PINP Levels Research Articles

Radiation-induced changes in skin type I and III collagen synthesis during and after conventionally fractionated radiotherapy

Background and purpose To measure local changes of collagen metabolism in irradiated breast skin and systemic changes in serum during and after radiotherapy and correlate these changes with skin thickness, erythema and palpable subcutaneous induration. Patients and methods Aminoterminal propeptides of type I and type III procollagens (PINP and PIIINP, respectively) were measured from skin suction blister fluid (SBF) in 21 breast cancer patients with breast conserving surgery and conventionally fractionated radiotherapy (RT) to a total dose of 50 Gy. Suction blisters were induced in the operated and contralateral breast skin before RT, at 2.5 weeks, at the end of RT, and at 1, 4, 7, 12 and 24 months post-treatment. Blood samples for serum were taken simultaneously with SBF induction. Skin thickness of the suction blister sites was measured with a high-frequency ultrasound device. The investigated sites were scored for erythema at the end of RT and palpable subcutaneous induration at 1 and 2 years post-treatment. Results In SBF the mean levels of PINP and PIIINP of the operated breast before RT were about 3–4 times higher than those in the contralateral breast due to the operation-related wound healing. The synthesis of PINP in irradiated breast after RT increased 7.7-fold ( P<0.001) 4 months post-irradiation. The PIIINP synthesis was at maximum at 1 month post-irradiation ( P<0.001). Both synthesis stayed elevated until 2 years. The level of PINP correlated significantly with the palpable skin induration at 1 and 2 years ( P=0.038 and P=0.003, respectively). The skin thickness of the irradiated breast was highest at 4 months post-treatment and significantly elevated until 1 year. The skin thickness correlated with the PINP level until 7 months and with PIIINP between 4 and 18 months. The PINP/PIIINP ratio reached the maximum at 4 months and stayed elevated until 2 years. No change in mean serum level of PINP was found during or after RT. Conclusions We demonstrated a maximum and elevated levels for PINP and PIIINP skin collagen metabolism determined from SBF during the 2 years' follow-up. Elevated levels of PINP and PIIINP correlated with the thickening of the skin and subcutaneous induration but not with erythema.

Osteoblast recruitment from stem cells does not decrease by age at late adulthood

This study was aimed to characterize the ability of human bone marrow mesenchymal stem cells (MSC) to differentiate into osteoblasts in vitro. Twenty-three women and 20 men at late adulthood (52–92 years of age) were selected for the study. MSCs were isolated and cultured in vitro and alkaline phosphatase (ALP) activity, secretion of amino-terminal propeptide of type I procollagen (PINP), type III procollagen (PIIINP) and osteocalcin were analyzed. Matrix mineralization was analyzed by the von Kossa staining and by calcium quantification. We found that the ALP and PINP levels compared with control increased to 2.8- and 2.9-fold, respectively, when cells were cultured for three weeks. ALP activity, PINP and calcium deposition in response to dexamethasone treatment increased by age in women and was unchanged in men. Overall our data suggests that the osteogenic potential of MSCs does not decrease by age in either women or men at late adulthood.

Effects of short‐term dexamethasone treatment on collagen synthesis and degradation markers in preterm infants with developing lung disease

Aim: To assess the effects of dexamethasone treatment on collagen turnover in preterm infants. Methods: The serum concentrations of the amino‐terminal propeptide of type I and III procollagens (PINP and PIIINP), which reflect rates of type I and III collagen synthesis, respectively, and the carboxyterminal telopeptide of type I procollagen (ICTP), which reflects the rate of type I collagen degradation, were monitored in 13 preterm infants receiving dexamethasone and 13 matched control infants without glucocorticoid treatment for a total period of 12 mo. Dexamethasone was started at a median age of 12 d and continued at tapering doses for a median total duration of 10 d. Blood samples were taken immediately after birth, at 7, 14 and 28 d of age and at 2, 3, 6, 9 and 12 mo. The same markers were also measured just before the initiation of dexamethasone and on days 1, 3, and 7 of treatment. Results: A striking decrease in all of the markers was already observed in every case on day 1 of dexamethasone, the suppression being greatest on day 3 and still considerable on day 7. The percentages from the pretreatment levels recorded on days 1, 3 and 7 were: for PINP 51, 26 and 45%; for PIIINP 63, 44% and 52%; and for ICTP 64, 41 and 51%. A rebound rise in PINP levels was seen in dexamethasone‐treated infants, the levels exceeding those of the controls at 3 and 6 mo of age. A similar phenomenon was noted concerning PIIINP at 3 mo. The levels settled down at 9 and 12 mo. Conclusion: Dexamethasone causes an immediate, inevitable, deep suppression of type I and III collagen synthesis and also type I collagen degradation. This should be taken into consideration, e.g. when assessing for the indications for steroid treatment in sick preterm infants and its dosing and duration.

A New Dimension of DNA Analysis: Genomic Profiling by Matrix CGH, Abstract 172, State-of-the-art lecture

Peripheral vasculature undergoes extensive vascular remodeling in the hypertensive state. Regulation of extracellular matrix turnover by the matrix metalloproteinase (MMP) system is an important step in the vascular remodeling process. However, the expression pattern of the vascular MMP system in human hypertension remained unknown.Internal mammary artery specimens were obtained from normotensive (n = 13) and hypertensive (n = 19) patients undergoing coronary artery bypass grafting surgery. Zymographic analysis indicated a threefold decrease in total gelatinolytic activity of MMP-2 and MMP-9 in hypertension. MMP-1 activity was also decreased by fourfold without a significant change in protein levels. Tissue levels of extracellular matrix inducer protein (EMMPRIN), MMP activator protein (MT1-MMP), MMP-1, MMP-2, and MMP-9, as well as tissue inhibitors of MMPs (TIMP-1 and TIMP-2) were assessed by immunoblotting and yielded a significant decrease in MMP-9, EMMPRIN, and MT1-MMP levels in hypertension. In addition, measurement of plasma markers of collagen synthesis (procollagen type I amino-terminal propeptide [PINP]) and collagen degradation (carboxy-terminal telopeptide of collagen type I [ICTP]) indicated no difference in PINP levels but suppressed degradation of collagen in hypertension. Evaluation of profibrotic growth factors demonstrated higher levels of fibroblast growth factor (FGF)-2 in tissue preparations from hypertensive patients but no difference in transforming growth factor-β1 levels.These findings demonstrate that not only MMP-1 and MMP-9, but MMP inducer and activator proteins are also downregulated in the hypertensive state. Augmented FGF-2 levels may contribute to parallel decreases in MMP activity and MMP induction system resulting in enhanced collagen deposition in hypertension.

Clinical usefulness of the serum N-terminal propeptide of type I collagen as a marker of bone formation in hemodialysis patients

Background: An intact collagen I amino-terminal propeptide (PINP) assay has been developed as a useful assay for bone formation. The present study was performed to investigate the clinical usefulness of serum PINP as a bone-formation marker in hemodialysis (HD) patients. Methods: PINP and other bone-formation markers, ie, bone alkaline phosphatase (BAP) and intact osteocalcin (OC), were determined in serum samples collected from 209 HD patients. Results: Serum PINP levels, in contrast to serum BAP and OC levels, did not change significantly during a single HD session (P = 0.069; n = 14). There were significant positive correlations between serum PINP and BAP (r = 0.723; P < 0.001) and OC values (r = 0.739; P < 0.001), as well as intact parathyroid hormone (r = 0.652; P < 0.001) and bone-resorption marker values: deoxypyridinoline (DPD; r = 0.823; P < 0.001), pyridinoline (PYD; r = 0.735; P < 0.001), and β-crosslaps (r = 0.705; P < 0.001). Serum PINP values correlated significantly more strongly than serum BAP values with all bone-resorption markers. Serum PINP values significantly correlated negatively with annual changes in bone mineral density (BMD) in the distal third of the radius (r = −0.286; P < 0.001). When subjects were divided into tertiles according to degree of bone loss, subjects with greater bone loss had significantly greater serum PINP, BAP, and OC levels, although PINP and OC provided greater discrimination than BAP. PINP-PYD and PINP-DPD ratios, indices of osteoblast function not confounded by enhanced bone resorption, significantly positively correlated with annual BMD changes in the distal third of the radius (PINP-PYD ratio, P = 0.008; PINP-DPD, P = 0.015). Conclusion: Serum PINP may provide a better marker of osteoblast function in HD patients and thus be clinically useful for predicting radius bone loss. © 2002 by the National Kidney Foundation, Inc.

Extracellular matrix building marked by the N-terminal propeptide of procollagen type I reflect aggressiveness of recurrent breast cancer.

The purpose of our study was to examine the association between extracellular matrix homeostasis and aggressive breast cancer as reflected by the synthesis of type I collagen marked by circulating concentration of the aminoterminal propeptide of type I procollagen (PINP). Pre-therapeutic serum PINP concentrations were measured in 154 healthy women and 100 patients referred with their first metastatic manifestation of breast cancer and correlated to the metastatic pattern, response to therapy, time to progression and survival with a minimal follow-up of 5 years. Fifty-four percent of the patients had serum PINP concentrations greater than the 95th percentile of the healthy controls and 38% were high PINP level patients with values clearly outside normal range (>125 ng/ml). Patients with high PINP levels were more sick (p = 0.002), had a higher tumor burden (p = 0.013) and revealed a lower responsiveness to anthracycline-based therapy (p = 0.0002) as well as an accelerated time to disease progression (p = 0.00001) and death (p = 0.0006). Median survival in the high serum PINP level group was less than half of that in the group with low PINP level (14.5 vs. 32 months). The lowest PINP levels were seen when the cancer was restricted to the lymph node and skin and increasing PINP levels were found if the cancer had spread to the lungs, the bones, the bone marrow and the liver. High PINP level at recurrence and lack of estrogen receptors (ER) independently reflected aggressive tumor behavior after recurrence with an equal great impact on time to progression and survival. Patients with a high PINP level and primarily ER-negative tumors survived a median of only 6 months with no one alive after 22 months. By contrast patients with a low PINP level and ER-positive tumors had a median survival of 37 months and 23% were still alive after 5 years. Aggressive breast cancer induces a strong fibroproliferative response with synthesis of type I collagen. Serum PINP levels may be a diagnostic and prognostic tool that indicate breast cancer activity, aggressiveness, expansion and metastasis and a predictor of outcome after anthracycline-based chemotherapy.

Effect of short‐term antenatal dexamethasone administration on type I collagen synthesis and degradation in preterm infants at birth

To assess the effects of antenatal corticoid administration on foetal collagen metabolism, cord serum concentrations of the aminoterminal propeptide and carboxyterminal telopeptide of type I procollagen (PINP and ICTP), which reflect rates of type I collagen synthesis and degradation, respectively, were measured in 67 consecutive preterm infants with gestational ages ranging from 24 to 32 wk. The samples were divided into three groups, depending on the administration and timing of antenatal corticosteroid treatment for enhancement of foetal lung maturity: cases in which the mothers had received a full 2-dose administration of dexamethasone on consecutive days 1 to 6 d before delivery (n = 23; Complete-Dexa), those who had received only a single dose of dexamethasone less than 24 h before delivery (n = 17; Partial-Dexa) and those who had not received any antenatal steroids (n = 27; No-Dexa). Infants in the Complete-Dexa group had significantly lower median PINP levels than those in the No-Dexa group (3,326 vs 4,028 microg/l; p = 0.036); the median PINP level in the Partial-Dexa group (3,999 microg/l) was close to that of the No-Dexa group. No significant differences in ICTP concentrations were seen between the groups. A significant suppression of foetal collagen synthesis but not degradation was found to be associated with antenatal dexamethasone administration. This should be taken into consideration, e.g. when assessing whether to administer repeated or single courses of corticosteroids antenatally in high-risk pregnancies.

Type I collagen markers in cord serum of appropriate vs. small for gestational age infants born during the second half of pregnancy

The serum concentration of the N-terminal propeptide of type I procollagen (PINP) reflects the synthesis rate of type I collagen, whereas the corresponding C-terminal telopeptide (ICTP) mirrors its degradation. PINP and ICTP were measured in a total of 690 cord serum samples from 592 appropriate-for-gestational-age (AGA) infants and 98 smal-for-gestational-age (SGA) infants. These markers were compared between AGA and SGA infants of different gestational ages, ranging from 23 to 41 weeks, and birth weights, from 620 to 4555 g. Both PINP and ICTP levels were very high in the preterm AGA infants and declined significantly with advancing gestational age, paralleling the shape of the fetal growth velocity curve. Regardless of the quite large interindividual variations observed in these markers, PINP was significantly lower in both the preterm and term AGA infants than in the SGA infants. This was also the case for ICTP in the preterm infants of gestational age less than 36 weeks. In stepwise multiple regression analyses, gestational age, being either AGA or SGA and head circumference were significant factors to explain the levels of PINP and ICTP. The levels of PINP and ICTP were correlated with each other highly significantly in both the AGA and SGA infants (rs = 0.700 and 0.692, respectively; P < 0.001 in both). The levels of type I collagen markers seem to follow closely the shape of the fetal growth velocity curve during different stages of gestation. However, because of the large interindividual variations observed, further studies are needed before the significance of these markers for the assessment of normal and abnormal fetal growth can be established.

The serum level of the amino-terminal propeptide of type I procollagen is a sensitive marker for prostate cancer metastasis to bone.

To assess the level of a bone-formation marker, the amino-terminal propeptide of type I procollagen (PINP), for its utility in indicating bone metastasis in patients with prostate cancer. Several bone formation markers, i.e. PINP, the carboxy-terminal propeptide of type I procollagen (PICP), bone-specific alkaline phosphatase (BALP), and bone Gla protein (BGP), a bone resorption marker (pyridinoline cross-linked carboxy-terminal telopeptide, ICTP), and prostate specific antigen (PSA) were measured in 40 patients without and 25 patients with bone metastasis. No patient had undergone previous treatment, except for six who developed bone metastasis while undergoing hormone therapy. All markers except BGP were significantly higher in patients with bone metastasis than in those without. The levels of PINP correlated best with the extent of disease, although the levels of PSA, BALP and ICTP also correlated well. While PINP had the largest area under the receiver-operator characteristic curve, PSA, BALP and ICTP also produced useful curves. The bone formation marker PINP seems to be useful for discriminating patients with and without bone metastasis. PINP may help in the early and accurate diagnosis of bone metastasis in such patients.

The luteinising hormone–releasing hormone analogue triptorelin with or without the aromatase inhibitor formestane in premenopausal breast cancer: effects on bone metabolism markers

Background: the combination of a luteinising hormone–releasing hormone (LH–RH) analogue and an aromatase inhibitor (AI) induces greater oestrogen suppression than the analogue alone in premenopausal breast cancer. However, very few data on the biological effects of such a combination are currently available. Aim of the study: the short-term effects of treatment with the LH–RH analogue triptorelin alone or in association with the AI formestane on bone metabolism were investigated in premenopausal breast cancer. Circulating levels of the bone formation markers carboxy-terminal and amino-terminal propeptides of type I procollagen (PICP and PINP) and the bone resorption marker cross-linked carboxy-terminal telopeptide of type I collagen (ICTP) were assessed. In addition, serum levels of insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3 and interleukin 6 (IL-6) were evaluated. Patients and methods: twenty-one patients with advanced breast cancer were randomly given triptorelin monthly alone ( n=10, arm A) or in combination with formestane fortnightly ( n=11, arm B). Blood samples were collected over a 3-month period. Results: serum PICP and PINP levels increased significantly over time ( P=0.0065 and 0.0197 in arm A and B, respectively); no change in ICTP levels was observed. A rise in IGF-I and IGFBP-3 levels was seen in each treatment group, but only the increase in IGF-I was significant ( P=0.0138, always). The on-treatment levels of the bone turnover markers and IGF-system components were inversely correlated with serum oestrogens. Neither treatment modalities significantly affected serum IL-6 levels over time. No difference in the behaviour of any of the assessed biomarkers was observed between patients with or without skeletal metastases. Conclusion: it is worth noting that complete oestrogen depletion, at least in our case series, seems to increase only osteoblastic activity markers. The observed modifications appear to be related to oestrogen depletion per se rather than the degree of oestrogen suppression or the different therapeutic regimen administered.

Biochemical Markers as Predictors of Rates of Bone Loss After Menopause

Biochemical markers of bone turnover may correlate with rates of bone loss in a group of postmenopausal women, but it is uncertain how useful they are in predicting rates of bone loss in the individual. The aim of this study was to determine the value of measurements of biochemical markers for the prediction of rates of bone loss in the individual. We studied 60 postmenopausal women (ages, 49-62 years), 43 of whom had gone through a natural menopause 1-20 years previously and 17 of whom had undergone hysterectomy 3-22 years ago. Lumbar spine bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry (DXA) over 2-4 years. Bone formation markers (bone-specific alkaline phosphatase [ibAP] and amino terminal of type I collagen [PINP] and osteocalcin [OC]) were measured in serum. Bone resorption markers (N-telopeptide of type 1 collagen [NTx] and immunoreactive free deoxypyridinoline [iFDpd]) were measured in urine and corrected for creatinine (Cr). Rates of bone loss were calculated as percent change per year. We found significant negative correlations (Spearman rank) between all measured biochemical markers and rate of change in bone density with r values ranging from -0.35 to -0.52. When markers and rates of bone loss were divided into tertiles, prediction of bone loss in an individual was poor (kappa < 0.2). There was an exponential relationship between rate of bone loss and years since menopause (YSM) in the 43 women having a natural menopause (r2 = 0.44; p = 0.008) indicating higher rates of loss in the early postmenopausal period. Levels of NTx, iFDpd, and PINP also showed a significant negative correlation with YSM. We conclude that there is a strong relationship between rates of spinal bone loss and levels of bone turnover markers. Although this is a small study, the results also suggest that using DXA measurements of the lumbar spine as the "gold standard," it is not possible to use biochemical markers to predict rate of bone loss in the individual.

Bone mineral density and serum levels of aminoterminal propeptides and cross-linked N-telopeptides of type I collagen in elderly men

Serum levels of aminoterminal extension propeptides (PINP), the carboxyterminal telopeptide (ICTP), and the cross-linked N-telopeptides (NTx) of type I collagen were determined in 78 healthy, elderly men aged 76 ± 5 years in 1993 and 1996 and compared with bone mineral density (BMD) measurements of their lumbar spine, femoral neck, and total body regions made using dual X-ray absorptiometry. Compared with 11 men who had normal lumbar spine (SBMD) and femoral neck BMD (NBMD), 13 of the subjects with SBMD and NBMD classified as osteopenic by t-score criterion had higher mean serum levels of PINP and alkaline phosphatase activity, but these increases were not statistically significant at the 95% confidence interval. In osteopenic men, a correlation between SBMD and NTx was detected ( r = −0.66, p = 0.01). Within the entire population, the serum NTx level correlated with NBMD ( r = −0.26, p < 0.05) and PINP ( r = +0.63, p < 0.0001), and the change in the circulating concentration of PINP over the 3 year interval correlated with the magnitude of change in total body BMD ( r = −0.28, p = 0.02), NBMD ( r = −0.24, p = 0.05), and SBMD ( r = −0.36, p = 0.03) as well as with the change in serum NTx levels ( r = 0.43, p < 0.001). The change in the circulating ICTP level was also related to the change in NBMD ( r = −0.24, p = 0.01). Together, weight and the serum PINP level accounted for 25% of total body BMD variance in elderly men. These results indicate that larger populations of men and women should be screened over longer time intervals to explore the value of serial measurement of serum collagen metabolites in predicting bone loss in the spine and hip.

Bone ultrasonometry and turnover markers in primary hyperparathyroidism.

Quantitative ultrasound (QUS) of bone and new markers of bone remodeling have been poorly investigated in mild primary hyperparathyroidism (PHPT). In this study 26 patients (20 females and 6 males) were evaluated. BUA and SOS were measured by QUS at the heel. Markers of bone remodeling assessed were bone alkaline phosphatase (BAP), osteocalcin (OC), procollagen type I N- and C-terminal propeptides (PINP et PICP), and procollagen type I C-terminal telopeptide in blood and urine (ICTP and CTX). Bone mineral density (BMD) was measured at the lumbar spine (LS), femoral neck (FN), and Ward's triangle (WT). The control group comprised 35 sex- and age-matched subjects. The statistically significant variables between the two groups were (P < 0.05) BUA, BMD(LS), BMD(FN), BMD(WT), BAP, and OC. Corresponding z-scores were -0.55 +/- 0.75, -0.66 +/- 0.77, -0.66 +/- 0.71, -0.67 +/- 0.52, 1.87 +/- 3.87, and 1.93 +/- 3.53, respectively. Although PICP and PINP levels were higher in PHPT patients as compared with controls, the difference was not significant. Several markers of bone turnover were moderately correlated with both QUS (r = -0.39 to -0.55) and BMD (r = -0.48 to 0.63). In conclusion QUS seems to be a relevant tool in the assessment of bone status for patients with mild PHPT.

A variation in Bone Alkaline Phosphatase levels that correlates positively with bone loss and normal levels of aminoterminal propeptide of collagen I in girls with anorexia nervosa

Anorexia nervosa (AN) is a very extended pathology among adolescent girls nowadays. These patients show a high degree of osteopenia; hence, study of their bone remodelling is of great interest. Serum bone alkaline phosphatase (bAP) and aminoterminal propeptide of procollagen I (PINP) provide good sensitivity in the analysis of bone alterations in postmenopausal osteoporosis. The aim of this study was to compare the usefulness of bAP and PINP in the study of bone remodelling in AN, and their possible correlation with the degree of osteopenia in this pathology. In order to help in the interpretation of the results, levels of the β-isomer of urinary carboxyterminal propeptide of collagen I (β-CTX) have also been included. Serum bAP (IRMA) Tandem R-Ostase, Hybritech), PINP (RIA, Orion Diagnostica) and CTX (CrossLaps ELISA, Osteometer) were determined in 41 girls with AN, aged 18.5±2.2 years (mean±SD) and in 31 healthy control women, aged 19±2.3 years. Bone mineral density (BMD) in lumbar spine was measured by DEXA in the AN group. We found that 41 of the 43 patients had BMD z-scores under −2. No significant differences were found in the levels of serum bAP nor in PINP and β-CTX levels between controls and patients, although values in the AN group were highly variable. All the BMD z-score values were negative, and their absolute value correlates positively with bAP ( P=0.0279) and almost with β-CTX ( P=0.0921) but not with PINP ( P=0.4627). Bone AP correlates with PINP in control girls ( P=0.017), but not in the AN group ( P=0.3573). Patients with AN were divided into three groups according to their levels of bAP: low (I), normal (II) or high (III). Patients with the highest bAP levels also presented the highest increase in bone resorption, according to their β-CTX levels, and the highest degree of osteopenia. However, values of PINP were similar in the three groups of patients. The bAP/β-CTX ratios in subgroups I, II and III of AN patients were 0.035, 0.065 and 0.073, a finding that suggests that bAP is not indicating the real degree of bone mineralization in these patients, because it is a contradiction that the formation/resorption ratio should be higher in the patients who have the highest bone loss. These results could suggest that bone loss in AN is produced by an increase in bone resorption (β-CTX), without variations in bone matrix formation (PINP); bAP levels are a good marker in the follow-up of osteopenia degree, but not a real indicator of bone mineralization, a similar situation to that of osteomalacia.

Bone density and bone metabolism are normal after long-term gluten-free diet in young celiac patients

Objectives: Osteoporosis and alterations of bone metabolism are frequent complications of celiac disease. We evaluated the impact of long-term gluten-free diet (GFD) initiated during childhood and adolescence on bone mineralization and bone metabolism. Methods: We studied 30 celiac patients on GFD for ≥5 yr. The mean age at diagnosis was 11.4 ± 5.0 yr, and the mean duration of GFD was 10.7 ± 4.3 yr. Results were compared with those obtained in 240 healthy controls. Bone mineral density (BMD) was measured in the lumbar spine and in the whole skeleton by dual-energy x-ray absorptiometry. Serum levels of bone-specific alkaline phosphatase (BALP) and N-terminal propeptide of type I procollagen (PINP) were measured as bone formation indices, and urine levels of N-telopeptide of type I collagen (NTx) as bone resorption index. Results: BMD measurements of celiac patients (lumbar spine: 1.131 ± 0.121 g/cm 2; total body: 1.145 ± 0.184 g/cm 2) did not differ from those of control subjects (lumbar spine: 1.131 ± 0.184 g/cm 2; total body: 1.159 ± 0.118 g/cm 2). The levels of BALP, PINP, and NTx of celiac patients did not differ from those of controls. Patients who started GFD before puberty had BMD and bone metabolism measurements comparable to those of patients who started GFD during puberty. Conclusions: Our data show that long-term dietary treatment ensures normal mineralization and bone turnover.

Bone density and bone metabolism are normal after long-term gluten-free diet in young celiac patients.

Osteoporosis and alterations of bone metabolism are frequent complications of celiac disease. We evaluated the impact of long-term gluten-free diet (GFD) initiated during childhood and adolescence on bone mineralization and bone metabolism. We studied 30 celiac patients on GFD for > or = 5 yr. The mean age at diagnosis was 11.4+/-5.0 yr, and the mean duration of GFD was 10.7+/-4.3 yr. Results were compared with those obtained in 240 healthy controls. Bone mineral density (BMD) was measured in the lumbar spine and in the whole skeleton by dual-energy x-ray absorptiometry. Serum levels of bone-specific alkaline phosphatase (BALP) and N-terminal propeptide of type I procollagen (PINP) were measured as bone formation indices, and urine levels of N-telopeptide of type I collagen (NTx) as bone resorption index. BMD measurements of celiac patients (lumbar spine: 1.131+/-0.121 g/cm2; total body: 1.145+/-0.184 g/cm2) did not differ from those of control subjects (lumbar spine: 1.131+/-0.184 g/cm2; total body: 1.159+/-0.118 g/cm2). The levels of BALP, PINP, and NTx of celiac patients did not differ from those of controls. Patients who started GFD before puberty had BMD and bone metabolism measurements comparable to those of patients who started GFD during puberty. Our data show that long-term dietary treatment ensures normal mineralization and bone turnover.

Serum levels of cross-linked N-telopeptides and aminoterminal propeptides of type I collagen indicate low bone mineral density in elderly women

Levels of aminoterminal propeptide (PINP) and the cross-linked carboxyterminal (ICTP) and aminoterminal (NTx) telopeptides of type I collagen were determined in the sera of 202 healthy women, 60–90 years of age, and correlated with densitometric measurements of their lumbar spine, femoral neck, and total body regions. Total skeleton bone mineral density (BMD) was associated most strongly with serum NTx levels ( r = −0.51, p < 0.0001). Serum NTx and PINP levels correlated with BMD at all regions measured and were significantly increased in osteopenic women (16.0 vs. 13.3 nmol bone collagen equivalents/L for NTx, p = 0.0006 and 46.5 vs. 40.9 μg/L for PINP, p = 0.02). Elevations of NTx and PINP over a 3 year interval correlated with decreases in BMD measured at the femoral neck and to increases in serum concentration of alkaline phosphatase activity and ICTP. Serum levels of ICTP, NTx, PINP, ICTP, estrone, and alkaline phosphatase activity were correlated and serum NTx values were related to circulating thyroxine and intact parathyroid hormone levels. NTx and PINP levels were significantly decreased in the sera of women receiving estrogen replacement therapy (12.0 vs. 14.8 nmol bone collagen equivalents/L for NTx, and 35.5 vs. 45.2 μg/L for PINP, p < 0.001). Multiple regression analysis indicated that 42% of the variability observed in total skeletal BMD could be explained by age, weight, and serum levels of NTx and estrone. Within this model of covariance, the serum NTx level alone accounted for 10.1% of total body BMD variability.

Markers of bone turnover in patients with differentiated thyroid cancer with and following withdrawal of thyroxine suppressive therapy.

To study whether levothyroxine (LT4) suppressive therapy exposes patients with differentiated thyroid cancer (TC) to an increased risk of osteoporosis. Markers of bone formation (serum alkaline phosphatase (ALP), osteocalcin (OC), type I procollagen carboxyterminal (PICP) and aminoterminal (PINP) propeptide) and resorption (serum type I collagen carboxyterminal telopeptide (ICTP) and urine hydroxyproline (HOP)), as well as serum intact parathyroid hormone (PTH), 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D (1,25(OH)2-D) were measured in 29 patients (25 women, 4 men) with a median age of 45 years, and in 38 age- and sex-matched controls. In a subgroup of 14 patients the measurements were repeated after 5 weeks' interruption of LT4 therapy. Since the primary treatment of TC the patients had used TSH suppressive doses of LT4 (a mean daily dose of 215 microg) for 9 to 11 years. The bone mineral density (BMD) of patients and controls was measured by dual energy X-ray absorptiometry. When on T4 therapy, patients had significantly higher mean levels of ALP (+21%, P < 0.05), OC (+35%, P < 0.01), PICP (+10%, P < 0.05), PINP (+46%, P < 0.001), ICTP (+21%, P < 0.05), and HOP (+37%, P < 0.001) compared with controls. After stopping treatment, OC (-42%, P < 0.001), PINP (-7%, P < 0.05), and ICTP (-54%, P < 0.001) decreased, whereas PICP (+24%, P < 0.001) and 1,25(OH)2D (+29%, P < 0.01) increased. BMD of the lumbar spine and the upper femur was similar in patients and controls. Patients with differentiated TC have high bone turnover when on LT4 suppressive therapy, After withdrawing treatment both bone formation and resorption decrease acutely. During development of hypothyroidism, serum PICP and PINP, which form from the same type I procollagen molecule and should change similarly, behaved differently. This may be due to different effects of hypothyroidism on their removal through separate receptors in the liver.

Collagen-related markers of bone turnover reflect the severity of liver fibrosis in patients with primary biliary cirrhosis.

The influence of a nonskeletal disease with increased connective tissue synthesis or degradation in the collagen-related markers of bone turnover has been evaluated in 34 women with primary biliary cirrhosis (PBC; age range 41-81 years), a disease with increased hepatic fibrosis, often associated with osteoporosis. Serum osteocalcin (BGP), and carboxy-terminal (PICP) and amino-terminal (PINP) propeptides of type I collagen were assessed as indexes of bone formation, whereas serum tartrate-resistant acid phosphatase (TRAP), and cross-linked carboxy-terminal telopeptide of type I collagen (ICTP), and urinary hydroxyproline (HYP), pyridinoline (PYR), deoxypyridinoline (DPYR), and type I collagen cross-linked N- (NTX) and C-telopeptide (CTX) were measured as markers of bone resorption. The histologic stage of the disease and serum amino-terminal propeptide of type III collagen (PIIINP) as an index of liver fibrogenesis were also evaluated. BGP levels were significantly lower, whereas PICP and PINP levels were higher in patients than in controls. Among the bone resorption markers, serum ICTP and urinary PYR, DPYR, HYP, NTX, and CTX levels were significantly higher in patients than in controls. Serum PIIINP levels were also increased in PBC patients. BGP did not correlate with PICP and PINP, but these markers of bone formation as well as ICTP, PYR, DPYR, and NTX correlated with serum PIIINP levels. Serum TRAP did not correlate with collagen-related markers of bone resorption. Moreover, patients with PIIINP and bilirubin above normal levels had higher PICP, PINP, ICTP PYR, DPYR, CTX, and NTX. These markers correlated with the histologic stage of the disease, but not with osteopenia measured by densitometric procedures in 22 patients. In conclusion, collagen-related markers of bone turnover do not reflect bone remodeling in PBC. The close association of these markers with PIIINP and the clinical and histologic stage of the liver disease suggests that they are influenced by liver collagen metabolism.

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 aminoterminal (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.