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Biomedical subjects

J C Birkenhäger

Publications and source records attributed to J C Birkenhäger.

At least 19 recordsLinked to original sources
PubMed2000

Adjacent genes, for COL2A1 and the vitamin D receptor, are associated with separate features of radiographic osteoarthritis of the knee.

OBJECTIVE: To study the association of the COL2A1 genotype, in relation to the vitamin D receptor (VDR) genotype, with features of radiographic osteoarthritis (ROA) in a population of elderly men and women. METHODS: In this cross-sectional study, we analyzed a population-based sample of 851 men and women ages 55-80 years from a large cohort study, the Rotterdam Study. We determined the prevalence of ROA of the knee according to the Kellgren/Lawrence (K/L) score and features of ROA (presence of osteophytes and narrowing of the joint space [JSN]) without considering clinical parameters of the disease. Genotypes were determined at a variable-number tandem repeats marker 1 kb downstream of the COL2A1 gene using a newly developed heteroduplexing method. The VDR genotype was previously determined by a direct molecular haplotyping polymerase chain reaction method to establish the phase of alleles at 3 adjacent restriction fragment length polymorphisms for Bsm I, Apa I, and Taq I. RESULTS: We found the COL2A1 genotype to be associated with a 2-fold increased risk for JSN, but not with osteophytes or the K/L score. We had previously found the VDR genotype to be associated with osteophytes and the K/L score, but not with JSN. When the COL2A1 genotype was analyzed in combination with the VDR genotype, we found evidence suggesting that the presence of haplotypes of the 2 genes was associated with increased risk for ROA. CONCLUSION: Our findings demonstrate that both the COL2A1 gene and the VDR gene are involved in ROA, but in separate features. The COL2A1 genotype is associated with JSN, while the VDR genotype is associated with osteophytes.

Aged↗
PubMed2000

Consequences of vitamin D receptor gene polymorphisms for growth inhibition of cultured human peripheral blood mononuclear cells by 1, 25-dihydroxyvitamin D3.

OBJECTIVE: In the vitamin D receptor (VDR) gene a BsmI restriction fragment length polymorphism (RFLP) in intron 8 and a translational start-site polymorphism, identified as a FokI RFLP, have been described. Crucial for a proper interpretation of these polymorphisms in association studies is the knowledge whether they have direct consequences for 1,25-(OH)2D3 action at cellular level. The present study was designed to assess functional significance of the FokI and BsmI VDR gene polymorphisms in peripheral blood mononuclear cells (PBMC) with a natural occurring VDR genotype for cell growth inhibition by 1,25-(OH)2D3. DESIGN: PBMC of women were isolated, VDR genotyped and in vitro inhibition by 1,25-(OH)2D3 of Phytohemagglutinin (PHA)-stimulated growth of PBMC was examined in relation to VDR genotype. RESULTS: PHA-stimulated growth and maximal growth inhibition were independent of VDR genotype. However, the FF genotype had a significant lower ED50 than the Ff genotype corresponding to an allele dose effect of 0.32 nM per f allele copy (P = 0.0036). For BsmI genotypes no differences in ED50 were observed. CONCLUSION: The present study demonstrates for the first time in cells with a natural VDR genotype a direct functional consequence of the VDR gene translational start-site polymorphism for the action of 1,25-(OH)2D3. Especially under conditions of vitamin D insufficiency these findings might have clinical implications.

Aged↗
PubMed1999

Evidence for involvement of 17beta-estradiol in intestinal calcium absorption independent of 1,25-dihydroxyvitamin D3 level in the Rat.

The sex steroid 17beta-estradiol (17beta-E2) has a broad range of actions, including effects on calcium and bone metabolism. This study with 3-month-old Brown Norway rats was designed to investigate the role of 17beta-E2 in the regulation of calcium homeostasis. Rats were divided in four groups, sham-operated, ovariectomized (OVX), and OVX supplemented with either a 0.025-mg or 0.05-mg 17beta-E2 pellet implanted subcutaneously. After 4 weeks, in none of the groups was serum calcium, phosphate, or parathyroid hormone altered compared with the sham group, while only in the OVX rats was a significant reduction in urinary calcium found. Bone mineral density and osteocalcin were modified, as can be expected after OVX and 17beta-E2 supplementation. OVX resulted in a nonsignificant increase in serum 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Supplementation with either one of the 17beta-E2 dosages resulted in an 80% reduction of 1,25(OH)2D3 and only a 20% reduction in 25-hydroxyvitamin D3 levels. OVX, as well as supplementation with 17beta-E2, did not affect serum levels of vitamin D binding protein. As a consequence, the estimated free 1,25(OH)2D3 levels were also significantly decreased in the 17beta-E2-supplemented group compared with the sham and OVX groups. Next, the consequences for intestinal calcium absorption were analyzed by the in situ intestinal loop technique. Although the 1,25(OH)2D3 serum level was increased, OVX resulted in a significant decrease in intestinal calcium absorption in the duodenum. Despite the strongly reduced 1,25(OH)2D3 levels (18. 1 +/- 2.1 and 16.4 +/- 2.2 pmol/l compared with 143.5 +/- 29 pmol/l for the OVX group), the OVX-induced decrease in calcium absorption could partially be restored by supplementation with either 0.025 mg or 0.05 mg of 17beta-E2. None of the treatments resulted in a significant change in calcium handling in the jejunum, although the trends were similar as those observed in the duodenum. 17beta-E2 did not change the VDR levels in both the intestine and the kidney. In conclusion, the present study demonstrates that 17beta-E2 is positively involved in intestinal calcium absorption, and the data strengthen the assertion that 17beta-E2 exerts this effect independent of 1,25(OH)2D3. In general, 17beta-E2 not only affects bone turnover but also calcium homeostasis via an effect on intestinal calcium absorption. (J Bone Miner Res 1999;14:57-64)

Animals↗
PubMed1998

Estrogen replacement decreases the level of antibodies against oxidized low-density lipoprotein in postmenopausal women with coronary heart disease.

The effect of estrogen replacement therapy (ERT) on plasma lipid concentrations and oxidation parameters was studied in 25 hypercholesterolemic women with coronary heart disease (CHD). During ERT, the low-density lipoprotein cholesterol (LDLc) concentration decreased from 4.31 +/- 0.72 to 3.85 +/- 0.62 mmol/L (P < .01) and high-density lipoprotein cholesterol (HDLc) increased from 1.42 +/- 0.30 to 1.55 +/- 0.33 mmol/L (P < .01). The concentration of autoantibodies against oxidized LDL decreased from 25.9 +/- 22.0 to 22.7 +/- 19.9 mg/L (P < .05), indicating that ERT may have antioxidative effects in vivo. The lag time to oxidation and the LDL subclass pattern did not change. Analysis of the influence of smoking on the efficacy of ERT showed that ERT significantly affected LDLc and HDLc concentrations in 15 nonsmoking women. However, in 10 cigarette smokers, no significant changes in LDLc or HDLc levels were observed. Smoking did not affect the concentration of autoantibodies to oxidized LDL or the lag time. Medroxyprogesterone acetate ([MPA] 10 mg daily) added to ERT decreased HDLc by 9% (P < .01) but did not affect the LDLc level, LDL subclass pattern, or lag time. In conclusion, ERT may have antioxidative effects in vivo and favorably affects dyslipidemia in hypercholesterolemic women with CHD, especially when they refrain from smoking.

Autoantibodies↗
PubMed1998

Regulation of osteocalcin production and bone resorption by 1,25-dihydroxyvitamin D3 in mouse long bones: interaction with the bone-derived growth factors TGF-beta and IGF-I.

Bone cells produce multiple growth factors that have effects on bone metabolism and can be incorporated into the bone matrix. Interplay between these bone-derived growth factors and calciotropic hormones has been demonstrated in cultured bone cells. The present study was designed to extend these observations by examining the interactions between either transforming growth factor-beta (TGF-beta) or insulin-like growth factor-I (IGF-I) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in a mouse long bone culture model with respect to osteocalcin production and bone resorption. In contrast to the stimulation in rat and human, in the fetal mouse long bone cultures, 1,25(OH)2D3 caused a dose-dependent inhibition of osteocalcin production. Both the osteocalcin content in the culture medium and in the extracts of the long bones was reduced by 1,25(OH)2D3. This effect was not specific for fetal bone because 1,25(OH)2D3 also reduced osteocalcin production by the neonatal mouse osteoblast cell line MC3T3. TGF-beta inhibited whereas IGF-I dose-dependently increased osteocalcin production in mouse long bones. The combination of TGF-beta and 1,25(OH)2D3 did not result in a significantly different effect compared with each of these compounds alone. The IGF-I effect was completely blocked by 1,25(OH)2D3. In the same long bones as used for the osteocalcin measurements, we performed bone resorption analyses. Opposite to its effect on osteocalcin, 1,25(OH)2D3 dose-dependently stimulated bone resorption. TGF-beta reduced and IGF-I did not change basal (i.e., in the absence of hormones) bone resorption. Our results show that 1,25(OH)2D3-enhanced bone resorption is dose-dependently inhibited by TGF-beta and IGF-I. Regression analysis demonstrated a significant negative correlation between 1,25(OH)2D3-induced bone resorption and osteocalcin production. The specificity for their effect on 1,25(OH)2D3-stimulated bone resorption was assessed by testing the effects of TGF-beta and IGF-I in combination with parathyroid hormone (PTH). Like 1,25(OH)2D3, PTH dose-dependently stimulates bone resorption. However, PTH-stimulated bone resorption was not affected by TGF-beta. Like 1,25(OH)2D3-stimulated bone resorption, IGF-I inhibited the PTH effect but at a 10-fold higher concentration compared with 1,25(OH)2D3. In conclusion, the present study demonstrates growth factor-specific interactions with 1,25(OH)2D3 in the control of osteocalcin production and bone. With respect to bone resorption, these interactions are also hormone specific. The present data thereby support and extend the previous observations that interactions between 1,25(OH)2D3 and bone-derived growth factors play an important role in the control of bone metabolism. These data together with the fact that TGF-beta and IGF-I are present in the bone matrix and potentially can be released during bone resorption support the concept that growth factors may control the effects of calciotropic hormones in bone in a localized and possibly temporal manner. Finally, in contrast to human and rat, in mice 1,25(OH)2D3 reduces osteocalcin production and this reduction is paralleled by stimulation of bone resorption by 1,25(OH)2D3. These data thereby show a dissociation between osteocalcin production and bone resorption.

Animals↗
PubMed1998

The additional effects of acipimox to simvastatin in the treatment of combined hyperlipidaemia.

OBJECTIVES: Nicotinic acid, an effective drug for treatment of combined hyperlipidaemia, is often not tolerated because of side-effects. Acipimox is a nicotinic acid like lipid lowering drug with less side-effects. We studied whether the addition of acipimox to simvastatin improves the lipid profile in patients with a combined hyperlipidaemia. DESIGN: Randomized double-blind placebo controlled crossover trial. SETTING: Outpatient lipid clinic of a tertiary referral centre. SUBJECTS: Eighteen patients with combined hyperlipidaemia treated with diet and 20-40 mg simvastatin for at least 3 months. INTERVENTION: Acipimox in a daily dose of 3 X 250 mg for 12 weeks. MAIN OUTCOME MEASURES: Effects on the concentration of LDLc, TG, HDLc, Lp(a) and Apolipoprotein B, as well as on LDL-size and LDL-resistance to oxidative modification. RESULTS: Acipimox reduced Lp(a) levels by 8% (P < 0.05). A substantial but not statistically significant change in TG (-32%) and HDLc (+6%) levels was seen. All patients were found to have small dense LDL, with a size of 229 +/- 4 A. LDL size and the resistance to oxidation, reflected in the lag phase during in vitro oxidation, were not affected by the addition of acipimox. In a subgroup of 8 patients with the most severe hypertriglyceridaemia (baseline TG > 4 mmol L- [1]), acipimox induced a significant increase in HDLc (+ 15%, P < 0.01). The effects on TG (-41%), LDLc (-10%) and lag phase (+17%) were also more pronounced than in the group with a lower baseline TG, but none of these changes reached the level of significance. CONCLUSIONS: Adding acipimox to simvastatin reduced Lp(a) and substantially but not significantly lowered TG. However, in patients with the highest TG levels. HDLc was also significantly improved.

Adult↗
PubMed1997

Vitamin D receptor genotype is associated with radiographic osteoarthritis at the knee.

Osteoporosis and osteoarthritis are age-related disorders of the skeleton with genetic components. Low bone density is a risk factor for osteoporotic fracture while osteoarthritis is associated with increased bone density. The 1,25-dihydroxyvitamin D3 receptor (VDR) gene locus was previously found to be associated with bone density. We therefore studied the relationship between radiographic osteoarthritis at the knee and VDR genotype in a population-based sample (n = 846), using molecular haplotyping of anonymous intragenic DNA polymorphisms. Radiographic osteoarthritis was defined using the Kellgren score, which is based on the assessment of osteophytes and joint space narrowing (JSN). We show that one VDR haplotype allele is significantly overrepresented in individuals with knee osteoarthritis and associated with a 2.27-fold increased relative risk (95% confidence interval 1.46, 3.52). Adjustment for bone density at the femoral neck did not change these results, indicating that the association is not mediated by bone density. The association appeared to be largely explained by the presence of osteophytes rather than JSN. Our results indicate a role of the VDR gene in the pathogenesis of osteophytes while linkage disequilibrium with another nearby gene, i.e., the collagen type IIa1 gene encoding the most abundant protein in cartilage, might contribute to the association.

Aged↗
PubMed1997

Growth hormone restores hepatic lipase mRNA levels but the translation is impaired in hepatocytes of hypothyroid rats.

During hypothyroidism, hepatic lipase (HL) activity is decreased. The low HL may be due to thyroid hormone insufficiency or to the concomitant fall in growth hormone (GH) activity. We studied HL expression in hepatocytes freshly isolated from hypothyroid rats with and without additional GH-substitution. In all animals HL mRNA was detected by RT-PCR in the hepatocytes, but not in the non-parenchymal cells. In hypothyroid cells HL mRNA levels were reduced by 40%, and the in vitro secretion of HL-activity and HL-protein was decreased by about 50%. In cells from GH-substituted hypothyroid rats, HL mRNA level was normalised, but the secretion of HL remained low. The specific enzyme activity of secreted HL was similar under all conditions. The discrepancy between HL mRNA and HL secretion in GH-supplemented rats may be due to (post)translational effects. Therefore we studied the HL synthesis and maturation in hepatocytes from hypothyroid and GH-substituted rats. Pulse-labelling experiments with [(35)S]methionine showed that the incorporation of [(35)S]methionine into HL protein was lower both in hypothyroid cells and in GH-supplemented cells than in control cells. During the subsequent chase, the intracellular processing and transport of newly synthesized HL protein in the hepatocytes from hypothyroid rats, whether or not supplemented with GH, was similar to control cells. We conclude that in livers of hypothyroid, GH-substituted rats translation of HL mRNA is inhibited despite restoration of HL mRNA levels.

Animals↗
PubMed1997

Longitudinal changes in ultrasound parameters of the calcaneus.

We examined with a median follow-up of 1.4 years (range 1.0-2.0 years) the rates of change per year in ultrasound parameters of the calcaneus. Speed of sound (SOS), Broadband ultrasound attenuation (BUA) and Stiffness were measured twice in 543 subjects (224 men) participating in the Rotterdam Study. SOS fell by -2.5 m/s per year in both sexes (95% CI -4.0 to -1.1 m/s per year in men and -3.6 to -1.4 m/s per year in women). Stiffness decreased by -0.62 (-1.33 to 0.09) per year in men and -0.66 (-1.24 to -0.08) per year in women. In men the rate of change in SOS and Stiffness tended to increase with age. BUA did not change significantly during follow-up in either sex. The prospectively assessed rates of loss differed considerably from those observed cross-sectionally, especially for SOS in men (cross-sectional -0.7 m/s per year, longitudinal -2.5 m/s per year). There was substantial variation between individuals both in changes per year in SOS and in changes per year in BUA. With a median follow-up time of 1.4 years, approximately 27% of the variation in the rate of change for SOS could be explained by measurement error while for BUA this was approximately 9% and for Stiffness 11%. Only a small percentage of subjects had changes larger than could be accounted for by measurement error (SOS: men 26.8%, women 21.6%; BUA: men 28.5%, women: 38.8%; Stiffness: men 32.6%, women 35.1%). The latter may limit the use of ultrasound measurements as a follow-up tool in individuals rather than in populations.

Age Factors↗
PubMed1997

Consequences of vitamin D receptor regulation for the 1,25-dihydroxyvitamin D3-induced 24-hydroxylase activity in osteoblast-like cells: initiation of the C24-oxidation pathway.

A direct relationship between vitamin D receptor (VDR) level and target cell responsiveness to 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) has been shown in osteoblast-like cell lines. However, we previously found an inverse relationship between the TGF beta-induced VDR up-regulation and subsequent 1,25-(OH)2D3-induced biological responses. A clear inhibition of the 1,25-(OH)2D3-induced stimulation of osteocalcin and osteopontin expression was observed. A biological response that has formerly been shown to be coupled to VDR level is 24-hydroxylase activity. This enzyme initiates the C24 oxidation of the side-chain, followed by cleavage and ultimate metabolic clearance of both 25-(OH)D3 and its metabolite 1,25-(OH)2D3. With UMR 106 (rat) and MG 63 (human) osteoblast-like cells, we show that after preincubation with TGF beta, which causes an increase in VDR level, 1,25-(OH)2D3 induction of 24-hydroxylase activity is also stimulated. In addition, we provide evidence that variations in VDR level induced by other means (PTH, EGF, medium change) are also closely associated with 1,25-(OH)2D3-induced 24-hydroxylase activity. Furthermore, we show that in MG 63 cells, but not in UMR 106 cells, TGF beta itself was able to increase the activity of the enzyme 24-hydroxylase. As 24-hydroxylation is the initial step in the further C24 oxidation of 1,25-(OH)2D3, our results indicate a close coupling of VDR level and the degradation of its ligand, 1,25-(OH)2D3. This mechanism may provide an important regulatory feedback in the action of 1,25-(OH)2D3 at target tissue/cell level.

24,25-Dihydroxyvitamin D 3↗
PubMed1997

Common C-to-T substitution at position -480 of the hepatic lipase promoter associated with a lowered lipase activity in coronary artery disease patients.

We studied the molecular basis of low hepatic lipase (HL) activity in normolipidemic male patients with angiographically documented coronary artery disease (CAD). In 18 subjects with a lowered HL activity (< 225 mU/mL), all nine exons of the HL gene and part of the promoter region (nucleotides -524 to +7) were sequenced. No structural mutations in the coding part of the HL gene were found, but 50% of the subjects showed a C-to-T substitution at nucleotide -480. Screening for the base substitution in 782 patients yielded an allele frequency of 0.213 (297 heterozygotes, 18 homozygotes). In a group of 316 nonsymptomatic control subjects, the allele frequency was 0.189, which is significantly less than in the CAD patients (P = .035). In the CAD patients, the C-to-T substitution was associated with a lowered lipase activity (heterozygotes -15%, homozygotes -20%). The patients were divided into quartiles on the basis of HL activity. Sixty percent (allele frequency 0.32) of the patients in the lowest quartile (HL activity < 306 mU/mL) had the gene variant against 27% (allele frequency 0.14) in the highest quartile (HL activity > 466 mU/mL). In the noncarriers, but not in the carriers, HL activity was related with plasma insulin, being increased at higher insulin concentration. Homozygous carriers had a significantly higher HDL cholesterol level-than noncarriers (1.13 +/- 0.28 mmol/L versus 0.92 +/- 0.22 mmol/L, P < .02). Our results show that a C-to-T substitution at -480 of the HL promoter is associated with a lowered HL activity. The base substitution, or a closely linked gene variation, may contribute to the variation in HL activity and affect plasma lipoprotein metabolism.

Alleles↗
PubMed1997

Vertebral deformities and functional impairment in men and women.

The objective of this study was to assess the prevalence and health effects of vertebral deformities in men and women. The study was carried out as part of the cross-sectional baseline phase of The Rotterdam Study, a prospective population-based cohort study of residents aged 55 years or over of a district of Rotterdam, The Netherlands. The prevalence of vertebral deformities according to a modification of the Eastell method and concomitant functional impairment were assessed in a random sample of 750 men and 750 women. The prevalence of moderate (grade I) vertebral deformities was 8 and 7% in men and women, respectively. For severe deformities (grade II), these percentages were 4 and 8%. In men, the prevalence of both moderate and severe deformities increased with age. In women, however, the prevalence of moderate vertebral deformities remained constant, opposite to a marked increase in severe deformities. Moderate vertebral deformity was significantly associated with impaired rising in men only. Severe vertebral deformity was associated with a significantly increased risk of general disability and the use of a walking aid in both men and women, impaired bending in men, and impaired rising in women. It is concluded that (1) vertebral deformities are only slightly less common in men than in women from the general population and (2) severe progression with age occurs in women only and (3) severe vertebral deformity is, particularly in men, related to functional impairment.

Aged↗
PubMed1997

The additional effects of acipimox to simvastatin in the treatment of combined hyperlipidaemia.

OBJECTIVES: Nicotinic acid, an effective drug for treatment of combined hyperlipidaemia, is often not tolerated because of side-effects. Acipimox is a nicotinic acid like lipid lowering drug with less side-effects. We studied whether the addition of acipimox to simvastatin improves the lipid profile in patients with a combined hyperlipidaemia. DESIGN: Randomized double-blind placebo controlled crossover trial. SETTING: Outpatient lipid clinic of a tertiary referral centre. SUBJECTS: Eighteen patients with combined hyperlipidaemia treated with diet and 20-40 mg simvastatin for at least 3 months. INTERVENTION: Acipimox in a daily dose of 3 x 250 mg for 12 weeks. MAIN OUTCOME MEASURES: Effects on the concentration of LDLc, TG, HDLc, Lp(a) and Apolipoprotein B, as well as on LDL-size and LDL-resistance to oxidative modification. RESULTS: Acipimox reduced Lp(a) levels by 8% (P < 0.05). A substantial but not statistically significant change in TG (-32%) and HDLc (+6%) levels was seen. All patients were found to have small dense LDL, with a size of 229 +/- 4 A. LDL size and the resistance to oxidation, reflected in the lag phase during in vitro oxidation, were not affected by the addition of acipimox. In a subgroup of 8 patients with the most severe hypertriglyceridaemia (baseline TG < 4 mmol L- [1]), acipimox induced a significant increase in HDLc (+15%, P < 0.01). The effects on TG (-41%), LDLc (-10%) and lag phase (+17%) were also more pronounced than in the group with a lower baseline TG, but non of these changes reached the level of significance. CONCLUSIONS: Adding acipimox to simvastatin reduced Lp(a) and substantially but not significantly lowered TG. However, in patients with the highest TG levels, HDLc was also significantly improved.

Adult↗
PubMed1996

Conformational change and enhanced stabilization of the vitamin D receptor by the 1,25-dihydroxyvitamin D3 analog KH1060.

The 1,25-dihydroxyvitamin D3 [1,25-(OH)2vitamin D3] analog KH1060 exerts very potent effects on cell proliferation and cell differentiation via the vitamin D receptor (VDR). However, the activities of KH1060 are not associated with an increased affinity for the VDR. We now show that increased stabilization of the VDR-KH1060 complex could be an explanation for its high potencies. VDR half-life studies performed with cycloheximide-translational blocked rat osteoblast-like ROS 17/2.8 cells demonstrated that, in the absence of ligand, VDR levels rapidly decreased. After 2 hr, less than 10% of the initial VDR level could be measured. In the presence of 1,25-(OH)2vitamin D3, the VDR half-life was 15 hr. After 24 hr. less than 20% of the initial VDR content was detectable, whereas, at this time-point, when the cells were incubated with KH1060 80% of the VDR was still present. Differences in 1,25-(OH)2vitamin D3- and KH1060-induced conformational changes of the VDR could underlie the increased VDR stability. As assessed by limited proteolytic digestion analysis, both 1,25-(OH)2vitamin D3 and KH1060 caused a specific conformational change of the VDR. Compared with 1,25-(OH)2vitamin D3, KH1060 induced a conformational change that led to a far more dramatic protection of the VDR against proteolytic degradation. In conclusion, the altered VDR stability and the possibly underlying change in VDR conformation caused by KH1060 could be an explanation for its enhanced bioactivity.

Animals↗
PubMed1996

[Ultrasound assessment of the calcaneus: for the time being a conservative approach in clinical use; the ERGO study (Erasmus Rotterdam Health and the Elderly)].

OBJECTIVE: To examine whether ultrasound measurements of the calcaneus can help to identify subjects with a risk for non-vertebral fractures. DESIGN: Cross-sectional survey. SETTING: The suburb of Ommoord in Rotterdam, the Netherlands. METHODS: 1421 subjects (631 men, 790 women) underwent both ultrasound measurements of the calcaneus and bone mineral density measurement of the femoral neck by dual energy X-ray absorptiometry (DXA). At the calcaneus speed of sound (SOS in m/s) and broadband ultrasound attenuation (BUA in dB/MHz) were measured. In addition, all subjects were asked about fractures in the preceding 5 years. The frequency of non-vertebral fractures was examined per tertile of SOS and BUA. In addition, we examined whether there was a trend in the number of fractures per tertile of SOS or BUA, within tertiles of femoral neck bone mineral density. RESULTS: The measures of SOS, BUA and bone mineral density (DXA-measured) are comparable as predictors of fractures. Subjects with values of SOS, BUA or bone mineral density in the lowest tertiles were all found to report two to three times as many fractures as subjects with values for these variables in the highest tertiles. Within tertiles of bone mineral density, subjects with a low SOS reported more fractures than subjects with a high SOS. For BUA a similar but less pronounced pattern was visible. Nevertheless, the area under the receiver operating characteristic (ROC) curve was 0.63 for SOS and 0.64 for BUA, comparable to 0.62 for bone mineral density of the proximal femur. Combining ultrasound and bone mineral density measurements had limited effect on the area under the ROC curve (0.65). CONCLUSIONS: Subjects with lower values of ultrasound parameters are at increasing risk of fracture, especially if low ultrasound values are accompanied by a lower bone mineral density. It remains to be seen whether ultrasound parameters are useful for screening.

Absorptiometry, Photon↗
PubMed1996

Evidence for coordinated regulation of osteoblast function by 1,25-dihydroxyvitamin D3 and parathyroid hormone.

From several animal studies and clinical observations it became evident that at target tissue level 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and parathyroid hormone (PTH) must act in an interrelated manner. In the present study we examined the interaction between 1,25-(OH)2D3 and PTH in the target cell of these hormones in bone, the osteoblast. In addition we studied the role of PTH-activated signal pathways. The three osteoblastic cell lines UMR 106, ROS 17/2.8 and MG-63 were used as model systems. In UMR 106 cells 1,25-(OH)2D3 and PTH caused a synergistic up-regulation of the vitamin D receptor (VDR) which was accompanied by a synergistic induction of VDR mRNA expression whereas in both ROS 17/2.8 and MG-63 cells no interaction was observed. In UMR 106 cells the effect of PTH on homologous up-regulation of VDR could be mimicked by the cAMP agonist forskolin and by dibutyrylic-cAMP. Phorbol ester activation of protein kinase C reduced basal as well as 1,25-(OH)2D3-induced up-regulation of VDR. 1,25-(OH)2D3 induced 24-hydroxylase activity in UMR 106 and MG 63 cells and, in contrast to VDR regulation, in both cell lines PTH and 1,25-(OH)2D3 synergistically induce 24-hydroxylase activity. Similar to VDR regulation the effect of PTH was mimicked by activation of cAMP production whereas protein kinase C activation reduced the induction by 1,25-(OH)2D3. Finally, we examined the interaction with respect to osteocalcin synthesis. In ROS 17/2.8 and MG-63 cells 1,25-(OH)2D3 stimulated osteocalcin production. In ROS 17/2.8 cells PTH as well as stimulation of cAMP production by forskolin enhanced 1,25-(OH)2D3-induced osteocalcin production whereas, as we have shown previously, activation of protein kinase C does not change 1,25-(OH)2D3-stimulated osteocalcin production. In MG-63 cells neither PTH nor forskolin significantly changed 1,25-(OH)2D3 induction of osteocalcin synthesis. From the present study it can be concluded that indeed at target cell level 1,25-(OH)2D3 and PTH act in a coordinated manner. On basis of the potentiation of 1,25-(OH)2D3 action by PTH in osteoblasts together with the previously reported inhibition of PTH-stimulated cAMP production by 1,25-(OH)2D3 we postulate a negative feedback-loop at target cell level. The activation of the cAMP pathway results in an enhancement of the 1,25-(OH)2D3 action whereas the protein kinase C pathway attenuates the 1,25-(OH)2D3 action. Finally, the present study provides a basis for the indications from in vivo observations about an interrelated action of 1,25-(OH)2D3 and PTH at the target cell. More generally it demonstrates on the basis of analyses of endogenous cellular responses evidence for an interplay between receptor-activated pathways of peptide and steroid hormones.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1996

Association of radiographically evident osteoarthritis with higher bone mineral density and increased bone loss with age. The Rotterdam Study.

OBJECTIVE: To investigate the relationship of osteoarthritis (OA) to bone mineral density (BMD) and rate of bone loss. METHODS: The study group consisted of 2,745 persons (1,624 women) from the general elderly population. Disability was assessed by the Health Assessment Questionnaire. Femoral neck BMD was measured at baseline and, in 1,723 subjects, after 2 years of followup. Knee and hip radiographic OA was assessed on anteroposterior radiographs. RESULTS: With the exception of knee radiographic OA in men, radiographic OA was associated with significantly increased BMD (3-8%). BMD increased significantly according to the number of affected sites and the Kellgren score. Radiographic OA was also associated with significantly elevated bone loss with age (in men, only for radiographic OA of the hip). A significant increase in relation to the number of affected sites and the Kellgren score (except with regard to knee OA in men) was found, independent of disability. CONCLUSION: Radiographic OA is associated with high BMD and increased rate of bone loss. This suggests a more pronounced difference in BMD earlier in life.

Age Factors↗