Procollagen Type 1 Amino-terminal Propeptide Levels Research Articles

Effects of Calcium Lactate-Enriched Pumpkin on Calcium Status in Ovariectomized Rats.

This study aimed to evaluate the effects of enriched pumpkin on calcium status in ovariectomized rats. The study was conducted in sixty female Wistar rats, which were divided into six groups: a group fed a standard diet (C) and five ovariectomized groups fed a standard diet (OVX_C) or a diet with calcium lactate (CaL), with calcium lactate-enriched pumpkin (P_CaL), with calcium lactate and alendronate (CaL_B), or with calcium lactate-enriched pumpkin with alendronate (P_CaL_B). After 12 weeks of the intervention, the rats were sacrificed, and their blood and tissues were collected. The calcium concentrations in serum and in tissues were measured using flame atomic absorption spectrometry (AAS). Serum concentrations of procollagen type-1 amino-terminal propeptide (PINP), parathyroid hormone PTH, estrogen (ES), and osteocalcin (OC) were determined with enzyme-linked immunosorbent assay (ELISA). It was found that enriched pumpkin increased the calcium level in the kidneys (194.13 ± 41.01 mg) compared to the C (87.88 ± 12.42 mg) and OVX_C (79.29 ± 7.66 mg) groups. The addition of alendronate increased the calcium level in the femurs (267.63 ± 23.63 mg) and more than six times in the kidneys (541.33 ± 62.91 mg) compared to the OVX_C group (234.53 ± 21.67 mg and 87.88 ± 12.42 mg, respectively). We found that the CaL, P_CaL, and CaL_B groups had significantly lower PINP serum concentrations (4.45 ± 0.82 ng/mL, 4.14 ± 0.69 ng/mL, and 3.77 ± 0.33 ng/mL) and higher PTH serum levels (3.39 ± 0.54 ng/dL, 3.38 ± 0.57 ng/dL, and 3.47 ± 0.28 ng/dL) than the OVX_C group (4.69 ± 0.82 ng/mL and 2.59 ± 0.45 ng/dL, respectively). In conclusion, pumpkin enriched with calcium lactate affects calcium status and normalizes PINP and PTH serum levels in ovariectomized rats. Diet with enriched pumpkin and alendronate increase calcium concentration in the femur. Enriched pumpkin causes calcium to accumulate in the kidneys of ovariectomized rats; alendronate significantly exacerbates this effect.

Effect of Cholecalciferol Supplementation on Bone Turnover Markers in Children and Adolescents With Type 1 Diabetes Mellitus

Background: Cholecalciferol is known to play an important role in bone mineral metabolism. Its deficiency may affect growth and status of bone markers in children. Aim of the study: to evaluate the correlation between serum 25(OH)D and bone markers and impact of vitamin D supplementation on serum bone formation [procollagen type 1 amino-terminal propeptide (P1NP)] and bone resorption [β-cross laps (CTx)] markers among children and adolescents with type 1 diabetes mellitus (DM). Materials and Methods: Total 58 children and adolescents with type 1 DM, who were given 2000 UI of cholecalciferol supplementation, were included in the study. These 58 children with available anthropometry, serum biochemistry, 25-hydroxyvitamin D ([25(OH)D]), and parathormone (PTH) were evaluated for bone formation (procollagen type 1 amino-terminal propeptide [P1NP]) and resorption (β-cross laps [CTx]) markers. Results: The mean age and body mass index of these children were 11.6 ± 2.3 years (boys: 11.7 ± 2.4; girls: 12.2 ± 1.4 years; p = 0.04) and 18.2 ± 3.9 kg/m2 (boys: 18.1 ± 3.8; girls: 17.8 ± 3.4 kg/m2; p = 0.206), respectively. Baseline serum P1NP levels were positively correlated with serum phosphates (r = 0.281, p < 0.001), PTH (r = 0.291, p < 0.001), and CTx (r = 0.425, p < 0.001) but not with age (r = -0.016, p = 0.404), BMI (r = -0.080, p = 0.032), serum calcium (r = -0.038, p = 0.107), and baseline 25(OH)D (r = -0.069, p = 0.035). Postsupplementation serum P1NP and CTx levels maintained similar correlations. There was a significant decline in serum P1NP (from 681 ± 223 ng/ml to 630 ± 279 ng/ml, p < 0.01) and CTx (from 1.63 ± 0.51 ng/ml to 1.37 ± 0.53 ng/ml, p < 0.01) following supplementation. Though decline in serum P1NP and CTx levels was observed in both boys and girls, among all supplementation patients, the effect was more marked in serum CTx than P1NP levels. Conclusions: Vitamin D supplementation in children resulted in decrease in both bone formation (P1NP) and resorption (CTx). The impact, however, was more marked on bone resorption than bone formation.

Relationship between bone turnover markers and oxidative stress in children with type 1 diabetes mellitus.

Oxidative stress in children with type 1 DM (T1DM) may negatively affect the bone. This study included 40 children with T1DM as the patient group and 40 healthy childrenof matched age and sex as the control group. Plasma alkaline phosphatase, procollagen type-1 amino-terminal propeptide (P1NP), and urinary deoxypyridinoline (DPD) were measured to assess bone turnover. Glutathione, superoxide dismutase (SOD), and malondialdehyde (MDA) were measured to assess oxidative stress. Patients with T1DM had a significantly lower P1NP level but a significantly higher urinary DPD level compared to the control group. Moreover, there were significantly lower glutathione and SOD levels with significantly higher MDA levels in patients with T1DM. We found a significant positive correlation between P1NP level and both glutathione and SOD levels but a significant negative correlation between P1NP and MDA in patients with T1DM. There was a significant negative correlation between DPD levels and both glutathione and SOD levels and a significant positive correlation between DPD and MDA. Moreover, glutathione was a significant predictor for both P1NP and DPD levels, while MDA was a significant predictor for P1NP levels. There is an association between oxidative stress and bone turnover markers in children with T1DM. Oxidative stress can negatively affect bone but the exact relationship between oxidative stress and bone turnover in T1DM has not been previously studied in pediatrics. For the best of our knowledge, our study was the first to assess the relationship between oxidative stress and bone turnover in children with T1DM. We revealed that increased oxidative stress in children and adolescents with T1DM may be involved in the impairment of bone turnover process, so treatment strategies toward better glycemic control and decreasing oxidative stress may be beneficial in preventing and treating diabetic bone disease in these children.

Editorial

Cbl and Cbl-b are E3 ubiquitin ligases and adaptor proteins, which perform regulatory roles in bone remodeling. Cbl −/− mice have delayed bone development due to decreased osteoclast migration. Cbl-b −/− mice are osteopenic due to increased bone resorbing activity of osteoclasts. Unique to Cbl, but not present in Cbl-b, is tyrosine 737 in the YEAM motif, which upon phosphorylation provides a binding site for the regulatory p85 subunit of PI3K. Substitution of tyrosine 737 with phenylalanine (Y737F, CblYF/YF mice) prevents Y737 phosphorylation and abrogates the Cbl–PI3K interaction. We have previously reported that CblYF/YF mice had increased bone volume due to defective bone resorption and increased bone formation. Here we show that the lumbar vertebra from CblYF/YF mice did not have significant bone loss following ovariectomy. Our data also suggests that abrogation of Cbl–PI3K interaction in mice results in the loss of coupling between bone resorption and formation, since ovariectomized CblYF/YF mice did not show significant changes in serum levels of c-terminal telopeptide (CTX), whereas the serum levels of pro-collagen type-1 amino-terminal pro-peptide (P1NP) were decreased. In contrast, following ovariectomy, Cbl −/− and Cbl-b −/− mice showed significant bone loss in the tibiae and L2 vertebrae, concomitant with increased serum CTX and P1NP levels. These data indicate that while lack of Cbl or Cbl-b distinctly affects bone remodeling, only the loss of Cbl–PI3K interaction protects mice from significant bone loss following ovariectomy.

The anti-epileptic drugs valproate, carbamazepine and levetiracetam cause bone loss and modulate Wnt inhibitors in normal and ovariectomised rats.

Secondary osteoporosis is the major concern associated with long term intake of antiepileptic drugs (AEDs). Women are the vulnerable targets owing to post-menopausal bone loss. In the present work, we evaluated the effect of 10 weeks of treatment with AED therapy (carbamazepine, CBZ, 75 mg/kg; sodium valproate, SVP, 300 mg/kg; levetiracetam, LTM, 150 mg/kg) on bone mineral density and microarchitecture at femoral epiphysis, lumbar vertebrae and proximal tibia of normal and ovariectomised Wistar rats. In addition, we measured serum levels of vitamin D, receptor activator of nuclear factor kappa β-ligand (RANKL), procollagen type 1 amino-terminal propeptide (P1NP) and wnt inhibitors (sclerostin and DKK-1) following AED therapy. Micro-computed tomography analysis of bones revealed significant reduction in BMD at femur epiphysis and lumbar vertebrae with all the three AEDs evaluated. At proximal tibia, only CBZ showed a significant decline. The reduction in BMD was more pronounced in ovariectomised rats. AEDs also resulted in alteration of micro-CT parameters. These changes were accompanied by an increased serum RANKL with all AEDs while vitamin D levels were reduced only with CBZ treatment and P1NP levels were reduced with SVP and CBZ. Serum sclerostin levels were elevated following all AEDs in normal and ovariectomised rats except with CBZ in normal rats. However, increase in DKK-1 levels was observed with only LTM. Ovariectomy itself resulted in increased RANKL, sclerostin and DKK-1 and reduced vitamin D and P1NP levels. Significant differences were discernible between normal and ovariectomised rats treated with AEDs in all the parameters. However, while sclerostin increased further upon AEDs treatment, P1NP decreased with SVP and CBZ and serum DKK-1 levels showed a declining trend with all the three AEDs studied. We confirm adverse effects on bone following AEDs in female rats. Further, our results demonstrate for the first time that these effects are more pronounced in ovariectomised rats as compared to normal rats and that this could be related to estrogen deficiency which in turn enhances bone resorption via increased RANKL and reduces bone formation via increased sclerostin and reduced P1NP. Finally, our study demonstrated for the first time that AED treatment displayed changes in the serum levels of wnt inhibitors and hence modulation of wnt inhibitors might be partly involved in their adverse effects on bone.

Real-world effectiveness of daily teriparatide in Japanese patients with osteoporosis at high risk for fracture: final results from the 24-month Japan Fracture Observational Study (JFOS)

Objective: The Japan Fracture Observational Study (JFOS), a prospective observational study, investigated the real-world effectiveness of daily teriparatide to reduce clinical fracture risk in osteoporotic patients.Methods: In routine clinical practice, Japanese patients initiated on teriparatide 20 μg/day by subcutaneous injection were enrolled. The primary end-point was the rate of clinical fractures at 6-month intervals over 24 months. Bone mineral density (BMD), procollagen type 1 aminoterminal propeptide (P1NP), back pain, and health-related quality-of-life (HRQoL) information was collected.Results: Of 1,996 patients at baseline, 90.1% were female, and mean age was 76.9 years. Teriparatide persistence at 12 and 24 months was 68.0% and 51.6%, respectively. Compared to the first 6-month treatment interval, the odds ratio of fractures decreased by 56.4% during 6–12 months, 51.6% during 12–18 months, and 58.8% during 18–24 months (all p < .01). After 24 months, BMD increased by 17.2% (lumbar spine) and 7.9% (total hip). After 6 months, P1NP levels increased by 259.3%. A reduction in back pain (100 mm visual analog scale) of 16.1 mm at 3 months was maintained through 24 months. HRQoL (pain, daily living activities, general health) improved by ≥10% at each post-baseline time point. Of 279 (14.6%) patients with ≥1 adverse event (AE), 71 (3.7%) experienced ≥1 drug-related AE (investigator assessed), including nausea (0.7%), dizziness (0.4%), and decreased appetite (0.3%). Osteosarcoma was not reported; there were no new safety signals.Conclusions: JFOS demonstrated effectiveness of teriparatide 20 μg/day to reduce the risk of clinical fractures in Japanese patients in a real-world setting.

Bone turnover markers in Paget's disease of the bone: A Systematic review and meta-analysis.

The aim of this systematic review and meta-analysis is to study the utility of the commonly used bone turnover markers in evaluating disease activity in patients with Paget's disease of bone before and after treatment with bisphosphonates. We found good correlation between the bone turnover marker concentrations and disease activity assessed by bone scintigraphy. Paget's disease of bone is a common skeletal disorder of the elderly. Bone turnover marker concentrations are used for diagnosis and follow-up. We aimed to compare the available bone turnover markers and determine their utility in assessing disease activity when compared to quantitative bone scintigraphy. We conducted a systematic review and meta-analysis searching MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus. We evaluated total alkaline phosphatase (total ALP), bone-specific alkaline phosphatase (bone ALP), procollagen type 1 amino-terminal propeptide (P1NP), serum, and urine C-terminal telopeptide (uCTx and sCTx, respectively), and urine N-terminal telopeptide (uNTx). The main outcome of interest was the correlation of disease activity with concentrations of bone turnover markers in Paget's disease patients before and after treatment with bisphosphonates. Correlation coefficients were pooled across studies using the random effects model. We included 17 observational studies and one trial reporting on 953 patients. Prior to treatment, all studied bone turnover markers had moderate to strong correlation with scintigraphic indices (correlation coefficients ranging from 0.58 to 0.80) with no statistically significant difference between the bone turnover markers overall (p = 0.08). P1NP, uNTx, and bone ALP tend to have higher correlation with scintigraphy. After starting treatment with bisphosphonate, there was moderate to strong correlation with disease activity with all markers except bone ALP (correlation coefficients ranging from 0.43 to 0.70). The findings of this meta-analysis suggest the Paget's disease activity is best monitored by following P1NP levels. However, total ALP, bone ALP, and uNTx are good alternatives as markers of disease activity in untreated patients. Total ALP and uNTx can be useful in following patients with Paget's disease after treatment if P1NP is not available. Clinicians, however, should take availability, cost, and the presence of liver disease into consideration when deciding which bone turnover marker is most appropriate when evaluating patients with Paget's disease.

Loss of Cbl–PI3K interaction in mice prevents significant bone loss following ovariectomy

Cbl and Cbl-b are E3 ubiquitin ligases and adaptor proteins, which perform regulatory roles in bone remodeling. Cbl−/− mice have delayed bone development due to decreased osteoclast migration. Cbl-b−/− mice are osteopenic due to increased bone resorbing activity of osteoclasts. Unique to Cbl, but not present in Cbl-b, is tyrosine 737 in the YEAM motif, which upon phosphorylation provides a binding site for the regulatory p85 subunit of PI3K. Substitution of tyrosine 737 with phenylalanine (Y737F, CblYF/YF mice) prevents Y737 phosphorylation and abrogates the Cbl–PI3K interaction. We have previously reported that CblYF/YF mice had increased bone volume due to defective bone resorption and increased bone formation. Here we show that the lumbar vertebra from CblYF/YF mice did not have significant bone loss following ovariectomy. Our data also suggests that abrogation of Cbl–PI3K interaction in mice results in the loss of coupling between bone resorption and formation, since ovariectomized CblYF/YF mice did not show significant changes in serum levels of c-terminal telopeptide (CTX), whereas the serum levels of pro-collagen type-1 amino-terminal pro-peptide (P1NP) were decreased. In contrast, following ovariectomy, Cbl−/− and Cbl-b−/− mice showed significant bone loss in the tibiae and L2 vertebrae, concomitant with increased serum CTX and P1NP levels. These data indicate that while lack of Cbl or Cbl-b distinctly affects bone remodeling, only the loss of Cbl–PI3K interaction protects mice from significant bone loss following ovariectomy.

Procollagen type 1 amino-terminal propeptide (P1NP) and risk of hip fractures in elderly Norwegian men and women. A NOREPOS study

The current study aimed to assess a possible association between the bone turnover marker procollagen type 1 amino-terminal propeptide (P1NP) and future hip fractures in elderly Norwegian men and women and to elucidate the relation between P1NP, bone mineral density and 25-hydroxyvitamin D (25(OH)D). Men and women aged 71 to 77 from two population based health studies in Norway (1999–2001) were followed for a median period of 7.3years with respect to hip fractures. The study was designed as a case-cohort study. P1NP and 25(OH)D were analysed in frozen serum samples obtained at baseline in hip fracture patients (n=340) and in randomly selected sex stratified sub-cohorts. Bone mineral density was measured by dual-energy X-ray absorptiometry (DXA) in a subset of participants. Cox proportional hazards regression with inverse probability weighting and robust variance was performed. No significant correlation between 25(OH)D and P1NP was found. A negative correlation between P1NP and BMD was observed in women (Rho=−0.36, p=0.001). A similar trend was observed in men. No association between quartiles of P1NP and rate of subsequent hip fractures was found. Spline analyses suggested a higher rate of hip fracture at P1NP levels above 60μg/L in both men and women. A higher hip fracture rate, which was independent of BMD, was also indicated in women with very low levels of P1NP.

Van Buchem disease: Clinical, biochemical, and densitometric features of patients and disease carriers

Van Buchem disease (VBD) is a rare bone sclerosing dysplasia caused by the lack of a regulatory element of the SOST gene, which encodes for sclerostin, an osteocyte-derived negative regulator of bone formation. We studied the demographic, clinical, biochemical, and densitometric features of 15 patients with VBD (12 adults and 3 children) and 28 related carriers of the gene mutation. The most common clinical findings in patients were facial palsy (100%) and various degrees of hearing impairment (93%); raised intracranial pressure had been documented in 20%. The clinical course of the disease appeared to stabilize in adulthood, with the majority of patients reporting no progression of symptoms or development of complications with time. Carriers of the disease had none of the clinical features or complications of the disease. Sclerostin could be detected in the serum in all but 1 VBD patients (mean 8.0 pg/mL; 95% confidence interval [CI], 4.9-11.0 pg/mL), and were lower than those of carriers (mean 28.7 pg/mL; 95% CI, 24.5-32.9 pg/mL; p < 0.001) and healthy controls (mean 40.0 pg/mL; 95% CI, 34.5-41.0 pg/mL; p < 0.). Serum procollagen type 1 amino-terminal propeptide (P1NP) levels were also significantly higher in adult patients (mean 96.0; 95% CI, 54.6-137.4 ng/mL versus mean 47.8; 95% CI, 39.4-56.2 ng/mL, p = 0.003 in carriers and mean 37.8; 95% CI, 34.5-41.0 ng/mL, p = 0.028 in healthy controls) and declined with age. Bone mineral density (BMD) was markedly increased in all patients (mean Z-score 8.7 ± 2.1 and 9.5 ± 1.9 at the femoral neck and spine, respectively); BMD of carriers was significantly lower than that of patients but varied widely (mean Z-scores 0.9 ± 1.0 and 1.3 ± 1.5 at the femoral neck and spine, respectively). Serum sclerostin levels were inversely correlated with serum P1NP levels (r = -0.39, p = 0.018) and BMD values (femoral neck r = -0.69, p < 0.001; lumbar spine r = -0.78, p < 0.001). Our results show that there is a gene-dose effect of the VBD deletion on circulating sclerostin and provide further in vivo evidence of the role of sclerostin in bone formation in humans. The small amounts of sclerostin produced by patients with VBD may explain their milder phenotype compared to that of patients with sclerosteosis, in whom serum sclerostin is undetectable.

Distinct effects of pioglitazone and metformin on circulating sclerostin and biochemical markers of bone turnover in men with type 2 diabetes mellitus

Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fractures and thiazolidinediones (TZDs) increase this risk. TZDs stimulate the expression of sclerostin, a negative regulator of bone formation, in vitro. Abnormal sclerostin production may, therefore, be involved in the pathogenesis of increased bone fragility in patients with T2DM treated with TZDs. We measured serum sclerostin, procollagen type 1 amino-terminal propeptide (P1NP), and carboxy-terminal cross-linking telopeptide of type I collagen (CTX) in 71 men with T2DM treated with either pioglitazone (PIO) (30 mg once daily) or metformin (MET) (1000 mg twice daily). Baseline values of sclerostin and P1NP were compared with those of 30 healthy male controls. Compared with healthy controls, patients with T2DM had significantly higher serum sclerostin levels (59.9 vs 45.2 pg/ml, P<0.001) but similar serum P1NP levels (33.6 vs 36.0 ng /ml, P=0.39). After 24 weeks of treatment, serum sclerostin levels increased by 11% in PIO-treated patients and decreased by 1.8% in MET-treated patients (P=0.018). Changes in serum sclerostin were significantly correlated with changes in serum CTX in all patients (r=0.36, P=0.002) and in PIO-treated patients (r=0.39, P=0.020), but not in MET-treated patients (r=0.17, P=0.31). Men with T2DM have higher serum sclerostin levels than healthy controls, and these levels further increase after treatment with PIO, which is also associated with increased serum CTX. These findings suggest that increased sclerostin production may be involved in the pathogenesis of increased skeletal fragility in patients with T2DM in general and may specifically contribute to the detrimental effect of TZDs on bone.

Patients with sclerosteosis and disease carriers: Human models of the effect of sclerostin on bone turnover

Sclerosteosis is a rare bone sclerosing dysplasia, caused by loss-of-function mutations in the SOST gene, encoding sclerostin, a negative regulator of bone formation. The purpose of this study was to determine how the lack of sclerostin affects bone turnover in patients with sclerosteosis and to assess whether sclerostin synthesis is decreased in carriers of the SOST mutation and, if so, to what extent this would affect their phenotype and bone formation. We measured sclerostin, procollagen type 1 amino-terminal propeptide (P1NP), and cross-linked C-telopeptide (CTX) in serum of 19 patients with sclerosteosis, 26 heterozygous carriers of the C69T SOST mutation, and 77 healthy controls. Chips of compact bone discarded during routine surgery were also examined from 6 patients and 4 controls. Sclerostin was undetectable in serum of patients but was measurable in all carriers (mean 15.5 pg/mL; 95% confidence interval [CI] 13.7 to 17.2 pg/mL), in whom it was significantly lower than in healthy controls (mean 40.0 pg/mL; 95% CI 36.9 to 42.7 pg/mL; p < 0.001). P1NP levels were highest in patients (mean 153.7 ng/mL; 95% CI 100.5 to 206.9 ng/mL; p = 0.01 versus carriers, p = 0.002 versus controls), but carriers also had significantly higher P1NP levels (mean 58.3 ng/mL; 95% CI 47.0 to 69.6 ng/mL) than controls (mean 37.8 ng/mL; 95% CI 34.9 to 42.0 ng/mL; p = 0.006). In patients and carriers, P1NP levels declined with age, reaching a plateau after the age of 20 years. Serum sclerostin and P1NP were negatively correlated in carriers and age- and gender-matched controls (r = 0.40, p = 0.008). Mean CTX levels were well within the normal range and did not differ between patients and disease carriers after adjusting for age (p = 0.22). Our results provide in vivo evidence of increased bone formation caused by the absence or decreased synthesis of sclerostin in humans. They also suggest that inhibition of sclerostin can be titrated because the decreased sclerostin levels in disease carriers did not lead to any of the symptoms or complications of the disease but had a positive effect on bone mass. Further studies are needed to clarify the role of sclerostin on bone resorption.

Impact of dialysate calcium concentration on the progression of aortic stiffness in patients on haemodialysis

Higher dialysate calcium (DCa) can result in an acute and transient increase in arterial stiffness. The aim of the present study is to evaluate the impact of DCa on the progression of arterial stiffness, calcium balance and bone metabolism in haemodialysis (HD) patients over a 6-month period. Method. We randomly assigned 30 patients on chronic HD to be dialysed with a DCa of 1.12 or 1.37 mmol/L for a period of 6 months. Aortic stiffness and brachial stiffness were respectively measured by carotid-femoral pulse wave velocities (cf-PWV) and carotid-radial pulse wave velocity (cr-PWV) at baseline and at 3 and 6 months. Central pulse pressure (PP) and augmentation index were determined by radial artery tonometry. Dialysis calcium balance and parathyroid hormone (PTH) were measured monthly. Procollagen type-1 amino-terminal propeptide (P1NP) and C-terminal telopeptide of type-I collagen (CTX) were measured as markers of bone formation and resorption, respectively. Data was analysed by linear mixed model. Twenty-seven patients (66 ± 13 years old) with a mean duration of HD of 5.8 ± 3.6 months completed the study. At baseline, the groups were similar with respect to age, serum levels of calcium, phosphate and PTH, blood pressure (BP), cf-PWV and cr-PWV. The cf-PWV at baseline and 3 and 6 months were, respectively, 13.4 ± 4.2, 14.7 ± 3.31 and 13.6 ± 2.5 m/s in the DCa 1.12 group and 14.6 ± 5.9, 15.8 ± 7.8 and 17.0 ± 7.0 m/s in the DCa 1.37 group. After correction for mean BP, cf-PWV increased with DCa 1.37 as compared to DCa 1.12 (Time-DCa interaction P = 0.002). However, there were no significant effects of DCa on progression of cr-PWV, central PP or augmentation index. During the intervention period, the mean PTH was slightly higher in the DCa 1.12 group as compared to the DCa 1.37 group (325 ± 185 versus 211 ± 128 ng/L, P = 0.054), and dialysis calcium balance was -8.1 ± 4.4 versus -0.2 ± 4.7 mmol/session, respectively, in groups with DCa 1.12 and DCa 1.37 (P = 0.0001). Treatment with DCa 1.12 mmol/L resulted in increasing levels of CTX as compared to DCa 1.37 (P = 0.02), whereas the P1NP levels did not change significantly in either group. In this study, aortic stiffness progressed with DCa 1.37, while it remained stable with DCa 1.12 over a 6-month period. These results suggest that higher DCa concentrations could be a risk factor for the progression of aortic stiffness in HD patients. In the context of limited oral calcium, the long-term safety of DCa 1.12 on bone metabolism remains to be established.

Bone structure and turnover in type 2 diabetes mellitus

We compared skeletal parameters in type 2 diabetic (T2DM) and non-diabetic postmenopausal women. Bone structure by dual energy x-ray absorptiometry (DXA) and HR-pQCT was not different, although procollagen type 1 amino-terminal propeptide (P1NP) and osteocalcin levels were lower in T2DM. T2DM is associated with increased fracture risk, but, paradoxically, with higher cross-sectional bone density (BMD) as measured by DXA. We sought explanations to this puzzle by investigating detailed structural and biochemical skeletal parameters in T2DM. Cross-sectional comparison of 25 postmenopausal T2DM women and 25 matched controls using DXA, high-resolution peripheral quantitative computed tomography (HR-pQCT) and biochemical bone turnover markers. BMD by DXA did not differ between T2DM and controls. HR-pQCT assessment also did not differ, with the exception of cortical area at the tibia, which tended to be lower in the diabetics (difference of 12 ± 6 [mean ± SD] mm, p = 0.06). P1NP and osteocalcin levels were lower in T2DM as compared to controls (P1NP, 34.3 ± 16 vs. 57.3 ± 28 ng/ml; p = 0.005; osteocalcin, 4.5 ± 2 vs. 6.2 ± 2 nmol/L; p = 0.001). Postmenopausal women with T2DM had lower levels of bone formation markers as compared to controls. Aside from a possible decrease in cortical bone area at a weight-bearing site, bone structure was not altered in T2DM. Lower bone turnover may be a skeletal parameter that is present in T2DM.

Effects of Yearly Zoledronic Acid 5 mg on Bone Turnover Markers and Relation of PINP With Fracture Reduction in Postmenopausal Women With Osteoporosis

In patients with osteoporosis treated with antiresorptive agents, reduction in bone turnover explains much of the observed fracture risk reduction. Lower levels of bone turnover markers (BTMs) appear to be associated with a lower risk of fracture in bisphosphonate-treated patients. BTMs were measured in a subset of subjects in the HORIZON Pivotal Fracture Trial. Annual infusions of zoledronic acid 5 mg significantly reduced BTMs: median decrease of 50% for beta-C-terminal telopeptides of type 1 collagen (beta-CTX), 30% for bone alkaline phosphatase (ALP), and 56% for procollagen type 1 amino-terminal propeptide (PINP). The mean level of BTMs decreased in treated patients but remained within the premenopausal range before the next injection. The percentage of zoledronic acid-treated patients with values below the premenopausal reference range at all time points was 1.7%, 17.8%, and 19% for bone ALP, CTX, and PINP, respectively. The third injection of zoledronic acid resulted in 60% reduction of beta-CTX within 9-11 days, followed by a gradual increase, indicating the persistence of osteoclastic bone resorption. The association between changes in BTMs and fracture incidence was assessed in 1132 patients who had PINP measurements at baseline and 1 yr. There was no association between low PINP levels at 1 yr and increased fracture incidence. In summary, (1) annual injections of zoledronic acid reduced BTMs in the premenopausal range, with a significant response persisting after the third infusion; and (2) low levels of PINP were not associated with increased fracture risk.