C-reactive protein and fibrinogen of bedridden older patients in a six-month vitamin D supplementation trial.

OBJECTIVE: To elucidate the association between vitamin D status, C-reactive protein (CRP) and fibrinogen. DESIGN: Secondary analysis of a randomised double-blind placebo controlled trial. SETTING: Four longterm care hospitals (1215 beds) in Helsinki, Finland. PARTICIPANTS: 218 long-term inpatients aged over 65 years. INTERVENTION: Eligible patients (n = 218) were randomized to receive 0 IU/d, 400 IU/d, or 1200 IU/d cholecalciferol for six months. METHODS: Plasma 25-hydroxyvitamin D (25-OHD), parathyroid hormone (PTH), high sensitive CRP, fibrinogen, amino-terminal propeptide of type I procollagen (PINP), and carboxy-terminal telopeptide of type I collagen (ICTP) were measured. RESULTS: The patients were aged (84.5 +/- 7.5 years), vitamin D deficient (25-OHD = 23 +/- 10 nmol/l), chronically bedridden and in stable general condition. The mean baseline CRP and fibrinogen were 10.86 mg/l (0.12 mg/l - 125.00 mg/l) and 4,7 g/l (2.3 g/l - 8.6 g/l), respectively. CRP correlated with ICTP (r = 0.217, p = 0.001), but not with vitamin D status. Supplementation significantly increased 25-OHD concentrations, but the changes in CRP and fibrinogen were insignificant and inconsistent. The post-trial CRP concentrations (0.23 mg/l -138.00 mg/l) correlated with ICTP (r = 0.156, p < 0.001), but no association was found with vitamin D status. The baseline and post-trial fibrinogen correlated with CRP, only. CONCLUSIONS: CRP concentrations are associated with bone turnover, but not with vitamin D status, and vitamin D supplementation has no major effect on CRP or fibrinogen concentrations in bedridden older patients.

Familial high serum PICP: high even in skin interstitial fluid, suppressible by topical corticosteroid treatment.

Circulating C-terminal propeptide of type I procollagen (PICP), mostly originating from bone, is mainly cleared by mannose receptors (MRs) in liver endothelial cells (LECs). We hypothesized that skin macrophage MRs could also play a role in local (in situ) clearance of PICP originating from skin type I procollagen synthesis. We tested this hypothesis in a male subject with a genetic systemic clearance defect, apparently due to an abnormality in MR function in LECs (or in PICP structure). Since skin macrophages may express the same MRs as LECs do, the genetic defect could affect them as well; hence, if elevated PICP concentrations even in skin interstitial fluid (IF) were found in our subject, it would suggest a role for local MR-mediated PICP clearance in skin. Since glucocorticoids (GCs) upregulate MRs in vitro, we measured the effect of topical GC on suction blister fluid (SBF)-PICP of the test person as compared with normal subjects. SBF-PICP was elevated in the case, which was consistent with the hypothesis. Furthermore, the GC-induced decrease was accentuated. The results suggest that skin macrophage MRs can have a role in skin PICP clearance in situ.

Serum markers of collagen metabolism and serum osteocalcin in relation to pubertal development in 57 boys at 14 years of age.

We investigated whether levels of serum collagen markers and serum osteocalcin are related to pubertal growth and development in a cross-sectional study of 57 healthy boys at 14 y of age. The level of the soft tissue marker, serum amino-terminal propeptide of type III procollagen (PIIINP) was higher in boys at Tanner stages G3 versus G2 (p < 0.01). The levels of the markers of bone collagen matrix differed only at a more advanced pubertal stage: the formation markers, carboxy-terminal and amino-terminal propeptides of type I procollagen, and the degradation marker, carboxy-terminal telopeptide of type I collagen were higher only at stage G4 versus G3 (p < 0.01). The marker of bone mineralization, serum osteocalcin was also higher only at stage G4 versus G3 (p < 0.01). Stage G4 was associated with the pubertal growth spurt. The results demonstrate that pubertal development should be taken into account when serum levels of collagen markers and osteocalcin are evaluated, and suggest that an increase in serum PIINP in boys at G3 might predict a normal pubertal growth spurt, but the finding remains to be confirmed in longitudinal studies.

Very low rate of type I collagen synthesis and degradation in newly diagnosed children with acute lymphoblastic leukemia.

In children with acute lymphoblastic leukemia (ALL), the metabolism of type I collagen, the major collagen of bones, may be changed at diagnosis and during early chemotherapy. In the present study, bone formation and degradation rates were evaluated longitudinally in 35 children with ALL, using two serum markers of bone collagen formation: the amino-terminal (PINP) and carboxyterminal (PICP) propeptides; and a marker of degradation: the carboxyterminal telopeptide of type I collagen (ICTP). These serum markers were determined at diagnosis, during induction treatment (at 1, 4, and 6 weeks), and during consolidation treatment (at 8 and 12 weeks). The changes in the serum markers suggested that, at diagnosis, type I collagen turnover (i.e., both synthesis and degradation) was remarkably low. The median serum levels of PINP, PICP, and ICTP were -2.6 SDS (standard deviation score), -1.5 SDS, and -2.5 SDS, respectively. The PICP and PINP levels declined further during the first week of therapy (p < 0.001), whereas the ICTP levels had risen by end of the induction phase (p < 0.05). By the end of the 12 week interval, the concentrations of the formation and degradation markers had returned to normal (p < 0.01). Our findings suggest that ALL is accompanied by low turnover of bone collagen. The abnormalities are at first aggravated, but then corrected, by treatment.

Changes in bone markers in children with asthma during inhaled budesonide and nedocromil treatments.

We evaluated serum and urinary markers of bone turnover in 14 children with asthma during inhaled budesonide and nedocromil treatments. Both the markers of formation (serum carboxy- and amino-terminal propeptides of type I procollagen and serum osteocalcin) and the markers of degradation (serum carboxy-terminal telopeptide of type I collagen and urinary pyridinium cross-links) decreased (p < 0.05) during budesonide treatment for 6 months. During inhaled nedocromil treatment (for the following 6 months), the markers returned to the normal levels. These transient decreases in the markers of both formation and degradation of bone suggest that inhaled budesonide may slightly decrease the bone turnover rate. However, normal "coupling" between formation and degradation seemed to operate, e.g. a change in one resulted in a corresponding change in the other, so that net bone loss did not necessarily occur.

Serum ionized calcium, intact PTH and novel markers of bone turnover in bedridden elderly patients.

Chronic immobilization could markedly affect calcium and bone metabolism in elderly people. To investigate this, and to test the theory of 'type II' osteoporosis in bedridden elderly patients with low vitamin D status, 55 such subjects were examined. Serum concentrations of ionized calcium (Ca++), intact parathyrin (PTH) and two novel markers of bone collagen formation (carboxyterminal propeptide of type I procollagen; PICP) and resorption (carboxyterminal crosslinked telopeptide of type I collagen; ICTP) were measured. The effects on these parameters after 40 weeks of supplementation with vitamin D (1000 IU d-1) and/or calcium (1 g d-1) were subsequently prospectively evaluated. Despite low (mean 11.6 nmoll-1) serum 25-hydroxyvitamin D levels (25-OHD), those of 1,25-dihydroxy-vitamin D (1,25-(OH)2D) were mostly normal. Neither correlated with Ca++ or PTH. PTH correlated negatively not only with Ca++ (r = -0.328, P < 0.05) but also with ICTP (r = -0.306, P < 0.05). Mean PICP was normal but ICTP was elevated and tended to correlate positively with Ca++ (r = 0.268, P = 0.06). Vitamin D supplementation did not change PICP or ICTP considerably, despite slightly increased 1,25-(OH)2D and slightly decreased PTH. Ca++ values were normal and remained stable. In conclusion, Ca++ and PTH are poor indicators of vitamin D status in chronically immobilized elderly subjects. Furthermore, the results suggest that the increased bone resorption is not due to 'type II' secondary hyperparathyroidism; rather the resorption is primarily increased. Correction of vitamin D deficiency does not seem to benefit ageing bones unless adequate mechanical loading is provided.

Familial high serum concentrations of the carboxyl-terminal propeptide of type I procollagen.

We describe a family with an apparently autosomal-dominant trait that caused extremely high circulating concentrations of the carboxyl-terminal propeptide of type I procollagen (PICP). All family members examined had normal values for other biochemical markers of bone formation and degradation and no related clinical abnormalities. Furthermore, their serum concentrations of the amino-terminal propeptide of type I procollagen (PINP) were normal. Although PINP and PICP are released from the same precursor molecule, PINP is cleared from the circulation via the scavenger receptor in liver endothelial cells, whereas PICP is cleared via the mannose receptor of these cells. We thus hypothesize that the clearance of circulating PICP is compromised in the affected subjects of this family, the result of either a defective mannose receptor function or an abnormal molecular structure of their PICP.

Effects of inhaled budesonide on serum markers of bone metabolism in children with asthma.

The effects of inhaled glucocorticoids on serum markers of bone formation were evaluated in asthmatic children. Serum total alkaline phosphatase (AP), bone alkaline phosphatase (BAP), osteocalcin, and the novel marker of bone formation, carboxypropeptide of type I procollagen (PICP), were measured. In the cross-sectional part, long-term glucocorticoid users were compared with sodium cromoglycate (SCG) users. In the boys (n = 16), but not in the girls (n = 11), PICP was significantly lower in the glucocorticoid users than in the SCG users. PICP correlated positively with BAP (n = 54; groups combined, r = 0.29, p < 0.05). In the longitudinal part, the effects of inhaled budesonide or SCG, both used for the first time, were evaluated before and after 1 and 5 months of treatment. The budesonide dose was 800 micrograms/m2/day for 1 month and thereafter half of that. The SCG dose was 30 mg/day throughout the study. Only during budesonide use did osteocalcin and PICP decrease, the median osteocalcin by 8% at 1 month (p < 0.05) and by 6% at 5 months (n = 15), and PICP by 5% at 1 month (p < 0.05) and by 28% at 5 months (n = 7, p < 0.01). AP and BAP did not change significantly. Decreased PICP suggests decreased bone formation rate. PICP might be clinically useful as a marker of early adverse effects of glucocorticoids on bone.

'Correction' of serum calcium values for albumin biased in geriatric patients.

Determination of serum ionized calcium concentration (Cal) is more tedious as a screening method than measuring serum total calcium concentration (CaT) and is not widely practicable. Thus, in clinical practice and even in research, it is customary to 'correct' the serum total calcium concentration (CaT) for that of albumin (Alb) to estimate the 'true' calcemic status,i.e. Cal. However, owing to confounding factors that are incompletely understood at present, the 'corrected' result is imprecise. The hypothesis of the present study was that in geriatric hypoalbuminemia, it could even be biased due to confounding factors associated with aging and related to the Alb level itself. To test this hypothesis, CaT, Alb and Cal were measured in 558 consecutive geriatric in-patients with varying degrees of hypoalbuminemia. The lower the Alb level, the more strikingly the sensitivity of CaT for detecting low Cal was impaired by the correction. In geriatric hypoalbuminemia, the correction is not merely imprecise but even biased (inaccurate). The bias increases with the degree of hypoalbuminemia (i.e. with the need for correction) and leads to underdiagnosis of 'true' (ionic) hypocalcemia.

Serum ionized calcium and the prevalence of primary hyperparathyroidism in age cohorts of 75, 80 and 85 years.

In the elderly, primary hyperparathyroidism (HPT) is often disguised as 'senility' which can, however, be alleviated or cured by parathyroid surgery. The prevalence of HPT in the non-selected 75- to 85-year-old subjects (n = 610) randomly sampled from census records was estimated by measurements of serum ionized calcium and intact parathyrin levels. The prevalence of cases that require clinical attention seems to be around 3% in women and less than 1% in men. Furthermore, this study indicates that, on average, the serum ionized calcium concentration remains stable even in the elderly.

Survival prognosis in geriatric patients admitted to permanent institutional care.

The influence of clinical and laboratory findings on the two-year survival prognosis was investigated in 558 geriatric patients admitted to permanent institutional care. The patients surviving for two years (52%) were somewhat younger (79 vs 82 years, p less than 0.01), and on admission had significantly higher diastolic blood pressure (p less than 0.001), serum thyroxin (p less than 0.05), serum albumin (p less than 0.01) and blood haemoglobin (p less than 0.05), but lower treatment score (p less than 0.001), serum creatinine (p less than 0.001), and fasting plasma glucose (p less than 0.05). Decreased survival prognosis was also found in patients with abnormal serum sodium, chloride, and potassium (p less than 0.05 or less). However, an excess mortality of patients with abnormal laboratory data occurred within the first month after admission. Stepwise logistic regression analysis disclosed that the three-month survival prognosis was significantly impaired by low blood pressure (less than 110/70 mmHg), high treatment score (greater than 22), elevated serum creatinine (greater than 150 mumol/L), use of digitalis and atrial fibrillation. Poor two-year survival was further associated with the use of diuretics, and diabetes mellitus. The risk for death was lowest in patients with elevated blood pressure (greater than 160/95 mmHg). These data verify the significance of the clinically common diseases and indicators of homeostasis in the assessment of geriatric hospital patients, and demonstrate the nature of "terminal decline" in geriatric practice.

Calcemic status of geriatric patients: a longitudinal study.

Serum ionized (CaI), total (CaT) and albumin-'corrected' total (CaA) calcium concentrations were measured in 108 geriatric long-term inpatients on admission and again 37 months (mean) later. Mean CaI, especially when pH adjusted, remained extremely stable, indicating well-preserved homeostatic calcemic control even in the terminal years in the elderly. Further, the results indicate that in addition to their previously shown invalidity in interindividual comparisons, CaT and CaA are inferior to CaI and can also be misleading in the detection of slight longitudinal changes in the 'true' calcemic status of an individual geriatric patient.