysis (FEO), whereas a 15‐bp duplication at the same site (84dup15) causes the syndrome of expansile skeletal hyperphosphatasia (ESH). Here we report the phenotype of patients harboring a 27‐bp duplication at position 75 (75dup27) in RANK. Affected individuals had hearing impairment and tooth loss beginning in the second or third decade. Radiographs of affected bones showed lytic and sclerotic lesions with bony enlargement and deformity. Serum alkaline phosphatase levels were elevated between 2 and 17 times above the normal range. Most patients had pelvic and skull involvement, and all had involvement of the mandible and maxilla. Most patients also had bony enlargement of the small joints of the hands, and one developed hypercalcemia during a period of immobilization. We conclude that the 75dup27 mutation of RANK causes a Pagets disease of bone‐like phenotype that is distinct from, but which overlaps with, FEO and ESH. A particularly striking feature was involvement of the mandible and maxilla, but it remains to be seen if this is a specific feature of the 75dup27 mutation until further kindreds with this mutation are reported.

Poor Glycemic Control Impairs the Response of Biochemical Parameters of Bone Formation and Resorption to Exogenous 1,25-Dihydroxyvitamin D3 in Patients with Type 2 Diabetes

Abstract: Osteoblast deficit plays a principal role in the development of diabetic osteopenia. We have previously reported that high glucose conditions impair the function of osteoblast-like MG-63 cells. This study was performed to assess the sensitivity of osteoblasts to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in patients with type 2 diabetes without insulin deficiency or overt diabetic complications. During stimulation with 1,25(OH)2D3 at 2.0 mg/day for 6 consecutive days in 9 type 2 diabetic patients, serum levels of bone alkaline phosphatase (BALP), osteocalcin (OC) and the carboxyterminal propeptide of type 1 procollagen, and the urinary excretion of pyridinoline and deoxypyridinoline (DPYR), were monitored. As parameters of glycemic control, the mean level of fasting plasma glucose (mFPG) throughout the 1,25(OH)2D3 stimulation test and the level of HbA1C were used. 1,25(OH)2D3 increased serum 1,25(OH)2D significantly by day 2, which was followed by a significant reduction in the serum level of intact parathyroid hormone. The maximal increment of serum OC adjusted for that of 1,25(OH)2D was negatively correlated with both mFPG and HbA1C levels (p50.05). Furthermore, the magnitude of 1,25(OH)2D3-induced bone resorption, as reflected by the maximal increase in urinary DPYR excretion, was negatively correlated with the mFPG level (p50.05). Basal BALP tended to be negatively correlated with HbA1C, although not to a significant extent. In conclusion, our findings would indicate that poor glycemic control impairs the responses of osteoblasts and osteoclasts to 1,25(OH)2D3 in normo-insulinemic type 2 diabetic patients.

Effect and safety of intermittent weekly administration of human parathyroid hormone 1-34 in patients with primary osteoporosis evaluated by histomorphometry and microstructural analysis of iliac trabecular bone before and after 1 year of treatment

In order to evaluate the efficacy and safety of intermittent subcutaneous administration of 1-34 N-terminal peptide of human parathyroid hormone (hPTH 1–34), 100 units of hPTH 1-34 was subcutaneously injected once a week for 1 year in ten patients with primary osteoporsis (one male and nine females) with no qualitative abnormality of the bone according to the results of iliac crest biopsy performed previously, followed by a second biopsy after the end of the 1-year administration. Written consent of the patients for participation in the study was obtained. The mean lumbar bone mineral density (LBMD) definitely increased, by 1.8%, 3.4%, and 4.6% after 12, 24, and 48 weeks of hPTH administration, in accordance with previous clinical studies. Histomorphometric analysis after double-tetracycline labeling was completed in six patients (one male and five females) after the exclusion of those who dropped out because of adverse events unrelated to the test drug, or refusal of continuation. Examination of thin hard-tissue sections revealed no qualitative abnormalities of bone tissue or bone marrow cavity, such as osteomalacia, woven bone, or osteitis fibrosa, precluding the contribution of qualitatively abnormal tissue elements to any changes of LBMD in response to hPTH 1-34 administration. Histomorphometric measurement in the second biopsy revealed a tendency for an increase of bone volume, a significant increase of osteoid surface, and a tendency for an increase in other parameters of bone formation, compared with values obtained in the preadministration biopsy. Indices of two-dimensional microstructure obtained by microfocus computed tomography (CT) and results of node-strut analysis indicated improvement of trabecular continuity. In five patients in whom three-dimensional reconstruction images were analyzed, there were significant increases of bone volume and trabecular thickness, and a significant decrease in the trabecular bone pattern factor, a parameter related to the continuity, suggesting an improvement of the three-dimensional trabcular microstructure. Intermittent weekly subcutaneous injections of hPTH (1-34) for 48 weeks increased trabecular bone volume and improved microstructure, without causing the appearance of abnormal bone elements in primary osteoporosis.

Vitamin K(2) (menaquinone 4) reduces serum undercarboxylated osteocalcin level as early as 2 weeks in elderly women with established osteoporosis.

Abstract. Twenty elderly osteoporotic women with vertebral fracture(s) were randomly allocated to two groups; women in the MK4 group received calcium with menaquinone 4 (MK4) at a dose of 45 mg/day for 2 weeks, and women in the control group received calcium alone for the same period. Serum intact osteocalcin (OC) and undercarboxylated osteocalcin (uc-OC) levels were measured by immunoradiometric assay and enzyme immunoassay, respectively, at baseline and on the 7th and 14th days following the start of the treatment. There were no differences in the baseline data including age, weight, phylloquinone, menaquinone 4, menaquinone 7, OC, and uc-OC levels between the MK4 group and the control group. Administration of MK4 significantly raised the MK4 level from 0.20 ± 0.10 (mean ± SE) pg/ml to 15.09 ± 5.62 pg/ml (P < 0.04), and reduced serum uc-OC levels from 2.80 ± 0.93 ng/ml to 1.76 ± 0.56 ng/ml (P < 0.05) at the end of the study, respectively. No significant changes in these levels were observed in the control group. Serum OC levels were stable during the period in both groups. In this randomized prospective study, the MK4 group shows a reduction in the serum uc-OC level within 2 weeks without any significant change in OC, suggesting that the uc-OC is changed to carboxylated OC. This early effect of MK4 on bone metabolism may be estimated by the measurement of serum uc-OC in elderly osteoporotic women with vertebral fractures.

Guidelines for diagnosis and management of Paget's disease of bone in Japan

We here propose guidelines for the diagnosis and management of Pagets disease of bone (PDB) in Japan. These guidelines provide basic information on the epidemiology, pathophysiology, clinical signs and symptoms, diagnosis, indications for treatment, and available therapy, including orthopedic surgery. PDB is a chronic disorder characterized by focal abnormalities of bone turnover. The characteristic feature of PDB is excessive osteoclastic bone resorption coupled to increased and disorganized bone formation. The most common symptom of PDB is pain in involved bones. The most serious complication of PDB is malignant bone or soft-tissue tumor. PDB is uncommon in Japan; our survey in 2003 found 169 patients with PDB. The prevalence of PDB in Japan is 0.15/100 000; in patients aged 55 years or more, the proportion reaches 0.41/100 000. A careful medical history and physical examination are essential for the diagnosis. The diagnosis of PDB is based on finding the typical features on radiographs. Bone scintigraphy and measurement of serum alkaline phosphatase are sensitive means of screening for PDB. Since PDB is a rare disease in Japan, bone biopsy is quite often used to exclude bone metastases. The only evidence-based indication for treatment of PDB is pain in involved bones. In Japan, etidronate and calcitonin are approved by the Ministry of Health, Labour and Welfare for treating PDB, but currently risedronate is also under development for treating PDB in Japan. Indications for surgical intervention in PDB include unstable fractures, osteoarthritis, malignant soft-tissue tumor, osteosarcoma, and bone deformity.

Guidelines on the use of biochemical markers of bone turnover in osteoporosis (2001)

1 Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan 2 Department of Orthopedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan 3 Department of Obstetrics and Gynecology, Tokyo Women’s Medical University, Tokyo, Japan 4 Department of Orthopedic Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan 5 Department of Obstetrics and Gynecology, Yokohama City University Medical School, Yokohama, Japan 6Research Institute and Practice for Involutional Diseases, Nagano, Japan 7 Department of Nuclear Medicine, Kawasaki Medical School, Kurashiki, Japan 8 Endocrinology Section, Tokyo Metropolitan Geriatric Hospital, Tokyo Japan 9 Department of Geriatric Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan 10 R & D Department, Mitsubishi Kagaku BCL, Tokyo, Japan

Significance of serum CrossLaps as a predictor of changes in bone mineral density during estrogen replacement therapy; comparison with serum carboxyterminal telopeptide of type I collagen and urinary deoxypyridinoline

The newly developed Elecsys Β-CrossLaps/serum assay measures C-terminal telopeptide of type I collagen and has thus been proposed as a reliable serum marker for bone resorption. We investigated its usefulness for monitoring the therapeutic effect of estrogen replacement therapy on bone turnover and bone mineral density (BMD) in patients with postmenopausal osteoporosis. Serum Β-CTx decreased by 43.2% ± 9.2% (mean ± SD), and 55.1% ± 7.0% at 3 and 6 months, respectively, after initiation of estrogen replacement therapy (ERT), which was significantly greater than the respective value of urinary excretion of deoxypyridinoline (DPD) (27.8% ± 4.1%, 34.1% ± 4.9%, respectively) or pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP) assay (14.5% ± 4.1%, 13.1% ± 5.0%, respectively). The percent reduction in serum Β-CTx at 1, 3, and 6 months after initiation of ERT was significantly correlated in a negative manner with the percent increase in spinal BMD at 6 months. Further, ROC analysis to determine the significance of the percent change in bone resorption markers after 3 months of ERT in predicting the gain in spine BMD after 6 months suggested that serum Β-CTx and urinary DPD might provide a more discriminating indicator than serum ICTP. In conclusion, the findings suggest that the Elecsys Β-CrossLaps/serum assay provides a sensitive, and thus useful, tool for assessing bone resorption state in Japanese patients.

Prevalence and clinical features of Paget's disease of bone in Japan

The present study aimed to evaluate the prevalence and clinical presentation of Pagets disease of bone (PDB) in Japan. As PDB is a very rare disease in Japan, a nationwide mail survey was conducted targeting doctors in the specialty most frequently diagnosing and treating PDB patients in Japan. First, the literature for all case reports in Japan published between January 1990 and December 2002 was reviewed to determine who was diagnosing and treating PDB in Japan. This literature review for all case reports in Japan revealed that 72.1% of cases in Japan were reported from departments of orthopedic surgery. A nationwide two-phase mail survey was conducted for the departments of orthopedic surgery of 2320 general hospitals accredited by the Japanese Orthopaedic Association. Phase 1 involved determining how many patients with PDB were followed at each hospital. If the answer was one or more, phase 2 of the survey gathered information on the clinical presentation of current patients. The mail survey yielded a final response rate of 75.4% for phase 1 and 87.6% for phase 2. Phase 1 indicated that the prevalence of PDB in Japan is about 2.8 cases per million capita. Phase 2 revealed a slight female predominance, lower frequency of familial clustering, higher frequency of femoral fracture in the affected femur, and a higher ratio of symptomatic PDB in Japan compared with findings in countries displaying a higher prevalence of PDB. The present epidemiological study revealed that the disorder is extremely rare in Japanese individuals, and that some differences exist with regard to the clinical features of PDB between Japanese patients and patients from high-prevalence countries.

Effect of calcitonin on total body bone mineral contents of experimental osteoporotic rats determined by dual photon absorptiometry

SummaryTotal body bone mineral (TBBM) content in rats was measured by dual photon absorptiometry (DPA). TBBM showed significant increases over 4 weeks in control groups with significant bone loss over the same time in prednisolone-injected rats on low calcium feed. Daily injections of calcitonin significantly reduced loss of bone mass. Both prednisolone- and prednisolone-calcitonin-injected groups showed significantly elevated serum alkaline phosphatase with the prednisolone-calcitonin group also exhibiting elevated serum calcium and phosphate levels, confirming the impact of the experimental protocol. TBBM measured by DPA in all groups correlated well (r=0.928,P<0.001 n=20) with the total ash weight suggesting that the method reflects total skeletal mineral content in the small animal. TBBM measurement by DPA proves well-suited to monitoring bone mineral in a small animal experimental setting.