摘要:

AbstractThe physiologic role of osteocalcin (OC), a vitamin K‐dependent protein specific to bone, remains elusive. It has been shown that rats maintained on chronic treatment with vitamin K1and its antagonist warfarin exhibit a marked decrease in bone osteocalcin because noncarboxylated osteocalcin does not bind to bone hydroxyapatite. To assess the role of OC in bone remodeling, we applied the warfarin model to growing lambs. We analyzed the bone changes after 3 months of concurrent warfarin and vitamin K1treatment. Four groups of four lambs were constituted at birth and received daily a saline solution (control group, CT), 4 mg/kd/day of vitamin K1(vitamin K group), 4 mg/kg/day of vitamin K1+ 75 or 150 mg/kg/day of warfarin (W75 and W150 group, respectively). In warfarin‐treated animals, bone osteocalcin levels were decreased, both in the metaphysis (9% compared to controls) and the diaphysis (30% compared to controls) of the metacarpals. The fraction of noncarboxylated osteocalcin measured every month in the serum was significantly higher in warfarin‐treated lambs than in controls at each timing point (37.6 ± 2.6% in W75 and 48.7 ± 5.2% in W150 versus 14.4 ± 3.8% in controls at 3 months). Compared to non‐warfarin‐treated animals (NW), the main histomorphometric parameters measured on the iliac crest after tetracycline double labeling were significantly reduced in the warfarin‐treated lambs: 12.2 ± 5.2 versus 18.6 ± 4.7% in NW (p<0.03) for the cancellous bone area, which reflects the trabecular bone density; 14.7 ± 6.1 versus 21.0 ± 3.6% in NW (p<0.03) for the eroded perimeter, and 0.315 ± 0.064 versus 0.561 ± 0.23 μm3/μm2/day in NW (p<0.02) for the tetracycline‐based bone formation rate. In conclusion, the depletion of osteocalcin in the bone of lambs induced within 3 months a marked osteopenia that resulted from a decrease in resorption and a more pronounced decrease in bone formation. Our data suggest that the presence of osteocalcin, the major gla‐containing protein of bone, may be important for the maintenance of a normal bone mass and rem

ISSN:0884-0431    

DOI:10.1002/jbmr.5650081202

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

年代:1993

数据来源: WILEY

摘要:

AbstractWe measured forearm bone mineral content at the beginning and end of a 5 year period in 307 untreated postmenopausal volunteers. We also measured height, weight, and a number of biochemical variables in plasma and urine after an overnight fast. The initial mean age of the subjects was 59.0 years (range 39–72), and the mean years since menopause was 10.0 (range 1–37). The mean forearm BMC fell from 1034 ± 9.6 (SEM) to 982 ± 9.3 mg/cm (P<0.001). The coefficient of correlation between the first and second measurements was 0.96. The mean rate of change was −1.0% per annum (with a 99% range of −4 to 1% per annum), which agreed well with previous estimates from cross‐sectional data. There was a significant negative correlation between rate of change in bone mass and initial value (r= −0.23;P<0.001), which was eliminated by expressing change as a percentage of initial bone mass. Of the other variables measured, the one that was most significantly related to the percentage change in bone mass was the urinary hydroxyproline/creatinine ratio (r= −0.35;P<0.001), which we regard as a marker only. By stepwise regression, the only significant determinants of the rate of change in bone mass were body weight (positive,P<0.001), years since menopause (positive,P<0.005), urine calcium (negative,P<0.01), and serum estrone (positive,P<0.05). The rate of change in BMC was not significantly related to dietary calcium, plasma alkaline phosphatase, serum DHEAS, or any other variable measured at the outset or to serum PTH or serum osteocalcin measured at

ISSN:0884-0431    

DOI:10.1002/jbmr.5650081203

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

年代:1993

数据来源: WILEY

摘要:

AbstractTo study the mechanism of bone loss in physical unloading, we examined indices of bone formation and bone resorption in the serum and urine of eight healthy men during a 7 day −6° head‐down tilt bed rest. Prompt increases in markers of resorption — pyridinoline (PD), deoxypyridinoline (DPD), and hydroxyproline (Hyp)/g creatinine—during the first few days of inactivity were paralleled by tartrate‐resistant acid phosphatase (TRAP) with significant increases in all these markers by day 4 of bed rest. An index of formation, skeletal alkaline phosphatase (SALP), did not change during bed rest and showed a moderate 15% increase 1 week after reambulation. In contrast to SALP, serum osteocalcin (OC) began increasing the day preceding the increase in Hyp, remained elevated for the duration of the bed rest, and returned to pre‐bed rest values within 5 days of reambulation. Similarly, DPD increased significantly at the onset of bed rest, remained elevated for the duration of bed rest, and returned to pre‐bed rest levels upon reambulation. On the other hand, the other three indices of resorption, Hyp, PD, and TRAP, remained elevated for 2 weeks after reambulation. The most sensitive indices of the levels of physical activity proved to be the noncollagenous protein, OC, and the collagen crosslinker, DPD. The bed rest values of both these markers were significantly elevated compared to both the pre‐bed rest values and the post‐bed rest values. The sequence of changes in the circulating markers of bone metabolism indicated that increases in serum OC are the earliest responses of bone to head

ISSN:0884-0431    

DOI:10.1002/jbmr.5650081204

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

年代:1993

数据来源: WILEY

摘要:

AbstractIt is well known that there is a relationship between muscle strength and bone density, but it is uncertain whether this relationship is site specific. The aim of this study was to assess the relationship of quadriceps strength to site‐specific bone mineral density (BMD) of the tibia and to BMD of the forearm. In 66 healthy women, aged 21–78 years, BMD was measured in the proximal tibia and the distal forearm by dual‐photon absorptiometry. Isometric and isokinetic strength of the quadriceps was measured using an isokinetic dynamometer (Cybex II). Highly significant correlations between BMD of the proximal tibia and quadriceps strength were found (RSranging from 0.79 to 0.84,p<0.0001). Also, BMD of the distal forearm was correlated with quadriceps strength (RSranging from 0.59 to 0.62,p<0.0001). In a stepwise multiple regression analysis, quadriceps strength was a better predictor of tibial BMD than age, body height, or weight. However, age, height, and weight were more predictive of forearm BMD than quadriceps strength. When studying the pre‐ and postmenopausal women separately, quadriceps strength was correlated with BMD of the proximal tibia but not to forearm BMD. In conclusion, the study provides support for a site‐specific relationship between muscle

ISSN:0884-0431    

DOI:10.1002/jbmr.5650081205

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

年代:1993

数据来源: WILEY

摘要:

AbstractThe present study was performed to clarify the role of high calcium concentration and the appearance of mononuclear cells at the resorptive site in bone remodeling. Our recent study revealed that the high concentration of extracellular calcium ([Ca2+]e) stimulated DNA synthesis in osteoblastic MC3T3‐E1 cells not only directly but also indirectly via monocytes. Human monocyte‐conditioned medium (CM) significantly stimulated DNA synthesis and inhibited alkaline phosphatase (ALP) activity. In contrast, when monocytes were cultured at high [Ca2+]econcentrations (more than 3 mM), CM from these monocytes significantly stimulated ALP activity in MC3T3‐E1 cells. Such stimulatory effect of CM was not observed at a high magnesium concentration (Mg2+, 5 mM). Treatment of monocytes with the calcium ionophore A23187 did not affect the CM‐induced effect on DNA synthesis and ALP activity in these cells. To determine the migration potency of MC3T3‐E1 cells and monocytes toward the high [Ca2+]e, chemotaxis assay was performed. The increasing [Ca2+]e(more than 3 mM) induced a chemotactic response of MC3T3‐E1 cells as well as monocytes, but the high concentration of Mg2+(5 mM) did not induce it. On the other hand, treatment with high [Ca2+]e(more than 3 mM) or CM significantly inhibited the 1,25‐(OH)2D3‐induced formation of tartrate‐resistant acid phosphatase (TRAP)‐positive multinucleated cells (MNC) from their precursors derived from mouse spleen cells. The present study indicated that an increase in [Ca2+]estimulated DNA synthesis and ALP activity of osteoblasts via monocytes, induced chemotaxis of osteoblasts as well as monocytes, and inhibited the formation of TRAP‐positive MNC, suggesting the importance of the high Ca2+concentration and mononuclear cells at the resorptive si

ISSN:0884-0431    

DOI:10.1002/jbmr.5650081206

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

年代:1993

数据来源: WILEY

摘要:

AbstractIn this study we tested the effects of sodium fluoride (NaF) in serum‐free cultures of human marrow stromal osteoblast‐like [hMS(OB)] cells. NaF (10−5M) stimulated hMS(OB) cell proliferation up to 220% of control cultures. NaF alone did not increase type I collagen production, but in the presence of 1,25‐dihydroxyvitamin D3[1,25‐(OH)2D3] (10−9M), NaF enhanced type I collagen production in a dose‐dependent way to 300% of 1,25‐(OH)2D3‐treated control cultures. The production of alkaline phosphatase (ALP) and osteocalcin (bone gla protein, BGP) was also enhanced in the presence of 1,25‐(OH)2D3to 170 and 200%, respectively, of 1,25‐(OH)2D3‐treated controls. Our results suggest that 1,25‐(OH)2D3potentiates fluoride‐mediated anabolism in hMS(OB) cell cultures and suggest that osteoblast precursors in bone marrow are

ISSN:0884-0431    

DOI:10.1002/jbmr.5650081207

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

年代:1993

数据来源: WILEY

摘要:

AbstractImmobilization is associated with increased bone resorption and decreased bone formation. We evaluated in a double‐blind trial the effect of intranasal administration of salmon calcitonin on biochemical parameters of bone turnover in 32 patients immobilized for a prolapsed intervertebral disk. Calcitonin in a dose of two times 200 IU/day partially inhibited the increase in the fasting 2 h urinary hydroxyproline/creatinine ratio (OHPr/Cr) and calcium/creatinine ratio (Ca/Cr). The increase in OHPr/Cr was 40% less in the calcitonin group compared to the placebo group (P= 0.01), and the increase in Ca/Cr was 80% less in the calcitonin group (P= 0.04). Calcitonin also partially inhibited the increase in serum cross‐linked carboxyl‐terminal telopeptide of collagen type I (P<0.05). The decrease in serum 1,25‐dihydroxyvitamin D after 10 days of immobilization was significantly less in the calcitonin‐treated group than in the placebo group (14 versus 29%, respectively;P<0.05). Intranasal calcitonin did not influence the pain scores as measured with a visual analog scale (VAS). The tolerability of the nasal calcitonin preparation was excellent. We conclude that nasal salmon calcitonin counteracts the early increase in bone resorption induced by immob

ISSN:0884-0431    

DOI:10.1002/jbmr.5650081208

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

年代:1993

数据来源: WILEY

摘要:

AbstractBisphosphonates are a safe and effective treatment for Paget's disease of bone, but little information is available about the factors influencing the duration of remission so obtained. We assessed 60 patients with Paget's disease treated with disodium pamidronate (APD). The mean duration of remission was 9.5 months (range 3–25). The major influences were the initial pretreatment alkaline phosphatase (ALP;r= −4.6,p<0.0001), minimum posttreatment ALP (r= −0.51,p<0.0001), and the rate of response of bone turnover to the first dose of APD (r= 0.61,p<0.0001). Multiple linear regression showed that the initial response to treatment was the most significant influence. Also, despite a minimum ALP within the normal range, the duration of remission varied considerably (4–25 months). This may be due to the difficulties in applying a population‐based normal range to in

ISSN:0884-0431    

DOI:10.1002/jbmr.5650081209

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

年代:1993

数据来源: WILEY

摘要:

AbstractThe mechanism of action of thyroid hormones on bone is still not clear. At low concentrations, they stimulate bone formation; at high concentrations, they elicit bone resorption in vitro and in vivo. In the present study we investigated the effect of T3and T4as well as their active and inactive analogs (TRIAC, SKF L‐94901, rT3, and DIT) on the IGF‐I and TNF‐α content in the medium of UMR‐106 rat osteoblastic cells and fetal rat limb bones. In the dose‐response studies, a biphasic increase in medium IGF‐I was observed in both cells and limb bones, with peak stimulatory concentrations of 10−8M for T3and 10−7M for T4in both systems. At higher concentrations, at which thyroid hormones elicit bone resorption, the stimulatory effect diminished and finally was no longer detectable. The active analogs TRIAC and SKF L‐94901 also enhanced IGF‐I release in UMR‐106 cells. The inactive compounds rT3and DIT failed to increase IGF‐I in these cultures. The protein content of the cell culture wells exposed to high concentrations of thyroid hormones was similar to those containing low concentrations, indicating that the decrease in IGF‐I content at high doses was not due to toxic effects. This was also confirmed by trypan blue exclusion. Time course studies with UMR‐106 cells revealed a significant increase in medium IGF‐I after 2 days of incubation. No significant further increase was observed after this up to 5 days of culture. In contrast, the medium of limb bone cultures showed a linear increase in IGF‐I content up to 7 days of culture. No TNF‐α production was observed in either UMR‐106 cells or fetal limb bones. Also, no increase in medium TNF‐α levels was seen in response to thyroid hormones. Based on our results, we conclude that IGF‐I may be responsible for some of the anabolic effects of thyroid hormones in bone tissue, but TNF‐α, at least in the models we used, does not play a ro

ISSN:0884-0431    

DOI:10.1002/jbmr.5650081210

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

年代:1993

数据来源: WILEY

摘要:

AbstractAlthough analogs and metabolites of vitamin D have been tested for their calciotropic activity, very little information has been available concerning the effects of these compounds on gene expression. In this study one analog of vitamin D, 1,25,28‐trihydroxyvitamin D2[1,25,28‐(OH)3D2], and one metabolite, 1,24,25‐trihydroxyvitamin D3[1,24,25‐(OH)3D3], were tested for their effect on intestinal calbindin‐D9KmRNA and protein as well as for their effect on intestinal calcium absorption and bone calcium mobilization. These compounds were also evaluated for their ability to compete for rat intestinal 1,25‐(OH)2D3receptor sites and to induce differentiation of human leukemia (HL‐60) cells as indicated by reduction of nitro blue tetrazolium. In vivo studies involved intrajugular injection of 12.5 ng 1,25‐(OH)2D3or test compound to vitamin D‐deficient rats and sacrifice after 18 h. 1,25,28‐Trihydroxyvitamin D2had no effect on intestinal calcium absorption, bone calcium mobilization, or intestinal calbindin‐D9Kprotein and mRNA. Competitive binding to 1,25‐(OH)2D3receptors was 0.8% of that observed using 1,25‐(OH)2D3. However, 20‐ and 40‐fold higher doses of 1,25,28‐(OH)3D2(250 and 500 ng) resulted in significant inductions in calbindin‐D9Kprotein and mRNA (3.5 to 7.4‐fold), although doses as high as 800 ng were found to have no effect on intestinal calcium absorption or bone calcium mobilization. 1,25,28‐Trihydroxyvitamin D2, although lacking in calciotropic activity, was found to induce differentiation of HL‐60 cells at high concentrations [ED50= 15 × 10−8M compared to ED50= 2.5 × 10−8M for 1,25‐(OH)2D3]. 1,24,25‐Trihydroxyvitamin D3was 93% as active as 1,25‐(OH)2D3in stimulating intestinal calcium transport but was relatively inactive in stimulating bone calcium mobilization. Competitive binding to the 1,25‐(OH)2D3receptor was 8% of that observed using 1,25‐(OH)2D3. Although 1,24,25‐(OH)3D3was 93% as active as 1,25‐(OH)2D3in stimulating intestinal calcium absorption, this compound was found to be 50% as active as 1,25‐(OH)2D3in stimulating calbindin‐D9Kprotein and mRNA. The lack of a direct correlation between calbindin protein and mRNA and intestinal calcium transport after 1,24,25‐(OH)3D3administration or after administration of high doses of 1,25,28‐(OH)3D2suggests that factors in addition to calbindin are involved, at

ISSN:0884-0431    

DOI:10.1002/jbmr.5650081211

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

年代:1993

数据来源: WILEY