Vitamin D receptor genotypes and bone mineral density.
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Bone Density↗
Biomedical subjects
H Kröger
Publications and source records attributed to H Kröger.
Prediction of fracture risk using axial bone mineral density in a perimenopausal population: a prospective study.
Several prospective studies have shown that the bone mineral density (BMD) measured in the appendicular or axial skeleton has an inverse relationship with the risk of subsequent fractures. However, most of these studies have concentrated on relatively old age groups, and the usefulness of measuring BMD at the time of menopause has not been established. In the present study, BMD was measured at the lumbar spine and femoral neck by dual X-ray absorptiometry (DXA) in a random stratified population sample of 3222 perimenopausal women (mean age 53.4 years, range 47-59 years). These women were followed for fractures over a period of 2 years. The fractures reported by a postal inquiry were verified from medical records. Fractures sustained in motor vehicle accidents were excluded from the analyses. During a mean follow-up of 2.4 years, 183 fractures occurred in 168 women. Wrist (n = 47), ankle (n = 31), and rib (n = 28) were the most common sites of a fracture. Women in the lowest quartile of spinal BMD had a 2.9 times greater risk of fracture than those in the highest quartile. The respective risk increased 2.2 times from the lowest to the highest quartile of femoral BMD, respectively. The relative risk for suffering from any fracture per one SD decrease in BMD was 1.50 (95% CI; 1.27-1.76) for the spine and 1.41 (1.21-1.64) for the femoral neck. The present study demonstrates that bone mass is important in the pathogenesis of fractures even in perimenopausal women. We conclude that the axial BMD measurement at the time of menopause can be of use in predicting subsequent fracture risk.
Absorptiometry, Photon↗
Antiinflammatory effects of NADPH oxidase inhibitors.
Proinflammatory cytokines prime the membrane-bound NADPH oxidase of neutrophils and monocytes of mice suffering from experimental arthritis so as to attain an activated state, which, upon a second stimulus, releases 6-fold increased levels of reactive oxygen species (ROS) than do unprimed phagocytes. Enhanced NADPH oxidase activity deregulates ROS-dependent signal transduction pathways of inflammation, which play a crucial role in the pathogenesis of arthritis. The antiarthritic reactivity of two inhibitors of NADPH oxidase, diphenylene iodoniumchloride (DPI) and staurosporine, was tested in male DBA/1 x B10A(4R) hybrid mice suffering from potassium peroxochromate arthritis. Daily doses of 2.8 mumol/kg of DPI or 30 nmol/kg of staurosporine sufficed to inhibit the arthritis by 50%. A complete inhibition was obtained with 10 mumol/kg of DPI, and 100 nmol/kg of staurosporine suppressed the arthritis by 85%. The onset, progression, and remission of arthritis correlated to both the activity of phagocytic NADPH oxidase (r = 0.750) and to overt disease symptoms as judged by the arthritis index. Our data support the hypothesis that oxidative stress plays a pivotal role in the pathology of arthritis, which can be therapeutically targeted by NADPH oxidase inhibitors.
Alkaloids↗
Modulation of inflammatory arthritis by inhibition of poly(ADP ribose) polymerase.
Poly(ADPR) polymerase (PARP; EC 2.4.2.30) is a nuclear enzyme, which, when activated by oxygen- and nitrogen-radical-induced DNA strand breaks, transfers ADP ribose units to nuclear proteins and initiates apoptosis by depletion of cellular NAD and ATP pools. The present study investigates whether the oxidative stress-dependent activation of PARP plays a role in the etiopathogenesis of arthritis. The antiarthritic reactivity of the biogenic PARP inhibitor nicotinamide was tested in DBA/1 x B10A(4R) mice suffering from potassium peroxochromate-induced arthritis. Daily doses of 4 mmol/kg of NA suppressed the arthritis by 35% and inhibited the phagocytic generation of reactive oxygen species, which increases sixfold during the development of arthritis. The onset, progression, and remission of arthritis correlated positively to the phorbolester-activated respiratory burst of neutrophils and monocytes, and a dose-dependent inhibition of NADPH oxidase activity was determined with human phagocytes. Our data support the hypothesis that oxidative stress-induced alterations in cellular signal transduction pathways play a pivotal role in the development of arthritis, which can be suppressed by the simultaneous inhibition of poly(ADPR) polymerase and NADPH oxidase.
Animals↗
Exacerbation of acetaminophen hepatotoxicity by thalidomide and protection by nicotinic acid amide.
1. The effects of racemic thalidomide (D[+]/L[-] alpha-phthalimido-glutarimide) on acetaminophen (AAP)-induced hepatitis were tested in male NMRI mice (n = 133) and quantified as serum activities of glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT). 2. A 2.1-fold increase of GOT and a 1.9-fold increase of GPT activities (P < 0.001) were observed in mice treated perorally with 500 mg/kg of AAP plus 150 mg/kg of thalidomide (Thal). In the absence of AAP, Thal did not display any detectable hepatotoxic effects. 3. The Thal-induced exacerbation of AAP hepatotoxicity was completely inhibited by nicotinic acid amide, a selective inhibitor of poly(ADP-ribose) polymerase (PARP) (P < 0.0001), suggesting a possible influence of Thal on the hepatic metabolism of NAD-adenoribosylation. 4. We see the main application of nicotinic acid amide as for the combinational use in pharmaceutical preparations of AAP in order to avoid hepatic damage in patients treated with AAP and Thal.
Acetaminophen↗
The effect of gynecological risk factors on lumbar and femoral bone mineral density in peri- and postmenopausal women.
The relationship between gynecological history and bone mineral density (BMD) of the lumbar spine and femoral neck was studied in 3126 perimenopausal women. The study population was a random, stratified sample of participants, selected from the Kuopio Osteoporosis Study, which consisted primarily of all 14,220 women aged 47-56 years in Kuopio Province in 1989. After exclusion of 1521 women reporting past or present hormonal replacement therapy (HRT), 1605 women formed the final study population. Present HRT users had significantly higher lumbar BMD but not femoral BMD, than non-hormone users. Postmenopausal status, late menarche, and bilateral oophorectomy were risk factors for low BMD. Protective factors against low BMD were increased body weight, increased number of pregnancies, as well as hysterectomy without bilateral oophorectomy. The majority (43.8%) of these operations had been performed due to the presence of leiomyomas. No significant correlation was found between nulliparity, breast-feeding or amenorrhea before the age of 30 and BMD. In the multiple regression analysis, gynecological variables could account for only 18.4-26.8% of the variance in BMD, while time since last periods, age, age at menarche, weight and hysterectomy were the most significant variables. We conclude that reproductive history gives rise to some special risk groups, to whom BMD measurements and osteoporosis prevention efforts should be directed. However, it is impossible to predict BMD by gynecological characteristics.
Bone Density↗
Fractures and low axial bone density in perimenopausal women.
The relationship between past fractures and current bone density (BMD) was analyzed in a population sample of 3222 women aged 48-58. BMD was determined with dual X-ray absorptiometry (DXA) at the spine and femoral neck. 702 women reported fractures. Wrist and ankle were the most common fracture sites. Fracture history increased the risk [OR (95% CI)] of low spinal BMD (of more than 1 SD below the study population mean) by 1.75 (1.41; 2.18). The sensitivity and specificity of fracture history to detect a low spinal BMD were 31 and 80%, respectively. One SD decreases of spinal and femoral BMD equalled to respective overall fracture risks (adjusted ORs) of 1.36 (1.24; 1.50) and 1.38 (1.25; 1.51). Both BMDs related more strongly to wrist fracture [1.73 (1.47; 2.05)/1.69 (1.43; 1.99)] than to all nonwrist fractures combined [1.24 (1.11; 1.37)/1.27 (1.14; 1.42)]. Ankle and rib fractures related only to spinal [1.21 (1.00; 1.46)/1.45 (1.12; 1.87)] but tibia and foot bone fractures only to femoral [2.04 (1.37; 3.04)/2.20 (1.42; 3.41)] BMD. Spinal BMD related more strongly to fractures due to falls on same level than to fractures due to all other trauma combined. Fracture history poorly screens out low perimenopausal BMD. The results suggest that pre- and perimenopausal fractures relate to low axial bone density and that the magnitude of this relation depends on the sites of fracture and densitometry as well as on the type of trauma.
Absorptiometry, Photon↗
Comparison of different models for interpreting bone mineral density measurements using DXA and MRI technology.
Bone mineral density measurements using dual X-ray absorptiometry (DXA) are commonly expressed as areal density (g/cm2). However, areal BMD (BMDareal) is dependent on bone size and this can lead to erroneous interpretations of BMD values. We have previously presented a simple method for calculating apparent volumetric bone mineral density (BMDvol) using ancillary DXA-derived data. In the present study we tested the validity of our model using in vivo volumetric data obtained from magnetic resonance imaging (MRI) of lumbar vertebrae. BMDareal and BMDvol of L3 were measured from sixteen pairs of identical twins (24 men, 8 women), aged 25-69 years. The dimensions of the lumbar vertebra L3 were measured from MR images and BMD values were corrected for these dimensions. The DXA-derived apparent volumetric bone mineral density (BMDvol) correlated moderately with MRI-derived BMDs (r values from 0.665 to 0.822). In contrast to BMDareal, BMDvol and MRI-derived BMDs were not related to body size variables. All these volume-corrected BMDs diminished the erroneous effect of vertebral size on areal BMD. We conclude that the simple DXA-derived BMDvol can be used for normalization of bone mineral density values in subjects of different body sizes, and especially in growing children.
Absorptiometry, Photon↗
Osteitis caused by bacille Calmette-Guérin vaccination: a retrospective analysis of 222 cases.
To evaluate the frequency, clinical features, and prognosis of patients with osteitis caused by bacille Calmette-Guérin (BCG) vaccination, medical records from Finnish children based on nationwide registration from 1960 to 1988 were retrospectively analyzed. During the study period, three different BCG vaccine preparations were used. In 222 children, diagnostic criteria of BCG osteitis were fulfilled. The age at onset of BCG osteitis varied from 0.25 to 5.7 years. The most common sites of osteitis were metaphyses of the long bones. The lower extremity (58%) was affected more often than the upper (14%). Osteitis was situated in the sternum in 36 patients (15%) and in the ribs in 27 (11%). The frequency of BCG osteitis, but not the clinical parameters, was closely associated with the vaccine preparation used. Only 6 children were left with some sequelae. With adequate treatment, the prognosis for children vaccinated with BCG is good.
BCG Vaccine↗
Risks of perimenopausal fractures--a prospective population-based study.
OBJECTIVE: To examine the associations between potential risk factors and fractures in perimenopausal women. SUBJECTS: A total of 3,140 women (mean age 53.4 +/- 2.8 (s.d.) years) were followed-up for 2.4 years after axial bone densitometry (lumbar spine and femoral neck) with regard to the occurrence of fractures. RESULTS: In all, 5.6% of the women sustained a fracture. There were 169 low energy fractures (falling on a level surface) in 157 women after the exclusion of 18 fractures caused by a high energy trauma. The wrist was the most frequent site of fracture (n = 46). Lumbar bone mineral density was 5.8% lower and femoral bone mineral density 4.6% lower among fracture cases compared with non-fracture cases (p < 0.0001). History of a fracture during 1980-1989 elevated the risk of all fractures 2.83-fold (95% confidence interval (CI) 1.95-4.10) and the risk of a first wrist fracture 2.25-fold (95% CI 1.10-4.62). The amount of weekly alcohol intake was higher among fracture cases than among non-fracture cases yielding an age-adjusted odds ratio (OR) of 1.45 (95% CI 1.05-2.02). Past or present use of hormone replacement therapy was protective against fractures (age-adjusted OR 0.70, 95% CI 0.50-0.96). If bilateral oophorectomy had been carried out under the age of 45 years, the risk of fracture was 3.64-fold (95% CI 1.01-13.04) compared with women operated upon after the age of 45 years. Age at menarche, parity, lactation and smoking history did not differ between the fracture and non-fracture groups. CONCLUSIONS: A former history of fractures, low baseline bone mineral density (BMD) and use of alcohol are predisposing factors associated with perimenopausal fractures, while hormone replacement therapy is protective in this respect.
Alcohol Drinking↗
Induction of arthritis in mice and rats by potassium peroxochromate and assessment of disease activity by whole blood chemiluminescence and 99mpertechnetate-imaging.
Arthritis develops in DBA/1xB10A(4R) mice and Wistar rats upon intraplantar injection of potassium peroxochromate (K3CrO8), and is here quantified by whole blood chemiluminescence (CL) and 99mpertechnetate-imaging (99mTcO4-), and related to overt disease symptoms (the arthritis index). During the aqueous decay of K3CrO8 to chromate (VI), the chromium(V)-bound oxygen is released as superoxide, hydroxyl radicals, singlet oxygen and hydrogen peroxide, the same reactants, which are produced by activated phagocytes during inflammation. Reactive oxygen species (ROS) trigger the breakdown of the sulfhydryl-dependent antioxidant defence system and induce the nuclear factor kappa B-dependent expression of pro-inflammatory cytokines, which prime phagocytic NADPH oxidases to the enhanced production of ROS. During both the acute inflammatory response and the onset of the secondary response in non-injected paws, the phorbolester-stimulated ROS production of phagocytes was significantly enhanced (p < 0.001) and correlated well to the arthritis index (r = 0.797) and the uptake of 99mTcO4- into inflamed joints. Chromate(VI), formed during the decay of K3CrO8, contributes to the progression of arthritis by inhibition of glutathione reductase, thereby increasing intracellular H2O2 concentrations. In addition, Cr(VI) reduced to Cr(V) by ascorbate, catalyzes hydroxyl radical production in the presence of hydrogen peroxide. A stable loop forms, in which ROS, continuously produced by Cr(VI)/Cr(V) redox-cycling, drive the primary response into chronic self-perpetuating inflammation. We see the main application of K3CrO8-induced arthritis and its assessment by both 99mTcO4- imaging and chemiluminescent immunosensoring of phagocytic activity in unseparated blood as for the rapid screening of novel anti-rheumatic drugs and treatments.
Animals↗
Ultrasound attenuation of the calcaneus in normal subjects and in patients with wrist fracture.
We determined broadband ultrasound attenuation (BUA) of the calcaneus, and bone mineral density (BMD) of the spine, proximal femur and radius in 137 healthy subjects (79 women and 58 men) and in 56 women with Colles' fracture. The repeated measurements on 9 healthy subjects indicated a short-term reproducibility (coefficient of variation) of 4 percent for BUA. There was a small (7 percent) but significant difference in BUA between normal men and women. The age-dependence in normal subjects was weak. When all the study subjects were pooled, modest correlations between BUA of the calcaneus and BMD at all measured skeletal sites were found (rs values 0.3-0.4). However, it was not possible to make an accurate prediction of the axial BMD, using BUA. BUA values were 13 percent lower in the wrist fracture patients than in the age-matched normals. In general, BUA could discriminate the fracture patients from normals as effectively as BMD. As suggested by the physical theory of ultrasound attenuation, our results support the idea that BUA reflects not only the bone density but also other factors related to the structural properties of bone.
Absorptiometry, Photon↗
Estimation of spinal bone density using conventional MRI. Comparison between MRI and DXA in 32 subjects.
We evaluated the usefulness of MRI T1 and T2 relaxation times in assessing bone mineral status. T1 and T2 relaxation times of L3 were measured in 16 pairs of identical twins (24 men, 8 women), aged 25-69 years. Bone mineral density (BMD), bone mineral content (BMC) and apparent volumetric bone mineral density (BMDvol) of L3 were measured from the same subjects using dual x-ray absorptiometry (DXA). T2 relaxation time correlated inversely with BMD and BMC (r -0.40 and r -0.47, respectively), whereas a significant positive correlation between T1 relaxation time and BMDvol was found (r 0.36). The measurement of T1 may give some information on bone mineral status in clinical MRI measurements when DXA is not available. It is possible that T1 and T2 reflect not only bone density, but also other factors related to bone structure.
Absorptiometry, Photon↗
Improvement of left ventricular morphology and function in obese subjects following a diet and exercise program.
The aim of this work was to compare left ventricular performance during weight reduction induced by either physical training and diet or diet alone. Forty-three moderately obese subjects received a hypocaloric diet of 800 kcal/d for 4 weeks; 22 of them were also subjected to an exercise program. By means of echocardiography, left ventricular dimensions and systolic time intervals were determined. Heart rate and blood pressure were measured at rest and during exercise. The addition of physical training resulted in a more favourable change in weight loss (-8.3 vs -6.3 kg), heart rate (-14 vs -7 bpm), systolic (-17 vs -8 mm Hg), and diastolic (-11 vs -6 mm Hg) blood pressure. Left ventricular mass (LVM) was diminished more pronounced by combined therapy (-10.0%) as compared to diet alone (-4.7%). Changes in LVM were correlated with weight loss but not with alterations in heart rate and blood pressure. Fractional shortening and mean circumferential fiber shortening velocity did not improve significantly whereas the ratio of preejection period/left ventricular ejection time (PEPi/LVETi) was shortened in the diet and diet plus exercise group by -10.7 and -17.9%, respectively. It was concluded that exercise training in combination with a hypocaloric diet reduces left ventricular dimensions, LVM and PEPi/LVETi more distinctly than diet alone.
Adult↗
Suppression of arthritis by an active center analogue of Cu2Zn2-superoxide dismutase.
The anti-arthritic and anti-inflammatory efficacy of CuPu(Py)2 ([N,N'-bis(2-pyridylmethylene)-1,4-butanediamine] (N,N',N",N"))-Cu(II), a serum-stable active center analogue of Cu2Zn2-superoxide dismutase (SOD; EC 1.15.1.1), was tested in male DBA/1 x B10A (4R) mice suffering from potassium-peroxochromate-induced (PIA) or collagen type II-induced arthritis (CIA). Parameters including the arthritis index, the plasma SOD activity, and the inhibition of phagocytic responses in unseparated blood were used for the assessment of disease activity. A dose-dependent suppression of arthritis was noted in both models. The ED50 was 2.5 +/- 0.4 mumol/kg/day of CuPu(Py)2 for PIA and 4.0 +/- 1.1 mumol/kg/day for CIA. The arthritis index correlated with both the levels of reactive oxygen species (ROS) generated by phorbol ester-activated neutrophils and monocytes in unseparated blood (r = 0.892) and the SOD-like activity in plasma (r = 0.857). CuPu(Py)2 inhibited also the lipoplysaccharide-induced release of tumor necrosis factor alpha from human monocytes and neutrophils in a dose-dependent manner. Unlike SOD, which exerts successful anti-rheumatic activity mainly upon intra-articular injection, the SOD-mimic CuPu(Py)2 can be applied systemically. Non-proteinaceous low molecular weight antioxidases may well be suited to control oxidative stress-derived damage in rheumatic diseases by modulation of ROS-dependent signal transduction pathways.
Animals↗
Bone mineral density and risk factors for osteoporosis--a population-based study of 1600 perimenopausal women.
Population-based epidemiological studies on osteoporosis are few. Our study evaluated the effects of menopause and certain putative behavioural risk factors on bone mineral density (BMD). Spinal and femoral neck BMD were measured with dual X-ray absorptiometry (DXA) from 1600 perimenopausal women aged 48-59 years (mean 53.2 years) with no diseases or medications known to affect bone metabolism. These women were a selected sample of the Kuopio Osteoporosis Risk Factor and Prevention Study population (n = 14,220). There was a wide variation of BMD among perimenopausal women. Menopause had a major effect on BMD. Postmenopausal women had significantly lower BMD in both spine (-6.2%) and femoral neck (-3.9%) as compared with premenopausal women. Multiple regression analysis showed that weight, menopausal status, age, and grip strength were significant independent predictors of both spinal and femoral BMD. Additionally, physical activity was found to be a significant predictor of femoral BMD, and alcohol consumption was a significant predictor of spinal BMD. However, current anthropometric and lifestyle factors explained only 18.7-25.4% of the variability of BMD. Therefore, the estimation of the risk factor status at menopause is not an adequate substitute for bone densitometry. However, our results may in part help clinicians to identify the risk groups at which to direct bone density measurements.
Absorptiometry, Photon↗
The effect of previous oral contraceptive use on bone mineral density in perimenopausal women.
The bone mineral density (BMD) of the lumbar vertebrae L2-4 and femoral neck was determined by dual-energy X-ray absorptiometry (DXA) in 3222 perimenopausal women-a random stratified sample of the population-based Kuopio Osteoporosis Study (OSTPRE). The mean age of the women was 53.4 years (range 47.9-59.6 years). Twenty-nine percent of the women were past users of oral contraceptives (OC) containing 50 micrograms or less of ethinyl estradiol and 7.4% (n = 250) of the women reported OC use for more than 6 years. There was a slight but statistically significant difference between OC users (n = 939) and non-users (n = 2283) in lumbar BMD (1.134 +/- 0.155 g/cm2 v 1.123 +/- 0.161 g/cm2, p = 0.014). A statistically significant difference was recorded also after adjustment for years since menopause, duration of hormonal replacement therapy (HRT) and present weight (p = 0.044). When the analysis was performed among women who had never used oestrogen replacement therapy (n = 1427) and among premenopausal women (n = 387), no differences in BMD were found between OC users and non-users. Similarly, femoral neck BMD did not differ between the groups. This population-based study demonstrated a slightly higher lumbar BMD among past OC users. However, OC users and non-users differed from each other in many behavioral characteristics. Thus, the differences in BMD may be accounted for more by other factors than by past OC use itself. The low-dosage estrogen OCs used today would not be expected to have any positive bone effects among future perimenopausal women.
Bone Density↗
The effect of fluoridated drinking water on axial bone mineral density--a population-based study.
Bone mineral density (BMD) of the spine and femoral neck was measured in a random stratified sample of 3222 perimenopausal women aged 47-59 years. A total of 969 women had used fluoridated drinking water (1.0-1.2 mg/l) for over 10 years. These women were compared with 2253 women with low levels of fluoride in drinking water (< 0.3 mg/l). BMD of the spine was significantly higher in the fluoride group than in the non-fluoride group (1.138 +/- 0.165 vs. 1.123 +/- 0.156 g/cm2, P = 0.026). Femoral neck BMDs did not differ between the groups. When the BMD values were adjusted for confounding factors (age, weight, menopausal status, calcium intake, physical activity level, deliveries, alcohol consumption and estrogen use), the differences between the groups increased (P < 0.001 for the spine and P = 0.004 for the femoral neck, respectively). There was no significant difference between the groups in the prevalence of self-reported fractures sustained during 1980-1989. We propose that the fluoridation of drinking water has a slight increasing effect on axial BMD in women in low fluoride areas.
Absorptiometry, Photon↗