ISSN:0884-0431    

DOI:10.1002/jbmr.5650090502

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1994

数据来源: WILEY

摘要:

AbstractIn a population‐based retrospective cohort study, Rochester women aged 35–69 years who were first diagnosed with one or more vertebral fractures in 1950–1979 were followed for the development of a subsequent hip fracture. The 336 women with no history of hip fracture at the time of their vertebral fracture experienced 52 proximal femur fractures in 4788 person‐years of follow‐up. The standardized morbidity ratio (SMR) of observed to expected hip fractures was 1.8 (95% CI, 1.3–2.4) and was higher for intertrochanteric than cervical femoral fractures (SMR, 2.3 versus 1.3;P= 0.07). Hip fracture risk among women with symptomatic vertebral fractures was slightly less than in those with asymptomatic vertebral fractures (SMR, 1.8 versus 2.3; not significant), and younger women had no higher risk of a subsequent hip fracture than women who were ≥60 years of age at the time of their vertebral fracture (SMR, 1.4 versus 1.8; not significant). Alternative explanations are possible, but these data are consistent with heterogeneity in the pathogenesis of different osteoporo

ISSN:0884-0431    

DOI:10.1002/jbmr.5650090503

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1994

数据来源: WILEY

摘要:

AbstractThis study is the first reported administration of 1α‐hydroxyvitamin D2(1α‐OHD2) to human subjects. A total of 15 postmenopausal osteopenic women were given increasing oral doses of 1α‐OHD2, beginning with a low dose of 0.5 μg/day. In 15 subjects, the doses were raised at weekly intervals to 1.0, 2.0, 4.0, and 5.0 μg/day, and in 5 of these subjects, the dose was further increased to 8.0 or 10.0 μg/day. Mean urine calcium ± SEM showed a dose‐related increase from 134 ± 17 mg/24 h on 0.5 μg/day to 198 ± 21 mg/24 h on 4.0 μg/day (p<0.05) and to 241 ± 35 mg/24 h on 5.0 μg/day (p350 mg/24 h, the upper limit of the laboratory normal range) at doses less than 5.0 μg/day; 5 subjects had hypercalciuria at or above 5.0 μg/day (3 at 5.0 μg/day, 1 at 8.0 μg/day, and 1 at 10.0 μg/day). Mean serum calcium increased slightly on the 4.0 μg dose only (p<0.05) but remained well within the normal range. Mean creatinine clearance and BUN, used as measures of renal function, showed no significant changes. Routine blood and urine assays also showed no significant changes. Serum osteocalcin, a marker of osteoblast activity, showed mean ± SEM dose‐related increases of 10 ± 7% on 1.0 μg/day (p<0.05), 19 ± 7% on 2.0 μg/day (p<0.05), 21 ± 6% on 4.0 μg/day (p<0.05), and 28% on 5.0 μg/day (p<0.05); in the 5 subjects receiving higher dosages, mean serum osteocalcin increased 32 ± 12% on 8.0 μg/day and 55 ± 29% on 10.0 μg/day. Mean urine hydroxyproline/creatinine ratios did not change significantly at any dose of 1α‐OHD2but trended downward with increasing dosages. These findings indicate that 1α‐OHD2is well tolerated at dosages that stimulate osteoblastic activity, as evidenced by increased serum osteocalcin, and that 1α‐OHD2may be a usef

ISSN:0884-0431    

DOI:10.1002/jbmr.5650090504

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1994

数据来源: WILEY

摘要:

AbstractWe sought to assess efficacy and safety of a new oral formulation (tablet) of tiludronate in Paget's disease of bone. We studied 128 patients with Paget's disease in an open‐label uncontrolled trial. Patients received a daily dose of 400 mg oral tiludronate (two tablets). Treatment was for 6 months. Serum alkaline phosphatase activity (SAP) and fasting urinary excretion of hydroxyproline/creatinine (OH/Cr) were measured every 3 months, as were biochemical parameters reflecting renal, hepatic, and hematologic functions. Analgesic efficacy was self‐evaluated from a visual analog scale (VAS). Statistical analysis revealed a significant reduction from baseline in SAP and OH/Cr levels, as well as VAS scores. In the whole population with evaluation under treatment, there was a reduction in initial SAP activity after 3 months (47.2 ± 2.2%, mean ± SEM) and 6 months (58.3 ± 2.3%). In the population with SAP levels above twice the upper limit at inclusion and with evaluation at month 3 and month 6 (n= 96), the reduction in SAP levels was 49.3 ± 2.4% after 3 months and of 59.5 ± 2.6% after 6 months (ANOVA time effect,p= 0.0001). Aside from mild gastrointestinal disturbances, as experienced with other oral bisphosphonates, clinical tolerance was good. Exhaustive biochemical investigation failed to reveal significant toxicity of tiludronate tablets at the dose of 400 mg/day. The dose of 400 mg daily of this new formulation appears to be a satisfactory tiludronate regimen for the treatment of Paget's disease

ISSN:0884-0431    

DOI:10.1002/jbmr.5650090505

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1994

数据来源: WILEY

摘要:

AbstractThis study analyzes the parathyroid function in four dogs before and after 2 years of a low‐calcium, high‐sodium, vitamin D‐deficient diet and the involution of the same function following (1) correction of dietary calcium deficiency and administration of IV 1,25‐(OH)2D (0.25 μg twice per day) during 1 month, (2) after an additional month of normal dog chow supplemented with oral vitamin D (25 μg per day), and, finally, (3) after 5 and 17 months of a diet with normal levels of calcium and vitamin D. The parathyroid function was evaluated through IV infusion of CaCl2and Na2EDTA with measurement of intact (I) and carboxyl‐terminal (C) immunoreactive parathyroid hormone (iPTH). The C‐iPTH/I‐iPTH ratio was calculated to assess the modulation of molecular forms ofiPTH induced by the various treatments. The 2 years of calcium and vitamin D deprivation lowered ionized calcium (1.23 ± 0.04, p<0.05) and 25‐OHD (4.02 ± 2.06 nM,p<0.005) and tended to decrease 1,25‐(OH)2D (80.8 ± 8.6 pM); it increased basal I‐ and C‐iPTH levels approximately eightfold (I‐iPTH, 40.2 ± 20.7,p<0.05; C‐iPTH, 185.4 ± 94.9,p<0.05) and stimulated I‐iPTH (60.2 ± 23.0 pM,p<0.05) and C‐iPTH (239.6 ± 80.7 pM,p<0.05) fivefold. A greater rise in nonsuppressible I‐iPTH levels than in C‐iPTH levels led to a decreased C‐iPTH/I‐iPTH ratio in hypercalcemia (12.5 ± 2.8 versus 27.8 ± 6.05 pM,p<0.005). Dietary deprivation also decreased the I‐iPTH calcium stimulation set point (1.25 ± 0.05 pM,p<0.05). Treatment with dietary calcium and IV 1,25‐(OH)2D normalized ionized calcium (1.34 ± 0.02 mM) and basal I‐iPTH level (6.09 ± 5.48 pM) more than basal C‐iPTH (69.8 ± 48.8 pM), causing the C‐iPTH/I‐iPTH ratio to increase from 4.80 ± 0.81 to 14.8 ± 6.1 (p<0.05). Stimulated I‐iPTH decreased (46.1 ± 15.3 pM,p<0.05), but stimulated C‐iPTH secretion did not change (282.4 ± 90.9 pM). A greater fall in the nonsuppressible I‐iPTH level as opposed to C‐iPTH level led the C‐iPTH/I‐iPTH ratio to increase back to a normal value (23.8 ± 1.40). The I‐iPTH calcium stimulation set point remained low at 1.28 mM. Further consecutive treatment modalities over 18 months did not cause additional significant change in basal, stimulated, or nonsuppressible C‐iPTH levels, but the same I‐iPTH levels tended to decrease further. This explained why all three C‐iPTH/I‐iPTH ratios tended either to increase (basal) or to increase significantly (stimulated and nonsuppressible,p<0.05). The I‐iPTH calcium stimulation set point again remained low. This study reveals that animals with hyperplastic parathyroid glands can control their I‐iPTH level by maintaining a lower set point of I‐iPTH stimulation by calcium and by

ISSN:0884-0431    

DOI:10.1002/jbmr.5650090506

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1994

数据来源: WILEY

摘要:

AbstractIn patients on antiepileptic drugs, bone loss has been mainly demonstrated at radial sites using old technology and has been ascribed to drug‐induced vitamin D deficiency rather than to any direct effects of the treatment on bone cells. We examined 38 epileptic patients (24 women and 14 men) aged 20–49 years who were using either carbamazepine or phenytoin or both. Bone mineral density (BMD) at the lumbar spine and three femoral sites was measured by dual‐energy x‐ray absorptiometry (DXA) and serum and urine markers of bone and mineral metabolism were determined. The latter included the C‐terminal extension peptide of type I procollagen (PICP), a putative serum marker of bone formation, and the cross‐linked carboxyl‐terminal telopeptide of human type I collagen (ICTP), a novel serum marker of bone matrix degradation. In female patients on phenytoin, weight‐ and height‐adjusted BMD was reduced at the femoral neck and the Ward's triangle (p<0.05) but was at the control level in the other patient groups at all four measurement sites. Compared with controls, the serum concentrations of 25‐hydroxyvitamin D and 1,25‐dihydroxyvitamin D were reduced by 26% (p<0.01) and by 27% (p<0.001) in female patients. These changes were independent of the therapy used. They were not present in male patients. For both genders the serum levels of vitamin D binding protein were normal. Both female and male patients had hypocalcemia, but women only showed hypocalciuria. The serum intact parathyroid hormone was 42% higher (p<0.01) in women and 26% (p= 0.07) in men. The serum markers of bone formation, bone alkaline phosphatase, osteocalcin, and PICP, were higher for both sexes, the percentage elevations being more striking in men (104%,p<0.001; 66%,p<0.001; and 63%;p<0.001, respectively) than in women (33%,p<0.01; 13%,p= NS; and 27%,p<0.05, respectively). Serum ICTP was 46% higher (p<0.001) in women and 22% (p<0.05) in men. We conclude that in patients on antiepileptic drugs, bone turnover is accelerated independently of the presence of hypovitaminosis D. Such biochemical alterations do not necessarily lead to reduc

ISSN:0884-0431    

DOI:10.1002/jbmr.5650090507

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1994

数据来源: WILEY

摘要:

AbstractParathyroid hormone‐related protein (PTHrP) plays a prominent role in the pathogenesis of humoral hypercalcemia of malignancy. However, it is also expressed in various nonmalignant tissues, particularly during fetal organogenesis and tissue differentiation. Thus, PTHrP is synthesized in skin, placenta, and mammary gland during lactation. Little is known, however, about the regulation of PTHrP synthesis and release in nontumoral cells. We investigated the regulation of PTHrP production by epidermal growth factor (EGF), a factor of major importance in the development of lactating breast, in primary cultures of rat mammary epithelial cells. EGF stimulated the production of immunoreactive and bioactive PTHrP in a time‐ and concentration‐dependent manner. A 12 h incubation with 10 ng/ml of EGF increased PTHrP production by 36.0 ± 7.1% (n= 7 experiments,p<0.01). This was accompanied by an increase in PTHrP mRNA steady‐state levels. The production of PTHrP was stimulated by the protein kinase C (PKC) activator phorbol‐12‐myristate‐13‐acetate (PMA) by 82.9 ± 9.7% (n= 4 experiments,p<0.01). The effects of PMA and EGF were additive. The EGF‐induced stimulation appeared to be independent of extracellular calcium concentration, prostaglandin, or cAMP synthesis, but may have involved tyrosine kinase‐mediated mechanisms. These results indicate that EGF was capable of increasing the production of PTHrP by cultured mammary epithelial cells. They also suggest that factors activating the PKC pathway are involved in the upregulation of PTHrP expression in mam

ISSN:0884-0431    

DOI:10.1002/jbmr.5650090508

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1994

数据来源: WILEY

摘要:

AbstractWe observed that lithium (3 mM) blocked the 1,25‐dihydroxyvitamin D [1,25‐(OH)2D3]‐stimulated bone resorption in fetal rat long bones in culture. Because this inhibitory effect was not seen when bone resorption was stimulated by parathyroid hormone or interleukin‐1, we reasoned that Li specifically inhibited events involved in the 1,25‐(OH)D3‐stimulated bone resorption. The increased bone resorption induced by vitamin D in culture is associated with differentiation and/or fusion of osteoclast progenitors. In the present work, we studied the effect of Li on the basal and 1,25‐(OH)2D3‐stimulated generation of multinucleated osteoclast‐like cells (MNC) and MNC containing tartrate‐resistant acid phosphatase (TRAP+) in long‐term human bone marrow cultures. Total MNC and TRAP+cells were counted after 3 weeks of culture. In the absence of both lithium and 1,25‐(OH)2D3, total MNC and TRAP+cell numbers were 146 ± 22 and 110 ± 18 per well, respectively (mean ± SEM); in the presence of Li, corresponding figures were 79 ± 17 and 59 ± 14. When the generation of MNC and TRAP+cells was stimulated with 1,25‐(OH)2D3, (10−8M), total MNC and TRAP+cells were 521 ± 66 and 473 ± 63, respectively, in the absence of Li and 251 ± 44 and 155 ± 27 in the presence of Li (p<0.05). The inhibitory effect of Li was dose dependent and was not observed when the cultures were exposed to parathyroid hormone instead of 1,25‐(OH)2D3. When Li was added to the cells the first week of culture only, we observed the full inhibitory effect; conversely, if Li was added for the last week of culture only, no inhibitory effect was seen. These data show that Li interferes with the recruitment of osteoclast‐like cells from their precursors, proba

ISSN:0884-0431    

DOI:10.1002/jbmr.5650090509

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1994

数据来源: WILEY

摘要:

AbstractTemporal and spatial distribution of a gene encoding murine bone morphogenetic protein 4 (mBMP‐4) during fracture repair were investigated in mice by RT‐PCR and in situ hybridization. For in situ hybridization, fractured ribs and surrounding tissues were decalcified and hybridized with a mBMP‐4‐specific complementary RNA probe labeled with digoxigenin‐11 UTP. mBMP‐4 messenger RNA (mRNA) was not detected in ribs without fracture, whereas it was detected only in the early phase of fracture from 12 to 72 h after the onset of fracture before new cartilage or bone formation. The mBMP‐4 mRNAs were present in cells distributed in three distinct regions, namely, the proliferating periosteum, the medullary cavity, and the muscles near the fracture site. These BMP‐4‐positive cells did not express bone gla protein mRNA, which is a marker of the mature osteogenic cell. RT‐PCR also showed a transient increase in the level of BMP‐4 mRNA in the early phase of fracture repair. The findings provide us with some new information. (1) The BMP‐4 gene is produced by less differentiated osteoprogenitor cells, not by differentiated osteoblasts. (2) The BMP‐4 gene is enhanced by the impact of fracture and localized in callus‐forming tissue before callus formation. Together with the activities of BMP‐4, as was previously described, our results suggest that newly produced BMP‐4 gene product is one of the local contributing factors in callus formation in the

ISSN:0884-0431    

DOI:10.1002/jbmr.5650090510

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1994

数据来源: WILEY

摘要:

AbstractAt the onset of the mineralization of bone, small membranous matrix vesicles are often observed. The information available on the production and release of these vesicles is limited. When treated with 10–20 nM of the phorbol ester 12‐O‐tetradecanoyl‐phorbol‐13‐acetate (TPA), the human osteosarcoma cell line U‐2 OS developed long cytoplasmic processes connecting adjacent cells. SEM and TEM show that TPA triggers a production and release of matrix vesicle‐like membrane vesicles, mainly from the cellular processes. Tetracycline HC1 was used to label intracellular bound calcium. The tetracycline HC1 label was primarily localized to the end‐feet of the cytoplasmic processes, indicating that these contain high concentrations of Ca2+, and to endoplasmic reticulum‐like structures in the cell bodies. Together with our previous demonstration of the release of alkaline phosphatase‐containing vesicles into the culture medium (Ringbom‐Anderson T, Åkerman KEO 1992 Calcif Tissue Int 50:533–540), the results presented here indicate that TPA induces a rapid induction of the primary steps of mineralizat

ISSN:0884-0431    

DOI:10.1002/jbmr.5650090511

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1994

数据来源: WILEY