Tadashi Moriwake

Altered Biochemical Markers of Bone Turnover in Humans During 120 Days of Bed Rest

Microgravity induces significant and progressive bone loss in both humans and animals. This is the consequence of disturbed bone remodeling. We performed a bed rest experiment to simulate microgravity and tried to clarify bone metabolism by measuring biochemical markers of bone turnover. Six healthy volunteers participated in 120 days of bed rest. The parameters of calcium homeostasis, calcitropic hormones, and biochemical markers of bone turnover were examined. After ambulatory control evaluation, all subjects underwent 120 days of bed rest. Metabolic evaluation was performed in a baseline period, and on days 7, 16, 50, 72, 92, and 108 during bed rest, and on days 10 and 25 during a recovery period. Bed rest induced an increase in urinary calcium (Ca) excretion and serum Ca and bone resorption markers. Urine pyridinoline, deoxypyridinoline, and type I collagen cross-linked N-telopeptide increased more rapidly than urinary Ca excretion and serum Ca. Tartrate-resistant acid phosphatase (TRAP) increased even in the recovery period. Carboxy-terminal propeptide of type I collagen, a bone formation marker, significantly decreased on days 50, 92, and 108 of bed rest. These changes of biochemical markers of bone metabolism, except for TRAP, rapidly returned toward control levels in the recovery period. Immunoreactive parathyroid hormone showed a modest decrease during bed rest and a significant increase in the recovery period. Insulin-like growth factor I (IGF-I) and its binding protein, insulin-like growth factor binding protein-3, increased during bed rest, indicating the possibility of resistance to IGF-I in bones under reduced mechanical stress and strain. Bone loss from unloading results from the combination of acceleration of bone resorption and subsequent retardation of bone formation.

An ultrasensitive assay revealed age-related changes in serum oestradiol at low concentrations in both sexes from infancy to puberty

OBJECTIVE Intensive studies of oestrogen receptors have suggested extragonadal functions of oestrogen. However, the in vivo extragonadal functions of oestradiol remain unclear because of the lack of an adequate assay system at low concentrations. In this study, we assessed the usefulness of a new ultrasensitive assay for children.

Growth Hormone Therapy in Achondroplasia

Achondroplasia is one of the most common causes of severe rhizomelic dwarfism. We have previously reported the growth-promoting effect of growth hormone (GH) in this disorder. In this expanded clinical study, dose dependency and the long-term effect of GH were also investigated. Prepubertal children with achondroplasia (82 males and 63 females) were randomly divided into 2 groups. Patients were treated with 0.5 IU/kg per week or 1.0 IU/kg per week subcutaneous recombinant human GH. Of 75 patients, the mutational analysis of fibroblast growth factor receptor-3 revealed that G1138A was detected in 70 and G1138C was found in 2. GH increased growth rate and height z score in a dose-dependent manner. GH also increased serum insulin-like growth factor (IGF)-I, IGF-binding protein-3 and osteocalcin. No adverse effects were observed in either group. We conclude that GH therapy is a useful method for improvement of severe growth retardation of achondroplasia.

Molecular defects in achondroplasia and the effects of growth hormone treatment

Seino Y, Moriwake T, Tanaka H, Inoue M, Kanzaki S, Tanaka T, Matsuo N, Niimi H. Molecular defects in achondroplasia and the effects of growth hormone treatment. Acta Pa; diatr 1999; Suppl 428: 118–20. Stockholm. ISSN 0803–5326

Potential Role of rhIGF-I/IGFBP-3 in Maintaining Skeletal Mass in Space

Bone loss during space flight may be induced by decreased activity of bone formation. To explore a new method for the bone loss in microgravity, the effects of insulin-like growth factor I (IGF-I), a potent stimulator for osteoblast activities, were studied in in vitro and in vivo system. The complex of IGF-I and its specific binding protein, IGFBP-3, may stimulate the osteoblastic activities via prolonged serum half life and increased cellular association of IGF-I. In an ovariectomy combined with neurectomy model, this complex stimulated bone turnover. IGF-I/IGFBP-3 may be a candidate for the treatment of bone loss induced by the microgravity.

Ultrasound assessment of tibial cortical bone acquisition in Japanese children and adolescents

Abstract. The purpose of the present study was to evaluate the normal process of cortical bone acquisition during childhood and adolescence, and the relationship between speed of sound (SOS), measured by the Sound Scan 2000 system, and linear growth. A total of 1689 healthy Japanese children and adolescents (862 males and 827 females, aged 7–19 years) were enrolled in the study. SOS (m/s) was measured at the right tibial midshaft and the standard SOS values in the children and adolescents were generated. Various growth parameters were also measured. SOS of tibia increased significantly with age in both males and females (P < 0.001 each). In both sexes, a spurt in SOS was noted 1 year after the standard age at which Japanese peak height velocity (PHV; cm/year) occurs, and SOS increased markedly after the age at which the length of tibia reached a maximum. Multiple regression equations for SOS were generated as a function of various growth parameters; for males, SOS = 3047 + 6.2 × height (cm) + 2.1 × weight (kg) − 9.8 × length of tibia (cm) (R2 = 0.50; P < 0.001) and for females, SOS = 2713 + 10.3 × height (cm) + 1.8 × weight (kg) − 15.5 × length of tibia (cm) (R2 = 0.49; P < 0.001). In both sexes, SOS correlated positively with body height and weight, but negatively with length of tibia. Our results indicate that SOS is quite useful for evaluating cortical bone status in children and adolescents; the results of these measurements may provide an explanation for the relative weakness of the mechanical properties of the bone during childhood and adolescence.

Recent progress in diagnosis and treatment of osteogenesis imperfecta

Osteogenesis imperfecta (OI) is an inheritable disorder characterized by bone fragility with various symptoms of connective tissue disorders. OI is commonly classified by Sillences classification into four types according to the clinical features. The cardinal symptom is pathologic fracture, which is often recognized before birth, is frequent during infancy and childhood, then decreases at puberty. Bone mineral density is markedly decreased in OI, especially of the lumbar spine. Bone deformities are frequently observed in the long bones of the extremities, and spinal deformities and compression fractures are also common. Growth retardation is extremely severe, especially in type III. Calcitonin has been the most common therapy for OI. Recently, bisphosphonates have been found to be potent drugs that increase bone mass in OI patients. To prevent further fracture or bone deformity, appropriate orthopedic managements, including intramedullary rodding, are critically important. Growth hormone is effective in stimulating bone growth during childhood. The pathogenesis of OI is quantitative or qualitative abnormalities of type I collagen. The clinical features of each type usually correspond to the type of mutation. Several possibilities for gene therapy have been proposed.

Analysis of linear growth in survivors of childhood acute lymphoblastic leukemia.

Abstract. Therapy for childhood acute lymphoblastic leukemia (ALL) is entering a new era in terms of quality-of-life. In the current study, 21 patients with childhood-onset ALL were assessed for linear growth, bone mineral density (BMD), and endocrinological status, focusing especially on longitudinal analysis of the growth of each patient. Linear growth was uniformly attenuated during therapy in all patients. In contrast, after the cessation of therapy, the growth of each patient varied widely from attenuated to dramatic catch-up growth. In pubertal survivors who had received chemotherapy and cranial irradiation during prepuberty, the degree of growth after the cessation of therapy was negatively correlated with changes in height Z scores during therapy (r = −0.76, P = 0.004). One of the factors involved in catch-up growth, urinary N-telopeptide/creatinine (U-NTx/Cr), was significantly higher in patients whose Z scores decreased after cessation of therapy (P = 0.01), despite normal pubertal development and normal endocrinological assessments. The present study revealed individual differences in linear growth after the cessation of therapy and suggests the importance of catch-up growth during puberty.

Malignant osteopetrosis treated with high doses of 1α-hydroxyvitamin D3 and interferon gamma

A male infant with malignant osteopetrosis was treated with high doses of 1 α -hydroxyvitamin D 3 and interferon gamma. Therapy with 1 α -hydroxyvitamin D 3 increased the serum calcium level despite the markedly elevated serum level of 1 α ,25-dihydroxyvitamin D before treatment. Recombinant human interferon gamma increased neither the bone mineral nor matrix turnover, and was not tolerated because of bone marrow suppression.

The Clinical Usefulness of Liquid Human Growth Hormone (hGH) (Norditropin® SimpleXxTM) in the Treatment of GH Deficiency

Human growth hormone (hGH) is an essential therapeutic drug for the treatment of GH deficiency. The development of recombinant GH using a pen injection system has enabled easy and safe treatment of GH-deficient patients; however, the process of dissolving hGH in the powder form is complicated and dangerous. In this study, we investigated the usefulness of a newly developed liquid form of hGH (Norditropin® SimpleXxTM) in the treatment of 51 patients with GH deficiency. Fifteen previously untreated patients with GH deficiency were treated with liquid hGH (group A), and 36 patients who had previously used hGH in the powder form were changed to the liquid form (group B). Both groups were treated with liquid hGH 0.5 IU/kg per week for 6 months. The growth rate of patients in group A increased from 4.0 ± 2.4 cm/year to 9.2 ± 2.9 cm/year. The patients in group B continued to grow at the same rate as before using the liquid hGH therapy. Questionnaires to the patients in group B demonstrated that 85% preferred the convenience of using the new liquid form of hGH. Our results indicate that liquid hGH has similar efficacy to that of powder hGH, but its improved convenience may have a beneficial effect on patient compliance.