[Personal instruction in a new model of education].
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Curriculum↗
Biomedical subjects
S Ljunghall
Publications and source records attributed to S Ljunghall.
[Continuous remodeling of the skeleton. Growth factors and cytokines direct the activity].
Bone is living tissue perpetually undergoing metabolism in a process known as remodelling, a sequence of cellular events occurring throughout the skeleton. The process is initiated in response to bone resorption by multinucleated osteoclasts. The capacity to stimulate osteoclastic activity is a property common to a multiplicity of hormones and cytokines--e g, parathyroid hormone, vitamin D, thyroxine, interleukin-1 and tumour necrosis factor. There is also a group of growth factors and cytokines, such as interleukin-6 and interleukin-11, that serve as stimulators of osteoclastic recruitment. Following bone resorption by osteoclasts, osteoblasts are recruited to the resorption lacuna, where they secrete osteoid which is then mineralised to form mature bone. The coupling of bone resorption and formation is governed by growth factors embedded in the mineralised bone matrix and released during resorption. These include transforming growth factor beta, insulin-like growth factor. Osteoporosis is caused by imbalance between the resorption and formation phases of the remodelling cycle.
Adult↗
Assessment of biochemical markers of bone metabolism in relation to the occurrence of fracture: a retrospective and prospective population-based study of women.
We have in a population-based setting evaluated biochemical markers of bone metabolism in 328 women, aged 40-80 years, and related it to contents of bone mineral measurements and the retrospective and prospective presence of fracture. The participants were recruited from the city population files. Serum samples for analysis of osteocalcin (Oc), procollagen I carboxy-terminal extension peptide (PICP), and carboxy-terminal telopeptide of type I collagen (ICTP) were taken, and forearm bone mineral content (BMC) was measured by single photon absorptiometry (SPA). Fracture history was recorded, and the information was verified and supplemented from both radiologic and orthopedic files. Five years later the registration of fractures was repeated. At the initial investigation, Oc was 23% lower in women who had sustained a fracture (n = 37) within 6 years before measurement (6.3 +/- 3.6 microgram/l vs 8.2 +/- 4.2 microgram/l (p = 0.006)), after adjusting for age and BMC difference. PICP and ICTP were not different from values in the women without fracture. However, in women aged 70-80 years with a fracture sustained during the previous 6 years, PICP was lower (128 +/- 32 microgram/l vs 144 +/- 34 microgram/l, p = 0.046). Oc and ICTP were significantly correlated to age and BMC (Oc-age r = 0.36, Oc-BMC r = -0.31, ICTP-age r = 0.44, ICTP-BMC r = -0.24). The correlations of PICP were weaker. Prospectively, logistic regression gave an odds ratio (OR) of 1.8 (p = 0.015) for a low PICP and fracture susceptibility, at a change of 1 SD, independent of age and BMC. In the age bracket 70-80, the odds ratio was 2.4 (p = 0.036). The odds ratio for ICTP, independent of age and BMC, was 1.9 (P = 0.043) for 1 SD decrease and subsequent fracture risk. We concluded that women who had sustained at least one recent fracture had an altered bone turnover with decreased bone formation but an unaltered resorption. Women with retrospectively registered fractures also sustained subsequent fractures. A decrease from the mean of the collagen markers PICP and ICTP was associated with an increased risk for future fracture. Utilizing these biochemical markers of bone metabolism in a female population, PICP and ICTP had a similar influence on the risk of future fracture as forearm BMC (OR = 1.6, p = 0.03).
Adult↗
Diet, bone mass, and osteocalcin: a cross-sectional study.
To determine the relationships among nutrients intake, bone mass, and bone turnover in women we have investigated these issues in a population-based, cross-sectional, observational study in one county in central Sweden. A total of 175 women aged 28-74 at entry to the study were included. Dietary assessment was made by both a semiquantitative food frequency questionnaire and by four 1-week dietary records. Dual energy X-ray absorptiometry was performed at five sites: total body, L2-L4 region of the lumbar spine, and three regions of the proximal femur. Serum concentrations of osteocalcin (an osteoblast-specific protein reflecting bone turnover) were measured by a radioimmunoassay. Linear regression models, with adjustment for possible confounding factors were used for statistical analyses. A weak positive association was found between dietary calcium intake as calculated from the semiquantitative food frequency questionnaire and total body bone mineral density (BMD) among premenopausal women. No association emerged between dietary calcium intake and site-specific bone mass, i.e., lumbar spine and femoral neck, nor was an association found between dietary calcium intake and serum osteocalcin. BMD at some of the measured sites was positively associated with protein and carbohydrates and negatively associated with dietary fat. In no previous studies of diet and bone mass have dietary habits been ascertained so carefully and the results adjusted for possible confounding factors. Neither of the two methods of dietary assessment used in this study revealed any effect of calcium intake on BMD at fracture-relevant sites among these healthy, mostly middle-aged women.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Inhibitory effects of 9-cis and all-trans retinoic acid on 1,25(OH)2 vitamin D3-induced bone resorption.
The effects of retinoic acid (RA), and calcitriol are mediated by specific nuclear receptors (RARs and VDR, respectively). Induction of RAR and VDR responsive elements in target genes requires a cofactor, the retinoid-X-receptor (RXR), with its ligand 9-cis RA. We have previously demonstrated the expression of RARs and RXRs in osteoblasts, and herein investigated the effects of the retinoids all-trans RA and 9-cis RA alone and combined with calcitriol on bone resorption in vitro, measured by 45Ca-release from prelabeled neonatal mouse calvarial bones. All-trans RA and 9-cis RA were powerful stimulators of bone resorption and essentially equipotent. At threshold concentrations (1 nM) both 9-cis RA and at-RA markedly inhibited the resorption induced by calcitriol (1 pM). The findings are compatible with a physiological role for retinoids in bone metabolism.
Animals↗
Heel ultrasound in women after long-term ERT compared with bone densities in the forearm, spine and hip.
To compare heel ultrasound values with bone densities at different measurement sites as determined by single photon absorptiometry (SPA) and dual-energy X-ray absorptiometry (DXA) in long-term users of estrogen replacement therapy (ERT), we analyzed data from 30 users of estradiol implants (mean duration of treatment 16 years) and 32 non-users, comprising 28 complete age-matched pairs. The precision errors in vivo of ultrasound measurements were 0.18%, 1.3% and 1.5% for speed of sound (SOS), broadband ultrasound attenuation (BUA) and stiffness index, respectively. In the controls, ultrasound parameters correlated well with values from SPA and DXA measurements (r = 0.51-0.63, p < 0.004). In long-term users of ERT, however, measurements with ultrasound did not correlate with DXA in the spine and hip (r = 0.01-0.31, NS) but correlated well with SPA in the forearm (r = 0.47-0.66, p < 0.009). Implant users, compared with non-users, had small and just significantly different values when measured by ultrasound (at most 12%, p = 0.03-0.04) but significantly higher bone mineral densities (18%-25%, p = 0.0001-0.01) in the forearm, spine and hip when measured by SPA or DXA. Data indicated that a substantial proportion of long-term users of estrogen may be non-responders concerning the effect of estrogen on bone qualities expressed in heel ultrasound values. In a multivariate regression analysis the effect of increasing age and increasing treatment duration were both negative for the ultrasound parameters.(ABSTRACT TRUNCATED AT 250 WORDS)
Absorptiometry, Photon↗
Pronounced elevation in circulating calcitonin in critical care patients is related to the severity of illness and survival.
OBJECTIVE: To study circulating levels of calcitonin in critically ill patients in relation to the severity of illness and survival. DESIGN: Cross-sectional and prospective. SETTING: The ICU in Gävle hospital, a secondary non-teaching hospital. PATIENTS: 37 consecutive ICU patients. MEASUREMENTS AND RESULTS: Serum calcium and immunoreactive calcitonin (iCT) were measured and the Apache II and the Multiple Organ Failure (MOF) scores were recorded during the first 24 h in the ICU. Patients were followed for hospital survival. Profound increase in circulating iCT was seen (mean 591, median 184, range 8-3445 pg/ml) in the studied sample and only 11% of the patients showed normal levels (< 40 pg/ml). iCT was higher in septic than nonseptic patients (p < 0.004) and was correlated to two indices of severity of illness (r = 0.50, p < 0.006 versus the Apache II score and p = 0.55, p < 0.003 versus the MOF score). Furthermore, iCT was correlated to the length of stay in the intensive care unit (r = 0.56, p < 0.001) and was elevated in the patients who did not survive when compared to survivors (p < 0.03). iCT was not significantly related to the degree of serum calcium (mean 2.22 +/- 0.15 SD mmol/l). Gel chromatography in a fast protein liquid chromatography (FPLC) system of serum from 4 patients with elevated iCT disclosed that a majority of the measured CT was not due to monomeric CT, but high molecular CT. CONCLUSIONS: Pronounced elevations in circulating iCT were seen during the first 24 h critically ill patients. As the major part of the iCT consisted of high molecular weight CT this would not induce hypocalcemia. Rather, the elevated iCT would be regarded as a part of the metabolic responses to illness.
APACHE↗
Vitamin D is related to blood pressure and other cardiovascular risk factors in middle-aged men.
A previous study has shown that serum levels of the active vitamin D metabolite 1,25-(OH)2-vitamin D were inversely related to blood pressure levels while the prohormone 25-OH-vitamin D was found to be related to insulin metabolism. Also other clinical and experimental data support the view that vitamin D metabolism is involved in blood pressure regulation and other metabolic processes. The present study was conducted in order to see if the above mentioned relationships between the vitamin D endocrine system and blood pressure, as well as other cardiovascular risk factors, could be found in a cross-section population-based study. Serum levels of 1,25-(OH)2-vitamin D, 25-OH-vitamin D, and blood pressure were therefore measured in 34 middle-aged men and metabolic cardiovascular risk factors were evaluated by means of intravenous glucose and fat tolerance tests, euglycemic hyperinsulinemic clamp, lipoprotein measurements, and lipoprotein lipase activity determinations. Serum levels of 1,25-(OH)2-vitamin D were found to be inversely correlated to the blood pressure (r = -0.42, P < .02), VLDL triglycerides (r = -0.47, P < .005), and to triglyceride removal at the intravenous fat tolerance test (r = 0.34, P < .05), while serum levels of 25-OH-vitamin D were correlated to fasting insulin (r = -0.35, P < .05), insulin sensitivity during clamp (r = 0.54, P < .001), and lipoprotein lipase activity both in adiposal tissue (r = 0.48, P < .005) and skeletal muscle (r = 0.38, P < .03).(ABSTRACT TRUNCATED AT 250 WORDS)
Adipose Tissue↗
Mortality of untreated primary hyperparathyroidism--a nontraditional indication for parathyroid surgery?
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Humans↗
Studies on two new vitamin D analogs, EB 1089 and KH 1060: effects on bone resorption and osteoclast recruitment in vitro.
We have investigated the effects on bone resorption of two new potent antiproliferative vitamin D3 analogs, EB 1089 and KH 1060, by studying recruitment of osteoclasts in murine bone marrow cultures and 45Ca release from prelabeled neonatal mouse calvarial bones. Binding studies to vitamin D receptor protein, from human osteosarcoma MG-63 cells, demonstrated kd values of 8.5 x 10(-11) for 1 alpha,25(OH)2D3, 6.5 x 10(-11) for KH 1060, and 2.7 x 10(-10) for EB 1089. 1 alpha,25(OH)2D3 and EB 1089 were equipotent stimulators of osteoclast recruitment in murine bone marrow cultures, with EC50 at 10(-10) mol/L, whereas KH 1060 was about tenfold more potent with an EC50 at 10(-11) mol/L. In serum-free media, 1 alpha,25(OH)2D3 enhanced 45Ca release from neonatal mouse calvarial bones with EC50 at 10(-11) mol/L, but in the presence of 10% fetal calf serum (FCS) the stimulatory effect was significantly diminished, with a threshold value at 10(-10) mol/L. EB 1089 stimulated bone resorption with an estimated EC50 at 3 x 10(-11) mol/L, whereas KH 1060 was about tenfold more potent than 1 alpha,25(OH)2D3, and stimulated bone resorption with an EC50 at 10(-12) mol/L. The effects of EB 1089 and KH 1060 on 45Ca release were not significantly affected by the addition of 10% FCS. Addition of vitamin D binding protein to serum-free incubations of neonatal mouse calvarial bones, significantly inhibited the bone resorbing effect of 1 alpha,25(OH)2D3, but did not affect EB 1089 and KH 1060 induced 45Ca release.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Vitamin D receptor genotypes in primary hyperparathyroidism.
Vitamin D and parathyroid hormone (PTH) constitute the main regulators of systemic calcium homeostasis. As well as its calcaemic effects, active vitamin D3(1,25(OH)2D3) has a direct regulatory role on parathyroid cells. Active vitamin D3 acts via its receptor (VDR), and binding of the ligand-receptor complex to specific promoter regions of the PTH gene inhibits transcription. Active vitamin D3 constitutes a principal regulator of parathyroid cell growth, and polymorphism in the VDR gene has recently been related to bone mineral density and suggested as predisposing to osteoporosis. Impaired effects of active vitamin D3 may contribute to the relatively enhanced secretion and cell proliferation seen in hyperparathyroidism (HPT). Indeed, VDR dysfunction, of essentially unknown character, has been demonstrated in the pathological parathyroid tissue of primary HPT as well as HPT secondary to uraemia. Consistent with the essential role of active vitamin D3 in parathyroid regulation, the VDR gene polymorphism was studied in 90 postmenopausal women with primary hyperparathyroidism. The VDR genotype bb was found in 60.0% of HPT patients and in 33.3% of the postmenopausal female controls (P < 0.001). As the b allele has been linked to decreased transcriptional activity or messenger RNA stability, reduced VDR expression may impede regulatory actions of vitamin D and may contribute to parathyroid tumorigenesis in these patients.
Aged↗
Diet and hip fracture risk: a case-control study. Study Group of the Multiple Risk Survey on Swedish Women for Eating Assessment.
BACKGROUND: The role of diet as a risk factor for osteoporotic fractures is unclear. Earlier studies have yielded conflicting results. METHODS: In two counties in central Sweden we investigated the association between dietary intake and the risk of proximal femoral fractures in a case-control study nested in a cohort. Women born in 1914-1948 were asked to fill out a food frequency questionnaire when invited to attend for mammographic screening between the years 1987 and 1990. More than 65,000 women completed the questionnaire. Those who had participated in the enquiry and subsequently sustained a first hip fracture were defined as cases. For every case, four individually matched controls, by age and county of residence, were selected from the cohort. A second questionnaire concerning confounding factors was mailed to controls and cases. In all, 247 cases and 893 controls could finally be included. Monthly intake of foods and daily intake of nutrients were calculated. RESULTS: When highest quartile of intake was compared to lowest, intakes of iron (adjusted odds ratio [OR] of 3.3, 95% confidence interval [CI]: 1.6-6.9), magnesium (adjusted OR = 2.7, 95% CI: 1.3-6.0) and vitamin C (adjusted OR = 1.9, 95% CI: 1.2-3.1) were found to be independent risk factors for hip fracture. High calcium intake did not protect against hip fracture. Smoking, low physical activity in leisure time, low body mass index, earlier fracture of the distal forearm and diabetes were all risk factors while postmenopausal hormone replacement therapy protected against hip fracture. DISCUSSION: This large study indicates new dietary risk factors for hip fracture. The association between high dietary intake of iron, magnesium and vitamin C and risk of hip fracture has not been reported previously. Further clinical and experimental studies are needed to confirm these findings and to investigate their mechanism of action.
Adult↗
Parathyroid hormone and blood pressure--is there a relationship?
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Humans↗
Regulation of bone cells by 1,25(OH)2D3.
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Animals↗
Pre-operative evaluation of risk factors for complications in patients with primary hyperparathyroidism.
Impairments in cardiovascular, respiratory and kidney function are considered as risk factors for complications following surgery. As the indication for surgery in asymptomatic primary hyperparathyroidism (HPT) is controversial, 123 patients undergoing surgery for HPT and 104 control subjects scheduled for common surgical procedures were evaluated pre-operatively. Compared with the age- and sex-matched control group, serum calcium (P < 0.001), creatinine (P < 0.01) and glucose (P < 0.02) were all increased in the HPT group, while peak expiratory flow (PEF) was decreased (P < 0.04). Furthermore, the patients with HPT, compared with controls, were more often receiving antihypertensive medication (P < 0.005) and were more likely to have a history of congestive heart disease (P < 0.01), thromboembolic diseases (P = 0.05), stroke (P = 0.06) or diabetes mellitus (P < 0.02). Increased frequencies of ST-segment depression (P < 0.001) and T-wave abnormalities (P = 0.05) at electrocardiography together with an increased prevalence of heart enlargement visible at chest radiography (P < 0.01) were also seen in the HPT group when compared with the controls. All HPT patients and controls survived, but one HPT patient suffered a myocardial infarction in the post-operative period. In conclusion, the present study showed the pre-operative risk factor profile to be altered in HPT subjects with impairments in both cardiovascular and respiratory functions as well as in kidney function and glucose control. These findings should be kept in mind when the indications for surgery in asymptomatic patients with HPT are discussed.
Aged↗
The influence of body composition on left ventricular mass and other echocardiographic and Doppler measurements in 70-year-old males.
Heart morphology and function are often related to body size. The most common way to standardize for body composition is to divide these measures by body surface area (BSA). It has, however, been suggested that left ventricular mass (LV mass) ought to be indexed for height and that cardiac output is influenced by the body fat distribution. As part of a health screening programme of 70-year-old males in Uppsala, Sweden, 100 consecutive men were investigated with echocardiography and Doppler with regard to cardiac morphology and function. These measures were related to an evaluation of body composition using an X-ray method (dual energy X-ray absorptiometry). Lean body mass was strongly related to BSA and body weight (r = 0.90 and 0.89, respectively; P < 0.0001), and to a lesser degree to height (r = 0.70, P < 0.0001). In the healthy part of the population (n = 39), relationships between LV mass on the one hand and lean body mass, BSA and height on the other were seen (r = 0.51, 0.51 and 0.50, respectively; P < 0.01). Stroke volume calculated according to Teichholtz (but not when calculated with Doppler) showed a significant correlation to lean body mass (r = 0.38, P < 0.05). Also, left ventricular diameter and the thickness of the free wall were related to lean body mass (r = 0.40 and 0.39, respectively; P < 0.05). All of the evaluated relationships were generally weaker and in most cases no longer significant when evaluated in part of the population with diseases known to affect the heart. No significant correlations were seen between the size of the left atrium, septal thickness or indices of diastolic function (E/A-ratio, isovolumic relaxation time, deceleration time) and the indices of body composition. No measures of cardiac morphology and function were significantly related to the amount of body fat or body bone. LV mass, stroke volume and left ventricular diameter were found to be correlated with lean body mass, but not with the amount of fat, in healthy 70-year-old males. Theoretically, it is optimal to adjust for lean body mass, but in clinical practice, BSA is to be preferred.
Aged↗
Hormonal regulation of serum lipoprotein(a) levels. Contrasting effects of growth hormone and insulin-like growth factor-I.
In response to treatment with growth hormone, serum levels of lipoprotein(a) increase, while those of LDL cholesterol decrease. To establish if increased levels of insulin-like growth factor-I may be of importance for these changes, we analyzed serum lipoprotein concentrations in 11 male patients with idiopathic osteoporosis who were treated with growth hormone (2 IU.m-2.d-1) or insulin-like growth factor-I (80 micrograms.kg-1.d-1) in a randomized, double-blind, cross-over study. LDL cholesterol was reduced by 0.7 mmol/L (P < .01) during growth hormone treatment but was not affected when the same patients received insulin-like growth factor-I. In contrast, mean lipoprotein(a) levels increased from 519 to 571 mg/L (P < .03) in response to growth hormone but were reduced from 538 to 478 mg/L (P < .04) during treatment with insulin-like growth factor-I. These results indicate that growth hormone exerts its effects on lipoprotein metabolism independent of insulin-like growth factor-I. Furthermore, the results suggest that treatment with insulin-like growth factor-I may reduce lipoprotein(a) levels.
Adult↗