Difference between total and intact assays for N-terminal propeptide of type I procollagen reflects degradation of pN-collagen rather than denaturation of intact propeptide.

BACKGROUND: The concentration of N-terminal propeptide of type I procollagen (PINP) in the serum reflects the rate of type I collagen formation. Intact PINP assay measures the trimeric propeptide while total P1NP assay measures both trimeric and monomeric forms. In this study we compared these two assays emphasizing the possible differences. METHODS: Intact and total PINP were measured from serum in healthy Finnish blood donors (n = 34) and in the patients with chronic renal failure before and after haemodialysis (n = 39). In addition, the serum of a normal man, pooled hospital serum samples and the serum of a patient with haemodialysis treatment were fractioned by gel filtration and trimeric and monomeric forms were located. Fractions were lyophilized and intact and total PINP were measured in each fraction. Samples from bedridden geriatric patients (n = 173) were also measured using intact and total PINP assays and a degradation marker of type I collagen (ICTP). RESULTS: The correlation between intact and total PINP in controls was 0.89 and their PINP concentrations were similar. In haemodialysis or bedridden geriatric patients, the PINP methods gave significantly different results. In gel filtration studies, intact PINP hardly measured monomeric form even if its concentration was disproportionately increased in haemodialysis patients. In bedridden geriatric patients, the difference of total and intact PINP correlated significantly to degradation marker ICTP. CONCLUSIONS: Difference between total and intact assays for PINP seem to reflect degradation of pN-collagen rather than denaturation of intact propeptide.

Does elevated parathyroid hormone concentration predict cognitive decline in older people?

BACKGROUND AND AIMS: Increased parathyroid activity has been associated with impaired cognitive function, although the predictive value of parathyroid hormone (PTH) for cognitive decline has not yet been fully investigated. This association was evaluated in random persons of age cohorts of 75, 80 and 85 years in a 10- year longitudinal prospective study. METHODS: Cognition of patients (n=514) was assessed with the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) at baseline and at intervals of one, five and ten years. Clinical data were collected and serum PTH, ionized calcium (Ca2+) and creatinine as well as apolipoprotein E (APOE) alleles were determined at baseline. RESULTS: Impaired cognition (MMSE<24 or CDR> or =1) was associated with older age, impaired renal function, and elevated PTH (> or =62 ng/L, IV-quartile) at baseline. Elevated PTH indicated a 2-fold risk of an at least 4-point decrease in MMSE (OR 2.20) and a 3-fold risk of an increase in CDR-class (OR 3.20) within the first year of follow- up. The risk remained significantly elevated even after controlling for age, gender, baseline cognition, serum Ca2+, creatinine, and APOE4 (OR 2.24 for MMSE; OR 2.12 for CDR). High PTH also predicted cognitive decline within a five-year follow-up (OR 3.20), but the association disappeared at ten years. CONCLUSIONS: Elevated PTH concentrations are associated with a five-year cognitive decline in a general aged population, independently of Ca2+ and renal function. The role of vitamin D deficiency, the most common cause of elevated PTH in the elderly, needs to be further investigated.

Parathyroid hormone as a mortality predictor in frail aged inpatients.

BACKGROUND: Some prospective cohort studies have associated parathyroid hormone (PTH) levels with survival independently of renal function, calcaemic and vitamin D status in the elderly. OBJECTIVE: In order to further evaluate the prognostic significance of subtle elevation of PTH and the involvement of vitamin D status in bedridden aged inpatients, the participants of a 6-month vitamin D supplementation trial were followed for 2 years. METHODS: Eligible patients (n = 218) of 4 long-term care hospitals (1,215 beds) were randomized to receive 0, 400 or 1,200 IU/day cholecalciferol for 6 months. In addition to routine analyses, plasma 25-hydroxyvitamin D (25-OHD), PTH and ionized calcium (Ca(2+)) levels were measured. Functional capacity was evaluated by activities of daily living (ADL) hierarchy scale and cognition was assessed by cognitive performance scale (CPS). Body mass index and glomerular filtration rate (GFR) were calculated. Mortality data was collected from patient records. RESULTS: The patients were aged (84.5 +/- 7.5 years), vitamin D deficient (25-OHD = 23 +/- 10 nmol/l) and frail (ADL 5.5, range 3-6; CPS 4.9, range 1-6). The PTH levels ranged from 12 to 268 ng/l, the cut points for IV quartile being 72 ng/l. The PTH levels in the IV quartile predicted a significant 1.58-fold over-mortality (95% CI 1.08-2.32, p = 0.020), resulting in a 9.1-month shortening (p = 0.019) in median life expectancy in patients with poorest renal function, but the prognostic significance of PTH was not explained by GFR. Furthermore, controlling for age, gender, body mass index, creatinine, 25-OHD, supplementation group, Ca(2+) and albumin levels did not abolish this significance. Mortality was predicted neither by baseline 25-OHD nor vitamin D supplementation. CONCLUSIONS: Even a subtle elevation of PTH is a relatively independent predictor of increased 2-year mortality in severely frail older inpatients with poor overall survival prognosis. Further prospective studies on the involvement of 1,25 dihydroxyvitamin D status in the predictive value of PTH are needed.

Low parathyroid hormone levels in bedridden geriatric patients with vitamin D deficiency.

OBJECTIVES: To identify the clinical conditions associated with low parathyroid hormone (PTH) in patients with vitamin D deficiency and to evaluate the stability of the blunted PTH response to vitamin D deficiency over 6 months. DESIGN: Secondary analysis of a randomized double-blind controlled vitamin D supplementation trial. SETTING: Four long-term care hospitals in Helsinki, Finland. PARTICIPANTS: Two hundred eighteen chronically bedridden patients. MEASUREMENTS: Plasma 25-hydroxyvitamin D (25-OHD), intact PTH, amino-terminal propeptide of type I procollagen (PINP), carboxy-terminal telopeptide of type I collagen (ICTP), activities of daily living (ADLs), and body mass index (BMI) were measured at baseline and at 6 months. Patient records were reviewed for demographic data. RESULTS: PTH was within reference values (8-73 ng/L) despite low 25-OHD level (<50 nmol/L) in 74.8% (n=163) of patients (mean age 84.5+/-7.5). Patients in the lowest PTH quartile (<38 ng/L) were characterized by a history of hip fractures (OR=2.9, P=0.01), low BMI (OR=0.9, P=.02), and high ICTP (OR=1.1, P=.03). PTH remained within reference values even after 6 months in 76.2% of the patients with persistent vitamin D deficiency in the placebo group. CONCLUSION: The absence of secondary hyperparathyroidism seems to be common and persistent in frail chronically bedridden patients with vitamin D deficiency. Attenuated parathyroid function appears to be associated with immobilization that causes accelerated bone resorption. Further studies addressing the possible adverse effects of low PTH are warranted.

Calculated serum calcium is an insufficient surrogate for measured ionized calcium.

Direct measurement of serum-ionized calcium (Ca2+) is the best available method to assess 'true' calcemia because serum total calcium is confounded by serum proteins, mainly albumin. However, calculated surrogates for Ca2+, albumin-adjustment particularly, have been widely used in the literature despite their insufficiency to evaluate calcemic status accurately. Recently, a new formula, in which serum total protein instead of albumin is used for adjustment of total calcium, has been suggested for very old hospitalized patients. We compared these two surrogates for Ca2+ with the direct measurement in both frail bedridden inpatients and in a general aged population. Both surrogates were equally insufficient in detecting hypocalcemia in both patient groups. However, the sensitivity and specifity for detecting hypercalcemia by both surrogates were relatively high in the bedridden inpatients. Precise assessment of calcemic status is particularly needed in research and in detecting mild hypo- or hypercalcemia. However, the calculated surrogates for Ca2+ have consistently failed in accurate assessment of 'true' calcemia. Thus, the direct measurement of Ca2+ should be favored instead of readily available automated surrogates. Adjustments of calcium for albumin or total protein may be useful in clinical practice in excluding hypercalcemia in very old bedridden patients, only.

Responses of parathyroid hormone to vitamin D supplementation: a systematic review of clinical trials.

The beneficial bone effects of vitamin D supplementation have been attributed to suppression of secondary hyperparathyroidism by 25-hydroxyvitamin D (25-OHD) levels at least 50nmol/l. In this systematic review, we have analyzed the results of 52 clinical trials, including 72 intervention groups and 6290 patients, on vitamin D supplementation in order to evaluate the experimental evidence and the effects of age and chronic immobility on responses of parathyroid hormone (PTH). The papers for this systematic review were selected through a search in PubMed and through a review of the reference lists of articles. Negative logarithmic (R(2)=0.318, p<0.001) and linear (R(2)=0.294, p<0.001) correlations were found between 25-OHD and PTH levels, when all pre- and post-trial values were scattered. Negative linear (R(2)=0.385, p<0.001) and logarithmic (R(2)=0.406, p<0.001) correlations were also found between the changes in 25-OHD and PTH levels. Age correlated negatively with changes in PTH (r=-0.476, p<0.001). The vitamin D supplementation of the chronically immobile patients resulted in a smaller decrease in PTH levels (-8.4 vs. -17.4%, p<0.001) despite a larger increase in 25-OHD levels (187.2% vs. 109.8%, p<0.001). According to the multiple regression analysis the changes in PTH were independently predicted by pre-trial PTH, changes in 25-OHD, age and chronic immobility, explaining 53.2% (R(2)=0.532) of the variation. This meta-analysis shows that responses of PTH to vitamin D supplementation are not only determined by the baseline PTH levels and changes in vitamin D status, but also by age and mobility of the patients. Our results also suggest that PTH decreases quite linearly during vitamin D supplementation at any given 25-OHD level. Longitudinal vitamin D supplementation studies on populations with wide range of mobility and age are needed to further elucidate their confounding effects. In determining the sufficient doses of vitamin D supplementation and adequate 25-OHD levels, these confounding effects and the inter-individual variation in responses of PTH to vitamin D supplementation should be taken into account.

Vitamin D supplementation has no major effect on pain or pain behavior in bedridden geriatric patients with advanced dementia.

BACKGROUND AND AIMS: In a few, earlier, uncontrolled trials, alleviation of chronic pain has been documented by vitamin D supplementation. This randomized double-blind placebo controlled trial addressed the association between pain and vitamin D deficiency and the effects of vitamin D supplementation on pain in institutionalized aged patients. METHODS: 216 long-term care patients were enrolled in Helsinki, Finland. Pain was assessed by three tools: Resident Assessment Instrument (RAI), Discomfort Behavior Scale, and Pain Assessment in Advanced Dementia Scale. Scores for Cognitive Performance Scale (CPS) and other clinical assessments were also collected from the RAI-database. Levels of 25-hydroxyvitamin D (25- OHD) and parathyroid hormone were also determined. Patients in pain (n=202) were randomized into three treatment groups, each receiving 0, 400, or 1200 IU cholecalciferol per day, respectively. Assessments were repeated after six-month vitamin D supplementation. RESULTS: Patients were aged (84.5+/-7.5 yrs), demented (CPS= 4.9+/-1.4, range 1-6), and chronically bedridden. Pain was present in 38.4% to 83.8% of patients depending on assessment tool. Low 25-OHD levels (<50 nmol/L) were very common (98.1%). However, vitamin D deficiency was not associated with pain or pain behavior. The supplementation resulted in a marked increase in 25-OHD levels. However, neither prevalence of painlessness nor pain scores changed significantly after vitamin D supplementation. CONCLUSIONS: We were not able either to show an association between vitamin D deficiency and pain or to observe alleviation of pain by vitamin D supplementation. The independent role of vitamin D in the etiology of pain remains controversial.

Elevated serum parathyroid hormone predicts impaired survival prognosis in a general aged population.

OBJECTIVE: Short-term studies on selected patients have indicated that elevated serum parathyroid hormone (PTH) is an independent risk factor of death. However, long-term data on unselected populations are lacking, thus far. In order to evaluate the predictive value of elevated serum PTH during the last years of life, random persons of age cohorts of 75, 80 and 85 years were followed for 17 years. DESIGN: A prospective cohort study. METHODS: Subjects (n=567) were investigated for calcaemic status including serum intact PTH, serum total calcium (CaT) and ionized calcium (Ca(2+)). Thorough clinical examinations included an assessment of co-morbidity. Mortality data were collected from National Census Records. RESULTS: Up to 93% of the subjects died within the follow-up. In contrast to Ca(2+) levels, high serum PTH (> or =63 ng/l, IV quartile cut point) was associated with significant over-mortality (HR=1.56, 95% CI: 1.29-1.88) and a 2.3-year reduction of median life expectancy. After controlling for age, gender, co-morbidity and creatinine, the prognostic impact of elevated serum PTH was still significant (HR=1.24, 95% CI: 1.01-1.53). The tendency for over-mortality was consistent in both genders, in all age groups as well as in subjects with varying co-morbidity, renal function, body mass index categories and Ca(2+) levels. CONCLUSIONS: Elevated serum PTH level is an independent predictor of impaired long-term survival prognosis in unselected aged population. Serum Ca(2+) did not emerge as a significant prognostic indicator. The long-term prognostic impact of vitamin D deficiency, the most common cause of elevated PTH levels in the elderly, remains to be investigated.

Vitamin D supplementation has minor effects on parathyroid hormone and bone turnover markers in vitamin D-deficient bedridden older patients.

OBJECTIVES: to evaluate the effects of vitamin D supplementation on parathyroid function and bone turnover in aged, chronically immobile patients. DESIGN: a randomised double-blind controlled trial. SUBJECTS: two hundred and eighteen long-term inpatients aged over 65 years. INTERVENTION: the patients were randomised into treatment groups of I-III, each receiving 0 IU, 400 IU and 1200 IU cholecalciferol per day, respectively. In case of inadequate consumption of dairy products, patients received a daily calcium substitution of 500 mg. MEASUREMENTS: plasma concentrations of 25-hydroxyvitamin D (25-OHD), intact parathyroid hormone (PTH), amino-terminal propeptide of type I procollagen (PINP), a marker of bone formation, and carboxy-terminal telopeptide of type I collagen (ICTP), a marker of bone resorption, were measured at baseline and after 6 months. RESULTS: the patients (age 84.5 years) were chronically bedridden. The baseline 25-OHD was low (23 nmol/l), correlated inversely with PINP, and tended to associate inversely with PTH. The prevalence of vitamin D deficiency (VDD) (25-OHD < 50 nmol/l) was 98% and PTH was elevated in 23% of the patients. Vitamin D supplementation significantly increased 25-OHD concentrations (124% group II, 204% group III) and decreased PTH (-7% group II, -8% group III). PINP tended to decrease, but ICTP tended to increase, and only their ratio decreased significantly. The tendency of ICTP to increase was inconsistent. Changes in 25-OHD correlated inversely with those in PTH and PINP. CONCLUSIONS: vitamin D supplementation has minor effects on PTH and bone turnover in chronically immobilised aged patients with VDD. Further comparative studies and meta-analyses are warranted to elucidate the confounding effects of different mobility levels on the benefits of vitamin D supplementation in patients with differing baseline PTH levels.