I Collagen Carboxyterminal Telopeptide Research Articles

Clinical significance of serum BAP, TRACP 5b and ICTP as bone metabolic markers for bone metastasis screening in lung cancer patients

BackgroundWe investigated the clinical significance of serum bone-specific alkaline phosphatase (BAP), tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) and type I collagen carboxyterminal telopeptide (ICTP) as bone metabolic markers for bone metastasis (BM) screening in lung cancer patients. MethodsNewly diagnosed advanced lung cancer patients with (N=130) and without (N=135) BM were enrolled in the study. Serum BAP, TRACP 5b and ICTP were measured before the treatment. ResultsBAP, TRACP 5b and ICTP values were higher in patients with BM compared with patients without BM (all P<0.0001). Area under ROC curve (AUC) of BAP, TRACP 5b and ICTP was 0.760, 0.753 and 0.835 (all P<0.0001), respectively. The cut-off values for BAP, TRACP 5b and ICTP were 21.8μg/l, 7.8 U/l and 8.8μg/l, respectively. When TRACP 5b and ICTP were combined, AUC was elevated to 0.895 (P<0.0001), and the cut-off values were TRACP 5b 7.6 U/l and ICTP 8.4μg/l. ConclusionsWe conclude that serum BAP, TRACP 5b and ICTP may serve as useful tools for BM screening in lung cancer patients.

Mechanisms of treatment of cancer pain with a topical Chinese herbal formula in rats.

Pain has a substantial impact on patients' activities and overall quality of life, but current conventional drugs have debilitating side effects, including gastrointestinal disorders. Thus there is a pressing need for new therapies with fewer side effects to alleviate cancer pain. We recently developed a topical herbal formula Xiaotan Tongluo analgesic gel (XTTL gel) based on the principles of traditional Chinese herbalism, and we have received positive feedback from bone cancer pain patients. The aim of this study was to determine the analgesic effects and explore the mechanisms of XTTL gel in a rat model of bone cancer pain. The rat model of bone cancer pain was established by inoculating Walker-256 rat carcinoma cells directly into the right tibial medullary cavity of Wistar rats. The rats were randomly assigned to three groups (n = 10 per group): (1) sham bone cancer control (sham group): vehicle (PBS) inoculation without carcinoma cells plus topical administration of blank gel; (2) Sham treatment control (vehicle group): Walker-256 cell inoculation plus topical administration of blank gel; (3) XTTL gel treatment (treatment group): Walker-256 cell inoculation plus topical administration of XTTL gel. XTTL gel treatments were applied daily for 7 days starting on day 14 following inoculation. Outcomes were assessed 21 days after inoculation by mechanical allodynia, histological staining, and by measuring concentrations of type I collagen carboxy-terminal telopeptide (ICTP) and bone-specific alkaline phosphatase (BAP) in serum. Fourteen days after cancer cell incubation, significant mechanical allodynia in the ipsilateral hind paw and tumor growth in proximal end of the tibia were observed in the vehicle and treatment groups but not in the sham group. At day 21, mechanical withdrawal thresholds in treatment group rats were significantly higher ((4.8557 +/- 0.8336) g) compared with those of the vehicle group ((1.8630 +/- 1.4369) g, P < 0.05). ICTP and BAP levels increased significantly in vehicle group rats ((101.5176+/- 11.0694) U/L and (370.7838 +/- 12.8273) U/L, respectively) compared with those of the sham group ((11.7553 +/- 1.1885) U/L and (185.7338 +/- 3.6761) U/L, respectively; P < 0.05). XTTL gel decreased the level of blood serum ICTP ((41.8998 +/- 6.4970) U/L, P < 0.05) but had little effect on blood serum BAP ((365.5338 +/- 18.5361) U/L, P > 0.05). Topical use of XTTL gel may have an analgesic effect on bone cancer pain, an effect mediated by lowering of ICTP levels and inhibiting bone resorption.

Treatment with spironolactone for 24 weeks decreases the level of matrix metalloproteinases and improves cardiac function in patients with chronic heart failure of ischemic etiology

The myocardial extracellular matrix is believed to be central to the remodelling that takes place following myocardial infarction. The contribution of markers of collagen metabolism to this process remains less well understood. The present study examined the contribution of some of the markers of collagen metabolism in cardiac remodelling, as well as the effect of spironolactone on the remodelling process. To investigate the pathological contribution of markers of collagen metabolism, including matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), type I collagen carboxyterminal telopeptide (ICTP) and procollagen type I carboxyterminal propeptide (PICP), in cardiac remodelling following ischemic cardiomyopathy, and to examine the pharmacoregulatory effects of spironolactone on collagen metabolism. Eighty-six consecutive patients (62 men and 24 women) with chronic heart failure of ischemic etiology (patient group) and 25 age-matched controls were enrolled in the study. The subjects in the patient group were randomly assigned into a spironolactone or nonspironolactone group. Plasma levels of MMP-9, TIMP-1, ICTP and PICP were measured using ELISA and radioimmunoassay techniques. Furthermore, left ventricular diastolic diameter and ejection fraction were assessed using two-dimensional and Doppler echocardiography. The plasma concentrations of MMP-9, TIMP-1 and the MMP-9 to TIMP-1 ratio, as well as ICTP, were significantly increased in the patient group. The PICP to ICTP ratio in the patient group was significantly lower than that in the age-matched control subjects. After a follow-up period of 24 weeks, the PICP to ICTP ratio increased, and MMP-9, TIMP-1 and the MMP-9 to TIMP-1 ratio decreased in the spironolactone subgroup. Biomarkers of collagen degradation were elevated and correlated with depressed heart function; spironolactone may partially reverse the dysregulation in collagen metabolism.

Relationships between mandibular cortical bone measures and biochemical markers of bone turnover in elderly Japanese men and women

The aim was to clarify the association between dental panoramic radiography measures of mandibular inferior cortical shape and biochemical markers of bone turnover in elderly men and women. Subjects were 80-year-old men (n = 85) and women (n = 153). Mandibular cortical shape and width were evaluated on dental panoramic radiographs. Bone formation and resorption, respectively, were estimated by serum levels of carboxy-terminal propeptide of type I collagen (PICP) and serum type I collagen carboxy-terminal telopeptide (ICTP). Eroded cortices of the mandible were significantly associated with increased serum PICP levels (P = .005) in women. Lower mandibular cortical width quartiles were also significantly associated with increased serum PICP levels in men (P = .020) and women (P = .006). Mandibular inferior cortical measures detected on dental panoramic radiographs may be associated with bone formation rates and be useful in predicting osteoporosis in elderly Japanese men and women.

Genetic and Constitutional Influences on Bone Turnover Markers: A Study of Male Twin Pairs

Biochemical markers of bone turnover originating from type I procollagen synthesis or type I collagen breakdown were examined in men using a classic twin study design based on monozygotic (MZ) and dizygotic (DZ) twins. The aim was to estimate the influence of heredity (genes and shared family childhood elements) and constitutional factors in determining procollagen type I amino-terminal propeptide (PINP), type I collagen carboxy-terminal telopeptide (ICTP), and urinary amino-terminal type I collagen telopeptide (NTx) marker levels in a sample of in 98 MZ and 108 DZ male twin pairs. We are not aware of any prior studies conducted in men that address the influence of genetic factors on bone turnover marker variability. The findings support a dominant role for heredity in the variation of bone resorption marker levels in men, with additive genetic effects explaining two-thirds of the variance in the bone resorption markers NTx and ICTP. Genetic factors may contribute less for PINP, a marker of bone formation. The genetic loci influencing PINP or NTx and body weight/disc axial area, although related in part, appeared to be largely independent, indicating that genetic effects on bone turnover are unlikely to be to a large degree a result of genetic regulation of individual body weight.

Stimulated type I collagen turnover in patients with giant cell tumor of bone.

The aim of this study was to determine type I collagen turnover in giant cell tumor of bone (GCT) by biochemical markers of type I procollagen aminoterminal propeptide (PINP) and type I collagen carboxyterminal telopeptide (ICTP) as synthesis and degradation markers, respectively. The serum concentrations of PINP and ICTP were measured in 11 patients with GCT using radioimmunoassay, and analyzed by the correlation to the grades of GCT progression described by Campanacci. Serum of the 11 healthy subjects was available for comparison. The serum concentration of PINP was significantly higher in patients with GCT (82.4 +/- 46.2 ng/ml) than in controls (40.8 +/- 12.1 ng/ml) (P < 0.01), and that of ICTP was also significantly higher in GCT (5.3 +/- 2.0 ng/ml) than in controls (3.2 +/- 0.8 ng/ml) (P < 0.01). In GCT, the PINP concentration of grade 3 (127.6 +/- 38.8 ng/ml) was higher than that in grade 1 patients (46.9 +/- 4.8 ng/ ml) (P < 0.01). ICTP concentration of both grades 2 (7.1 +/- 1.4 ng/ml) and 3 (5.8 +/- 1.8 ng/ml) patients was significantly higher than that of grade 1 (3.5 +/- 0.6 ng/ ml) patients (P < 0.01, P < 0.05, respectively). Two cases of serum concentration of PINP and ICTP after resection of GCT demonstrated that these biomarkers decreased to the control levels in the absence of GCT. Our results indicated that type I collagen turnover evaluated by ICTP and PINP was stimulated in the presence of GCT. Moreover, this enhanced metabolic turnover reflects the grade of GCT.

Elevated serum markers of collagen degradation in patients with mild to moderate dilated cardiomyopathy.

Left ventricular (LV) dilation and myocardial remodelling are hallmarks of heart failure in idiopathic dilated cardiomyopathy (DCM). Interstitial collagen is essential for LV integrity and function while degradation of collagen by collagenases, especially matrix-metalloproteinases (MMPs), are suggested to contribute to ventricular dilation. In the present study, serological markers of collagen metabolism were investigated. Serum levels of MMP-1 and its inhibitor (TIMP-1), the markers for collagen degradation type I (collagen carboxyterminal telopeptide (ICTP)) and synthesis (carboxyterminal propeptide of type I procollagen (PICP)) were quantified by ELISA and RIA of 43 patients with DCM and 47 age-matched control subjects. Free MMP-1 serum concentration was significantly increased in the DCM group (5.29+/-0.83 vs. 2.22+/-0.29 ng/ml; P=0.01) as well as the free TIMP-1 concentration (206.54+/-12.65 vs. 181.44+/-8.55 ng/ml; P=0.05). The free MMP-1/TIMP-1-ratio was higher in DCM than in the control group (0.030+/-0.005 vs. 0.012+/-0.001; P=0.01). ICTP was significantly increased (7.60+/-1.21 vs. 3.44+/-0.19 microg/l; P<0.001). PICP was not significantly increased (125.29+/-8.93 microg/l vs. 113.11+/-5.47 microg/l; P=n.s.). Free MMP-1 and MMP-1/TIMP-1-ratio correlated with LV end diastolic diameter [cm/m(2) body surface area (BSA)] (r=0.28; P=0.03 and r=0.34; P=0.01, respectively) as well as with cardiac index (CI) (r=-0.32; P=0.04 and r=-0.33; P=0.04, respectively) in patients with DCM. Serum markers of collagen degradation are elevated and might be valuable markers for progression of LV dilation in patients with DCM.

Biochemical markers of bone metabolism in relation to adrenocortical and growth suppression during the initiation phase of inhaled steroid therapy.

Growth suppression is usually most evident during the first year of inhaled steroid therapy. Steroid-induced changes in bone metabolism may contribute to this growth suppression. The aim of the present study was to evaluate the changes in biochemical markers of bone metabolism in relation to adrenal and growth suppression during the initiation phase of inhaled steroid therapy. Seventy-five school-aged children with new asthma were enrolled into budesonide (BUD, n = 30), fluticasone propionate (FP, n = 30) or cromone (CROM, n = 15) treatment groups. BUD dose was 800 microg/d during the first two months and 400 microg/d thereafter. The respective FP doses were 500 and 200 microg/d. Biochemical markers of bone metabolism were measured before treatment and after 2 and 4 mo of therapy. In the control (CROM) group, the mean concentrations of serum osteocalcin (OC), carboxyterminal propeptide of type I procollagen (PICP) (formation markers) and type I collagen carboxyterminal telopeptide (ICTP) (degradation marker) tended to increase. In the BUD group, OC and PICP decreased during the 4 mo by a mean of 23% (p < 0.001) and 15% (p < 0.05), respectively, while ICTP did not change significantly. In the FP group, OC and ICTP decreased during the first 2 mo by a mean of 19% (p < 0.01) and 21% (p < 0.01), respectively, returning to the pretreatment level at 4 mo, while PICP tended to increase during the 4 mo (14%, p = 0.12). In the steroid treated children whose height SD score decreased during the first 12 mo of therapy, both OC and PICP decreased during the first 4 mo by a mean of 20% (p < 0.01) and 21% (p < 0.001), respectively. In those children who had no growth suppression, the changes were not significant: -4% in OC and +13% in PICP. Furthermore, in children who developed evidence of adrenocortical suppression (on the basis of a low-dose ACTH test), OC decreased more (23%, p < 0.01) than in those with normal adrenocortical function (10%, p = 0.06). In conclusion, both inhaled BUD and FP caused dose-dependent effects on biochemical markers of bone metabolism. The children who developed growth or adrenocortical suppression were likely to have changes also in bone metabolism.

Biochemical Markers of Bone Metabolism in Relation to Adrenocortical and Growth Suppression During the Initiation Phase of Inhaled Steroid Therapy

Growth suppression is usually most evident during the first year of inhaled steroid therapy. Steroid-induced changes in bone metabolism may contribute to this growth suppression. The aim of the present study was to evaluate the changes in biochemical markers of bone metabolism in relation to adrenal and growth suppression during the initiation phase of inhaled steroid therapy. Seventy-five school-aged children with new asthma were enrolled into budesonide (BUD, n = 30), fluticasone propionate (FP, n = 30) or cromone (CROM, n = 15) treatment groups. BUD dose was 800 μg/d during the first two months and 400 μg/d thereafter. The respective FP doses were 500 and 200 μg/d. Biochemical markers of bone metabolism were measured before treatment and after 2 and 4 mo of therapy. In the control (CROM) group, the mean concentrations of serum osteocalcin (OC), carboxyterminal propeptide of type I procollagen (PICP) (formation markers) and type I collagen carboxyterminal telopeptide (ICTP) (degradation marker) tended to increase. In the BUD group, OC and PICP decreased during the 4 mo by a mean of 23% (p < 0.001) and 15% (p < 0.05), respectively, while ICTP did not change significantly. In the FP group, OC and ICTP decreased during the first 2 mo by a mean of 19% (p < 0.01) and 21% (p < 0.01), respectively, returning to the pretreatment level at 4 mo, while PICP tended to increase during the 4 mo (14%, p = 0.12). In the steroid treated children whose height SD score decreased during the first 12 mo of therapy, both OC and PICP decreased during the first 4 mo by a mean of 20% (p < 0.01) and 21% (p < 0.001), respectively. In those children who had no growth suppression, the changes were not significant: −4% in OC and +13% in PICP. Furthermore, in children who developed evidence of adrenocortical suppression (on the basis of a low-dose ACTH test), OC decreased more (23%, p < 0.01) than in those with normal adrenocortical function (10%, p = 0.06). In conclusion, both inhaled BUD and FP caused dose-dependent effects on biochemical markers of bone metabolism. The children who developed growth or adrenocortical suppression were likely to have changes also in bone metabolism.

Doxycycline and tissue repair in rats

Iterations in collagen turnover are integral to tissue repair. Repair gone awry, as a result of excess collagen accumulation or degradation, can contribute to pathologic ventricular remodeling. Pharmacologic interventions that would attenuate either aspect of faulty repair have therefore attracted interest. Tetracyclines, which inhibit both collagen synthesis and degradation, as well as angiogenesis, may hold promise, unrelated to their antimicrobial properties, in this regard. Assessment of their potential in rodent hearts with experimental injury can be problematic, given the often microscopic nature of tissue repair and brief involvement of matrix metalloproteinases (MMPs). We therefore selected a subcutaneous model in which granulation and fibrous tissues form over several weeks in response to croton oil and where fibrous tissue is subsequently resorbed because of high levels of collagenolytic activity. Untreated rats were compared with those given daily oral doxycycline (40 mg/kg). We harvested pouch tissue and exudate weekly for 5 weeks to assess hydroxyproline concentration and MMP activity (gelatin substrate zymography) of pouch wall and mononuclear cell count of pouch exudate. At week 2, neovascularization in pouch wall was measured by means of intravenous infusion of carmine-red dye in gelatin. The resultant “vascular cast” was solubilized and dye content quantitated with the use of spectrophotometry. Serum was assayed weekly for type I collagen carboxyterminal telopeptide (ICTP), a marker of collagen degradation. During weeks 1 and 2 and compared with untreated controls, doxycycline-treated rats had attenuated pouch tissue weight, collagen concentration, MMP2 lytic activity and vascularity, and reduced exudate volume and mononuclear cells. In vitro, doxycycline inhibited tissue gelatinolytic activity in a dose-dependent manner. At weeks 4 and 5, pouches were larger and collagen concentration was higher in doxycycline-treated rats, and serum ICTP levels were reduced at weeks 3 and 4. During the initial phase of pouch development, doxycycline exerts an inhibitory effect on tissue formation, likely mediated through its attenuation of angiogenesis and modulations of collagen turnover. As repair proceeds in subsequent weeks, doxycycline retards collagen degradation and pouch resorption by inhibiting MMPs. Doxycycline offers a multifaceted pharmacologic profile with which to modify various aspects of tissue repair in the rat. (J Lab Clin Med 2002;139:295-302)

The role of cytokines in the changes in bone turnover following bone marrow transplantation.

Osteoporosis is a common disease among patients undergoing transplantation and a loss of bone mass is usually detected after bone marrow transplantation (BMT), particularly during the immediate post-BMT period. Post-BMT bone loss is primarily related to gonadal dysfunction and immunosuppression. Cytokines, especially interleukin 6, play an important role in the pathogenesis of postmenopausal osteoporosis. However, the pathogenetic role of cytokines in post-BMT bone loss is unknown and data on the changes of cytokines in accordance with bone turnover markers are scarce. The aim of this study was to assess the relationship between bone turnover markers and cytokines, which are regularly sampled at peripheral blood and bone marrow before and after allogeneic BMT. This prospective study included two analyses. The first was a study of 46 BMT recipients (M/F 28/18), examining the relationship between bone turnover markers and serum cytokines that were measured before and at 1 week, 2 weeks, 3 weeks, 4 weeks and 3 months after BMT. Serum intact parathyroid hormone was measured before BMT and at 3 weeks after BMT and its relation to other cytokines and bone turnover markers was evaluated. The second analysis was a study of 14 (M/F 9/5) of 46 patients in whom bone marrow plasma cytokines [interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha)] were measured at 3 weeks after BMT. The relationship between bone marrow plasma cytokines and bone turnover markers was studied because bone marrow is the microenvironment where the real changes in bone turnover occur. Serum type I collagen carboxyterminal telopeptide (ICTP), a bone resorption marker, increased progressively until 4 weeks (peak) after BMT and then decreased thereafter. Serum osteocalcin, a bone formation marker, decreased progressively until 3 weeks after BMT and then increased thereafter. Serum IL-6 increased until 2 weeks after BMT and declined thereafter. Serum TNF-alpha increased until 3 weeks after BMT and declined thereafter. There was a significant positive correlation between serum ICTP and bone marrow IL-6 levels at 3 weeks after BMT, when a marked change in bone metabolism occurs following BMT. However, a correlation between bone turnover markers and bone marrow TNF-alpha or peripheral blood cytokines was not found. At 3 months after BMT, there was a significant negative correlation between the mean daily steroid dose and the serum osteocalcin level (r = -0.43, p < 0.05). The correlation between the Mean daily steroid dose and serum ICTP was also significant (r = 0.41, p < 0.05). Our data suggest that the progressive increase in bone resorption during the immediate post-BMT period is related to both steroid dose and the increase in bone marrow IL-6, which is a potent stimulator of bone resorption in vivo.

Relation of collagen type I alpha 1 (COLIA 1) and vitamin D receptor genotypes to bone mass, turnover, and fractures in early postmenopausal women and to hip fractures in elderly people

Background: In a previous study, we showed an association between the vitamin D receptor (VDR) gene BsmI restriction fragment polymorphism and peak bone mass in young Finnish adults. Design: The previous finding prompted us to study the relationship of the same polymorphism, as well as of the polymorphism in the Sp1 binding site of the collagen type I alpha 1 (COLIA 1) gene, to bone mineral density (BMD). BMD was measured by dual-energy X-ray absorptiometry and adjusted for age, weight, height, and lifestyle factors. Also studied was the relationship of VDR and COLIA 1 genotypes to markers of bone turnover [serum osteocalcin, type I procollagen carboxy- (PICP), and aminoterminal (PINP) propeptide, and type I collagen carboxyterminal telopeptide (ICTP)] and bone fractures in 513 early postmenopausal women (1–5 years postmenopausal), as well as hip fractures in 172 very old people. Results: The BB, Bb, and bb genotypes of the VDR gene, as well as the SS, Ss, and ss genotypes of the COLIA 1 gene, were distributed similarly among 402 early postmenopausal women with osteopenia in the lumbar spine and among 111 women with normal BMD ( P=0.12 for VDR, P=0.53 for COLIA 1). There was no relation between the VDR and COLIA 1 genotypes and lumbar spine BMD among osteopenic women, among normal women, or in the combined study population. Among the women with vertebral osteopenia, the femoral neck BMD did not associate significantly with the VDR or COLIA 1 polymorphisms. The frequencies of the different VDR and COLIA 1 genotypes were similar among women with or without a history of a low-energy fracture. There was a borderline association between the VDR genotype and serum osteocalcin concentrations, with the Bb genotype associated with the highest median level ( P=0.037). In a population-based sample of very old individuals (>85 years), the frequencies of the different VDR and COLIA 1 genotypes were similar among those with ( n=64) and without ( n=108) a history of hip fracture. Conclusion: The present data suggest that, in the Finnish population, the VDR and COLIA 1 genotypes do not determine the bone mass of early postmenopausal women or their bone turnover rate. The polymorphisms are not associated with risk of hip fractures in elderly people or with low-energy fractures in early postmenopausal women.

Efecto de budesonida sobre la densidad y el metabolismo óseo en niños asmáticos

To assess the effect of inhaled budesonide on the mineral density, content and bone metabolism in children with asthma. From September 1996 to July 1997, a cross-sectional study was conducted in 38 prepubertal children aged 6 to 11 years, selected from the pediatric chest outpatient clinic of the Instituto Autónomo Hospital Universitario de Los Andes, Mérida, Venezuela. Three study groups were assembled: 9 asthmatic children treated with inhaled budesonide (300 micrograms/day) for over 6 months (Group A); 14 asthmatic children not treated with inhaled corticosteroids (Group B); and 15 non-asthmatic children (Group C). All of them underwent testing of bone formation and resorption markers, and measurement of bone mineral density (DMO) and content (CMO). Statistical analysis consisted of central tendency and dispersion measures, analysis of variance, and Fisher and Scheffe tests for comparison of means. In the groups studied (A, B, and C) calcium serum levels were 9.1 +/- 0.3; 9.6 +/- 0.4; 9.3 +/- 0.6 mg/ml, respectively; osteocalcin levels were 14.8 +/- 4.6; 13.0 +/- 2.5; 11.9 +/- 3.4 ng/dl; the type I collagen carboxyterminal telopeptide (ICTP) levels were 19.6 +/- 16.5; 14.2 +/- 15.4; 13.0 +/- 18.3 micrograms/l; the DMO levels were 0.67 +/- 0.06; 0.68 +/- 0.06; 0.69 +/- 0.06 g/cm2; and the CMO levels were 1,158.8 +/- 217.4; 1,106.4 +/- 256.1; 1,176.5 +/- 240.5 g, respectively. No statistically significant differences were observed between the groups. The administration of 100-400 micrograms/day of inhaled budesonide for a period of six months, did not change the bone mineral density and metabolism of asthmatic children.

Does apolipoprotein E genotype relate to BMD and bone markers in postmenopausal women?

Objectives: Bone mineral density (BMD) and development of osteoporosis are partly determined by genetic factors. The associations between one of suggested candidate, apolipoprotein E (apo E) genotype to bone mineral density (BMD) and bone biochemical markers was studied in 464 subjects recruited from a population-based group of early postmenopausal women ( n=13 100). Additionally, the influence of apo E genotype on BMD changes during a 5-year follow-up with or without hormone replacement therapy (HRT) was investigated. Methods: Participants were randomized into two treatment groups: HRT group: Sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate with or without vitamin D 3, 100–300 IU/day+calcium lactate, 500 mg/day ( n=232), and the non-HRT group: Calcium lactate, 500 mg/day alone or in combination with vitamin D 3, 100–300 IU/day ( n=232). BMD was measured from the lumbar spine and proximal femur at baseline and after 5 years of treatment ( n=352). In a subgroup ( n=59), the serum concentrations of bone biochemical markers (intact osteocalcin (OC), bone-specific alkaline phosphatase (BAP) and type I collagen carboxy-terminal telopeptide (ICTP)) were measured at baseline and after 1 year of follow-up. Results: At baseline, the BMDs were similar between the five apo E genotype groups (2/3, 2/4, 3/3, 3/4, 4/4). No significant differences in lumbar or femoral neck BMDs of women with the apo E4 allele were found compared with those without it. There was a statistically significant difference in 5-year BMD changes between the HRT and non-HRT groups. After 5 years, the BMD of the femoral neck had remained constant and the mean lumbar spine BMD had increased by 1.5% in the HRT group, whereas both BMDs had decreased by 4–5% in the non-HRT group. However, the apo E genotype did not modify the changes in BMD in either group. Additionally, the baseline concentrations of bone metabolic markers and their 1-year changes showed no genotype-related associations. Conclusions: The results of our population-based study indicate that apo E genotype does not modify lumbar or femoral neck BMDs or serum bone biochemical markers or their response to HRT in early postmenopausal Caucasian women.

Disturbance in bone turnover in children with a malignancy at completion of chemotherapy.

Osteoporosis and pathological fractures have been observed in children with a malignancy. The mechanisms of osteopenia in childhood malignancies have not been well established. The purpose of the present study was to evaluate changes in bone turnover and in bone hormonal metabolism in children with a malignancy at completion of their chemotherapy. Serum levels of human intact osteocalcin, type I collagen carboxyterminal propeptide (PICP), type I collagen carboxyterminal telopeptide (ICTP), 25-hydroxyvitamin D [25-(OH)-D], 1,25-dihydroxyvitamin D [1, 25-(OH)(2)-D], intact parathyroid hormone, insulin-like growth factor I (IGF-I), IGF binding protein 3 (IGFBP-3), alkaline phosphatase, calcium, and phosphate were analyzed in 22 children with acute lymphoblastic leukemia and in 26 children with other malignancies. Results were expressed as Z-scores [mean (95% confidence intervals)] relative to healthy Caucasian-children. The marker of collagen degradation (ICTP) was significantly increased [1.43 (1.10-1.76), P < 0.0001] compared to reference values, whereas the markers of bone formation (PICP, osteocalcin) were not changed [0.07 (-0.55 to 0.49), 0.35 (-0.05 to 0.74), respectively, NS]. Serum 25-(OH)-D, 1,25-(OH)(2)-D, and calcium were significantly reduced [-0.65 (-0.87 to -0.42), -0.68 (-0.92 to -0. 42), -1.42 (-1.80 to -1.04), P < 0.0001, respectively]. Disturbance in bone turnover with low serum 25-(OH)-D, 1, 25-(OH)(2)-D, and calcium was observed in children with a malignancy at completion of their chemotherapy. A controlled study determining the possible benefits of vitamin D and calcium supplementation on bone turnover could be considered in these patients.

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.