Urinary collagen peptides: Source of markers for bone metabolic processes in kidney transplant recipients.

INTRODUCTION: Kidney transplant recipients (KTRs) are at an increased risk of fractures. Total urinary hydroxyproline excretion served as marker for bone resorption (BR) but was replaced by ß-CrossLaps (CTX), a C-terminal collagen α-1(I) chain (COL1A1) telopeptide. We investigated the low-molecular-weight urinary proteome for peptides associated with changes in bone metabolism after kidney transplantation. METHODS: Clinical and laboratory data including serum levels of CTX in 96 KTR from two nephrology centers were correlated with signal intensities of urinary peptides identified by capillary electrophoresis mass spectrometry. RESULTS: Eighty-two urinary peptides were significantly correlated with serum CTX levels. COL1A1 was the predominant peptide source. Oral bisphosphonates were administered for decreased bone density in an independent group of 11 KTR and their effect was evaluated on the aforementioned peptides. Study of the peptides cleavage sites revealed a signature of Cathepsin K and MMP9. Seventeen of these peptides were significantly associated with bisphosphonate treatment, all showing a marked reduction in their excretion levels compared to baseline. DISCUSSION: This study provides strong evidence for the presence of collagen peptides in the urine of KTR that are associated with BR and that are sensitive to bisphosphonate treatment. Their assessment might become a valuable tool to monitor bone status in KTR.

A phase 1 pooled PK/PD analysis of bone resorption biomarkers for odanacatib, a Cathepsin K inhibitor.

To develop a framework for evaluating the resorption effects of Cathepsin K (CatK) inhibitors and to inform dose regimen selection, a pharmacokinetic/pharmacodynamic (PK/PD) model for odanacatib (ODN) was developed based upon data from Phase 1 studies. Pooled PK/PD data from 11 studies (N = 249) were fit reasonably to a population inhibitory sigmoid Emax model. Body weight on E0 (baseline uNTx/Cr, urinary N-terminal telopeptide normalized by creatinine) and age on Emax (fractional inhibition of the biomarker response) were significant covariates for biomarker response. Simulations of typical osteoporosis patients (by age, sex and weight) indicated minimal differences between sexes in concentration-uNTx/Cr relationship. There was no evidence that regimen (daily vs. weekly dosing) influenced the PK/PD relationship of resorption inhibition for odanacatib. PK/PD models based on data from odanacatib (ODN) Phase 1 studies demonstrated that uNTx/Cr was an appropriate bone resorption biomarker for assessment of the effects of a CatK inhibitor. The models also identified the determinants of response in the PK/PD relationship for ODN (body weight on E0 and age on Emax).

Urinary cross-linked carboxyterminal telopeptide, a bone resorption marker, decreases after vaso-occlusive crises in adults with sickle cell disease.

People with sickle cell disease often report severe bone pain with repeated bouts of vaso-occlusive crises, but the extent of skeletal injury incurred during these painful episodes remain unclear. We sought to quantify bone degradation by comparing urinary concentrations of carboxyterminal cross-linked telopeptide of type I collagen (CTX-1), a well-described marker of bone resorption, in a prospective cohort of 52 adults with sickle cell disease enrolled in the Sickle Cell Pain Markers Study. We also questioned if changes in urinary CTX-1 concentrations correlated with changes in hemolysis and inflammatory markers measured both during and after resolution of a painful vaso-occlusive episode. Thirty-one of the 52 adults enrolled in the study had paired urine samples for CTX-1 analysis. Urinary CTX-1, corrected for urine creatinine, significantly decreased from a mean of 3.45 µg/mmol during vaso-occlusive crises to 2.62 µg/mmol at recovery (p = 0.01). Thus, increased bone loss appears to correlate with acute vaso-occlusive crises in sickle cell disease. Our finding that urinary CTX-1 can be used to probe bone degradation in sickle cell disease provides an important new tool for diagnosing and monitoring response to therapy for people with sickle cell-related bone loss.

Association between polycyclic aromatic hydrocarbons exposure and bone turnover in adults.

BACKGROUND: Cigarette smoking is a risk factor of osteoporosis and bone fracture. Tobacco smoke contains several polycyclic aromatic hydrocarbons. Thus, we hypothesized that environmental polycyclic aromatic hydrocarbon exposure is associated with bone loss and fracture risk. The present study examined the association between polycyclic aromatic hydrocarbon exposure and bone turnover in the general adult population. METHODS: A total of 1408 eligible participants from the National Health and Nutrition Examination Survey (NHANES 2001-2006) were included in this cross-sectional analysis. The levels of urinary N-telopeptide and serum bone-specific alkaline phosphatase, which are biomarkers of bone resorption and formation, respectively, were assessed. Meanwhile, polycyclic aromatic hydrocarbon exposure was evaluated using the concentrations of urinary polycyclic aromatic hydrocarbon metabolites. The association between polycyclic aromatic hydrocarbon exposures and N-telopeptide, and bone-specific alkaline phosphatase levels was assessed using a multivariate linear regression model. RESULTS: All polycyclic aromatic hydrocarbon metabolites except 3-phenanthrene were significantly associated with increased N-telopeptide levels (P < 0.05) after adjustment of relevant covariables. However, no significant relationship was observed between polycyclic aromatic hydrocarbon metabolites and bone-specific alkaline phosphatase levels. This relationship remained significant after the participants were assessed according to sex (P < 0.05). Additionally, all polycyclic aromatic hydrocarbon metabolites showed a positive association with N-telopeptide levels in participants aged <60 years (P < 0.05). CONCLUSION: Polycyclic aromatic hydrocarbon exposure is associated with increased bone resorption among the general adult population in the United States. Further studies must assess the potential mechanisms associated with the adverse effects of polycyclic aromatic hydrocarbon exposure on bone loss.

The Effect of a Low Glycemic Index Pulse-Based Diet on Insulin Sensitivity, Insulin Resistance, Bone Resorption and Cardiovascular Risk Factors during Bed Rest.

We determined the effects of a low glycemic-index pulse-based diet (i.e., containing lentils, chick peas, beans, and split peas) compared to a typical hospital diet on insulin sensitivity assessed by the Matsuda index from the insulin and glucose response to a two-hour oral glucose tolerance test, insulin resistance assessed by the homeostatic model assessment of insulin resistance (HOMA-IR), bone resorption assessed by 24 h excretion of urinary n-telopeptides(Ntx) and cardiovascular risk factors (blood lipids, blood pressure, arterial stiffness and heart rate variability) during bed rest. Using a randomized, counter-balanced cross-over design with one-month washout, six healthy individuals (30 ± 12 years) consumed the diets during four days of bed rest. The Matsuda index, HOMA-IR, urinary Ntx and cardiovascular risk factors were determined at baseline and after the last day of bed rest. Compared to the typical hospital diet, the pulse-based diet improved the Matsuda index (indicating increased insulin sensitivity; baseline to post-bed rest: 6.54 ± 1.94 to 6.39 ± 2.71 hospital diet vs. 7.14 ± 2.36 to 8.75 ± 3.13 pulse-based diet; p = 0.017), decreased HOMA-IR (1.38 ± 0.54 to 1.37 ± 0.50 hospital diet vs. 1.48 ± 0.54 to 0.88 ± 0.37 pulse-based diet; p = 0.022), and attenuated the increase in Ntx (+89 ± 75% hospital diet vs. +33 ± 20% pulse-based diet; p = 0.035). No differences for changes in cardiovascular risk factors were found between the two diet conditions, with the exception of decreased diastolic blood pressure during day three of bed rest in the pulse-based versus hospital diet (61 ± 9 vs. 66 ± 7 mmHg; p = 0.03). A pulse-based diet was superior to a hospital diet for maintaining insulin sensitivity, preventing insulin resistance, attenuating bone resorption and decreasing diastolic blood pressure during four days of bed rest.

Denosumab Improves Glomerular Filtration Rate in Osteoporotic Patients With Normal Kidney Function by Lowering Serum Phosphorus.

Higher serum phosphorus (Pi) increases the risk for chronic kidney disease (CKD). It was reported that a single administration of denosumab or zoledronate significantly suppressed serum Pi levels as well as those of bone resorption markers in serum. Also, previous evidences suggest a link between bone anti-resorptive therapy and vasoprotective/renoprotective effects through mechanisms that remain unexplored. The aim of this study is to assess the renoprotective effect of denosumab and involvement of denosumab-induced reduction in serum Pi in osteoporotic patients. Osteoporotic patients (n = 73) without overt proteinuria in dipstick test results were treated with denosumab (60 mg) every 6 months during the study period (24 months). Estimated glomerular filtration rate based on serum cystatin C (eGFRcys) was used as a filtration marker and tartrate-resistant acid phosphatase-5b (TRACP-5b) as a bone resorption marker. For analysis of non-CKD patients (n = 56), those with eGFRcys <60 mL/min/1.73 m2 were excluded. A single injection of denosumab suppressed serum Pi as well as TRACP-5b during the first 6 months, whereas age-related decline in eGFRcys was significantly reversed, with an increase of 2.75 ± 1.2 mL/min/1.73 m2 after 24 months noted. Multivariate analysis showed that serum Pi reduction following the initial denosumab injection was positively associated with serum TRACP-5b suppression during that same period (ß = 0.241, p = 0.049). In addition, a positive association of serum Pi suppression, but not of corrected calcium or TRACP-5b, with eGFRcys increase after 24 months (ß = 0.321, p = 0.014) was found after adjustments for gender, age, BMI, antihypertensive drug use, albumin, and eGFRcys. The same was observed in osteoporotic cases restricted to non-CKD patients. In conclusion, serum Pi reduction resulting from phosphorus load decrement from bone induced by denosumab is a determinant for eGFRcys increase. Early introduction of bone antiresorptive therapy can retain glomerular filtration in osteoporosis cases, including non-CKD patients. © 2019 American Society for Bone and Mineral Research.

Exercise Alleviates Osteoporosis in Rats with Mild Chronic Kidney Disease by Decreasing Sclerostin Production.

Chronic kidney disease-mineral bone disorder (CKD-MBD), comprising mineral, hormonal, and bone metabolic imbalance, is a major CKD-related issue; it causes osteoporosis prevalence in CKD patients. Osteocyte-derived sclerostin inhibits the osteogenic Wnt/ß-catenin signaling pathway; its levels rise when kidney function declines. Exercise modulates the physiological functions of osteocytes, potentially altering sclerostin production. It may aid bone and mineral electrolyte homeostasis in CKD. Mild CKD was induced in rats by partial nephrectomy. They were divided into: sham (no CKD), CKD, and CKD + exercise (8 weeks of treadmill running) groups. Micro-CT scanning demonstrated that the CKD + exercise-group rats had a higher bone mineral density (BMD) of the spine and femoral metaphysis and higher femoral trabecular bone volume than the CKD-group rats. Bone formation rates were not significantly different. The CKD + exercise-group rats had lower serum sclerostin (157.1 ± 21.1 vs 309 ± 38.1 pg/mL, p < 0.05) and CTX-1 (bone resorption marker) levels. Immunohistochemistry revealed higher tibial ß-catenin concentrations in the CKD + exercise-group rats. Serum FGF-23, intact parathyroid hormone (iPTH), alkaline phosphatase (ALP), calcium, and phosphate levels showed no significant differences between these groups. Thus, exercise improves BMD and bone microstructure in mild CKD by inhibiting sclerostin production, but does not alter serum minerals.

Serum calcium concentration is maintained when bone resorption is suppressed by osteoprotegerin in young growing male rats.

Serum calcium (Ca) is maintained in a narrow range through regulation of Ca metabolism in the intestine, kidney, and bone. Calcium is incorporated and resorbed from bone during bone remodeling via cellular processes as well as by exchange. Both routes contribute to calcium homeostasis. To assess the magnitude of bone turnover contribution to calcium homeostasis we labeled bone with a Ca tracer and measured Ca release following stimulation or suppression of bone resorption. Young growing male rats (n = 162) were dosed with 45Ca to label skeletal Ca. After a one-month period to allow the label to incorporate into the skeleton, rats were treated with a bone resorption antagonist (OPG), a bone resorption agonist (RANKL), or vehicle control (PBS). Serum and urine 45Ca and total Ca, and serum TRACP5b (a bone resorption biomarker), were monitored for 45 days following treatment. Tracer data were analyzed by a compartmental model using WinSAAM to quantify dynamic changes in Ca metabolism and identify sites of change following treatment. In RANKL treated rats, both serum 45Ca and serum TRACP5b were increased by >70% due to a 25-fold increase in bone resorption. In OPG treated rats, both serum 45Ca and serum TRACP5b were suppressed by >70% due to a 75% decrease in bone resorption, a 3-fold increase in bone formation, and a 50% increase in absorption. Because TRACP5b and 45Ca responded similarly, we conclude that Ca release from bone into serum occurs mostly via osteoclast-mediated bone resorption. However, because serum Ca concentration did not change with altered resorption in response to either RANKL or OPG treatment, we also conclude that serum Ca concentration under normal dietary conditions in young growing male rats is maintained by processes in addition to cellular bone resorption.

Higher sympathetic activity as a risk factor for skeletal deterioration in pheochromocytoma.

Despite the potential biological importance of sympathetic activity in human bone metabolism, its effects on bone microarchitecture, a key determinant of bone quality, has not been thoroughly studied. In the present study, we investigated the lumbar spine trabecular bone score (TBS) as an indicator of skeletal deterioration in pheochromocytoma. Among 620 consecutive patients with newly diagnosed adrenal incidentaloma, 29 with histologically confirmed pheochromocytoma (a catecholamine-secreting neuroendocrine tumor) and 266 with nonfunctional adrenal incidentaloma were defined as cases and controls, respectively. After adjustment for confounders, subjects with pheochromocytoma had 2.9% lower lumbar spine TBS than those without pheochromocytoma (P = 0.038). Moreover, urinary normetanephrine level, but not urinary metanephrine level, was inversely correlated with lumbar spine TBS (P = 0.009). Subjects in the highest urinary normetanephrine quartile showed markedly lower lumbar spine TBS than those in the lowest quartile (P = 0.018), in a dose-response manner across increasing urinary normetanephrine quartile categories (P for trend = 0.021). Consistent with the results of previous studies, subjects with pheochromocytoma had significantly lower bone mass at the lumbar spine and higher serum level of C-terminal telopeptide of type I collagen than controls (P = 0.013 and 0.002, respectively). These findings provide clinical evidence that catecholamine excess and the resultant sympathetic overstimulation in pheochromocytoma may contribute to bone fragility, especially in the trabecular bone, through a weak microarchitecture in addition to a lower bone mass and increased bone resorption, and support the possibility of pheochromocytoma as a secondary cause of osteoporosis.

Effects of a 20-week concurrent training program on bone metabolism in elderly women / Efecto de 20 semanas de entrenamiento concurrente sobre el metabolismo óseo de adultas mayores

The present study evaluated the effect of a 20-week concurrent training program on bone metabolism in elderly women. The sample consisted of 51 elderly women living in the municipality of Muriaé (MG), distributed into two groups: a concurrent training group (CTG = 25), with an average age of 69.44 ± 6.82 years, and a control group (CG = 26), with mean age of 68.30 ± 6.34 years. Biophysical parameters were determined based on weight, height and body mass index. Bone metabolism was assessed by collecting second-morning urine samples before and after intervention to analyze levels of the biochemical marker deoxypyridinoline (DPD), which quantifies bone resorption. Results: The results showed a post-intervention decline in DPD content in the GTC when compared to controls (p = 0.007) and an improvement in the variables weight, BMI and DPD between the GTC and GC (p = 0.000). Conclusion: Concurrent training was efficient in improving bone metabolism in the elderly population studied.

El presente estudio evaluó los efectos de 20 semanas de entrenamiento concurrente sobre el metabolismo óseo de adultas mayores. La muestra fue compuesta por 51 mujeres adultas mayores, residentes en el municipio de Muriaé (MG), voluntarias, distribuidas en dos grupos, un grupo participó en entrenamiento concurrente (GTC=25), con una edad media de 69,44±6,82 años y un grupo control (GC=26) con una media de 68,30±6,34 años. Los parámetros biofísicos se determinaron por medio del peso corporal, la estatura e índice de masa corporal. Para la evaluación del metabolismo óseo, se realizó la recolección de la orina matinal en el pre y post-test, utilizando como reactivo el marcador bioquímico de deoxipiridinolina (DPD) que cuantifica la reabsorción ósea. Los resultados mostraron una reducción en la concentración de DPD en el GTC cuando se compararon los grupos (p = 0,007) y la mejora de las variables, peso corporal, IMC y DPD entre el GTC y el GC en el post-test (p = 0,000). Se percibe que el entrenamiento concurrente, para las mujeres adultas mayores fue eficiente en la mejoría de las condiciones de salud del metabolismo óseo.

Maintenance of Serum Ionized Calcium During Exercise Attenuates Parathyroid Hormone and Bone Resorption Responses.

Exercise can cause a decrease in serum ionized calcium (iCa) and increases in parathyroid hormone (PTH) and bone resorption. We used a novel intravenous iCa clamp technique to determine whether preventing a decline in serum iCa during exercise prevents increases in PTH and carboxy-terminal collagen crosslinks (CTX). Eleven cycling-trained men (aged 18 to 45 years) underwent two identical 60-min cycling bouts with infusion of Ca gluconate or saline. Blood sampling for iCa, total calcium (tCa), PTH, CTX, and procollagen type 1 amino-terminal propeptide (P1NP) occurred before, during, and for 4 hours after exercise; results are presented as unadjusted and adjusted for plasma volume shifts (denoted with subscript ADJ). iCa decreased during exercise with saline infusion (p = 0.01 at 60 min) and this was prevented by Ca infusion (interaction, p < 0.007); there were abrupt decreases in Ca content (iCaADJ and tCaADJ ) in the first 15 min of exercise under both conditions. PTH and CTX were increased at the end of exercise (both p < 0.01) on the saline day, and markedly attenuated (-65% and -71%; both p < 0.001) by Ca. CTX remained elevated for 4 hours after exercise on the saline day (p < 0.001), despite the return of PTH to baseline by 1 hour after exercise. P1NP increased in response to exercise (p < 0.001), with no difference between conditions, but the increase in P1NPADJ was not significant. Results for PTHADJ and CTXADJ were similar to unadjusted results. These findings demonstrate that bone resorption is stimulated early in exercise to defend serum iCa. Vascular Ca content decreased early in exercise, but neither the reason why this occurred, nor the fate of Ca, are known. The results suggest that the exercise-induced increase in PTH had an acute catabolic effect on bone. Future research should determine whether the increase in PTH generates an anabolic response that occurs more than 4 hours after exercise. © 2018 American Society for Bone and Mineral Research.

Association of Urinary Citrate With Acid-Base Status, Bone Resorption, and Calcium Excretion in Older Men and Women.

Context: Elevated urine net acid excretion (NAE), indicative of subclinical metabolic acidosis, has been associated with higher bone turnover. Urine citrate, which is a common clinical measure, changes in response to acid-base status but its association with bone turnover is uncertain. Objective: We evaluated the association between change in urine citrate and change in bone turnover and calcium excretion. Design, Intervention, and Participants: A total of 233 healthy men and women ≥60 years old were randomly assigned to 1.0 mmol/kg/d potassium bicarbonate (KHCO3), 1.5 mmol/kg/d KHCO3, or placebo for 84 days. Outcome Measures: Urine citrate, NAE, N-telopeptide of collagen type-I (NTX), calcium excretion, and serum amino-terminal propeptide of type 1 procollagen (P1NP) were measured before and after intervention. Results: Urine citrate increased dose dependently after KHCO3 supplementation (P trend < 0.001). The urine citrate change was significantly inversely associated with P1NP change (P = 0.021) but not with change in NTX (P = 0.051) or calcium excretion (P = 0.652). The NAE change was positively associated with change in NTX and calcium excretion (P ≤ 0.003) but not with change in P1NP (P = 0.051). When the urine citrate change and NAE change were included in the same model, the urine citrate change was not associated with change in NTX, calcium excretion, or serum P1NP (P ≥ 0.086), whereas change in NAE remained associated with change in NTX and calcium excretion (P ≤ 0.003). Conclusion: Urine citrate may not be a suitable alternative to NAE when assessing acid-base status in relation to bone turnover in older adults.

[Calciuria as a metabolic marker for various conditions and diseases].

The article analyzes the literature on the features of human calcium homeostasis. The authors describe the etiopathogenetic role of calcitropic hormones, the plasma and urine acid-base status, various ions, lifestyle and nutrition and other factors contributing to hypercalciuria due to increased intestinal absorption, bone resorption, impairment of tubular calcium reabsorption, etc. They discuss the role of calciuria as a factor in forming urinary calculi and present their own observations.

Preliminary investigation of urine N-telopeptide concentration as a biomarker of bone resorption in dogs receiving glucocorticoids.

OBJECTIVES: The influence of glucocorticoid therapy on bone resorption in dogs using a urine N-telopeptide assay was investigated. MATERIALS AND METHODS: Thirty-one dogs receiving oral glucocorticoids and 31 age-matched healthy control dogs were enrolled. Urine N-telopeptide concentration was measured using a commercially available immunoassay and results were expressed as a ratio against urinary creatinine concentration. Dogs receiving glucocorticoids were divided into three subgroups based on daily glucocorticoid dose and three subgroups based on treatment duration. Urine N-telopeptide concentration was then compared between groups. RESULTS: Urine N-telopeptide concentration was significantly higher in dogs receiving glucocorticoids compared to the control group. CLINICAL SIGNIFICANCE: This preliminary study demonstrates significant increase in urine N-telopeptide concentration in dogs receiving glucocorticoid therapy compared to control dogs. Further studies are needed to assess whether this increase in urine N-telopeptide concentration correlates with decreases in bone mineral density as has been identified in humans.

BONE TURNOVER IN OSTEOPOROTIC WOMEN DURING LONG-TERM ORAL BISPHOSPHONATES TREATMENT: IMPLICATIONS FOR TREATMENT FAILURE AND "DRUG HOLIDAY" IN THE REAL WORLD.

OBJECTIVE: Little data exist to support concerns over bone turnover suppression during prolonged oral bisphosphonate treatment and on consequences of the recommended "drug holiday." This study was performed to assess bone resorption rates in postmenopausal osteoporotic women on prolonged oral bisphosphonate treatment and in response to switching to "drug holiday" intravenous bisphosphonate, or continuation of oral bisphosphonates. METHODS: The frequency distribution of the bone resorption marker urinary deoxypyridinoline crosslinks (uDPD), was obtained retrospectively from 211 osteoporotic women attended at an academic hospital endocrine clinic, treated for >2 years with oral bisphosphonates. In some patients, uDPD was re-assessed following modification or continuation of treatment. RESULTS: The mean duration of oral bisphosphonates treatment was 7.2 ± 3.1 years. uDPD was within reference range for premenopausal women in 61.6% of the patients, below in 7.6% of the patients, and above upper limit in 30.8%. uDPD decreased significantly following intravenous zoledronic acid, increased significantly during "drug holiday," and slightly decreased in those continued on oral bisphosphonate treatment. CONCLUSION: In this real-world study, the majority of women on prolonged oral bisphosphonates maintained bone resorption rates within the normal reference range for premenopausal women. The likelihood for inadequate suppression was considerably greater than that of over-suppression. Implementing a "drug holiday" resulted in a marked increase in bone resorption rates. Additional studies should explore the potential role of bone turnover markers in the evaluation of patients on prolonged oral bisphosphonates and during "drug holiday" in different settings and using additional markers. ABBREVIATIONS: BMD = bone mineral density; IQR = interquartile range; uDPD = urinary deoxypyridinoline crosslinks.

Differential response of bone and kidney to ACEI in db/db mice: A potential effect of captopril on accelerating bone loss.

The components of renin-angiotensin system (RAS) are expressed in the kidney and bone. Kidney disease and bone injury are common complications associated with diabetes. This study aimed to investigate the effects of an angiotensin-converting enzyme inhibitor, captopril, on the kidney and bone of db/db mice. The db/db mice were orally administered by gavage with captopril for 8weeks with db/+ mice as the non-diabetic control. Serum and urine biochemistries were determined by standard colorimetric methods or ELISA. Histological measurements were performed on the kidney by periodic acid-schiff staining and on the tibial proximal metaphysis by safranin O and masson-trichrome staining. Trabecular bone mass and bone quality were analyzed by microcomputed tomography. Quantitative polymerase chain reaction and immunoblotting were applied for molecular analysis on mRNA and protein expression. Captopril significantly improved albuminuria and glomerulosclerosis in db/db mice, and these effects might be attributed to the down-regulation of angiotensin II expression and the expression of its down-stream profibrotic factors in the kidney, like connective tissue growth factor and vascular endothelial growth factor. Urinary excretion of calcium and phosphorus markedly increased in db/db mice in response to captopril. Treatment with captopril induced a decrease in bone mineral density and deterioration of trabecular bone at proximal metaphysis of tibia in db/db mice, as shown in the histological and reconstructed 3-dimensional images. Even though captopril effectively reversed the diabetes-induced changes in calcium-binding protein 28-k and vitamin D receptor expression in the kidney as well as the expression of RAS components and bradykinin receptor-2 in bone tissue, treatment with captopril increased the osteoclast-covered bone surface, reduced the osteoblast-covered bone surface, down-regulated the expression of type 1 collagen and transcription factor runt-related transcription factor 2 (markers for osteoblastic functions), and up-regulated the expression of carbonic anhydrase II (marker for bone resorption). Captopril exerted therapeutic effects on renal injuries associated with type 2 diabetes but worsened the deteriorations of trabecular bone in db/db mice; the latter of which was at least in part due to the stimulation of osteoclastogenesis and the suppression of osteogenesis by captopril.

Urinary Cross-linked N-terminal Telopeptide of Type I Collagen Levels of Infants with Osteogenesis Imperfecta and Healthy Infants.

The urinary cross-linked N-terminal telopeptide of type I collagen (uNTx) levels in infantile osteogenesis imperfecta (OI) have not been well studied. Here we investigated the levels of uNTx in infants with OI and healthy infants. We collected spot urine samples from 30 infants with OI (male/female, 14/16; Sillence classification, I/II/III/IV: 15/3/6/6; age, 5.2±4.4 months) and 120 healthy infants (male/female, 75/45; age, 5.1±4.1 months) for the measurement of uNTx levels. The uNTx levels of the OI infants were significantly lower than those of the healthy infants (mean±SD, 1,363.7±530.1 vs. 2,622.2±1,202.6 nmol BCE/mmol Cr; p＜0.001). The uNTx levels of the infants with type I OI were significantly lower than those of the age-matched healthy infants, although an overlap was observed between the 2 groups. Among the 1-month-old infants, the uNTx levels of the infants with types I, III or IV OI were significantly lower than those of the healthy infants, without overlap (1,622.5±235.8 vs. 3,781.0±1,027.1 nmol BCE/mmol Cr; p＜0.001). These results indicate that uNTx levels are significantly lower in infants with OI than in healthy infants, and they suggest that uNTx might be useful as a reference for diagnosing OI.

Effect of low level laser therapy on local bone resorption during orthodontic treatment: a randomized controlled trial / Efecto del laser terapéutico en la reabsorción osea local durante tratamientos de ortodoncia: un ensayo clínico aleatoriamente controlado

The aim of this study was to assess whether the application of low-level laser therapy (LLLT) during the first stage of orthodontic treatment has an effect on local bone resorption and is detectable at the systemic level by measuring deoxypyridinoline levels (Pyrilinks) in urine. This was a randomized (1:1), double-blind, active-controlled, parallel-group trial. 28 adult patients who were going to start orthodontic treatment were randomly divided into the control group (n: 13) and the experimental group (n: 15), the latter of which received LLLT. All of the subjects underwent testing of urine samples: the first one on the day before the beginning of orthodontic treatment (T0), and the second one 5 days after bracket placement to measure Pyrilinks values (Dpd/Cr) in urine. Group differences were evaluated with Student's paired t-test. At the beginning of the study, the Pyrilinks were in the normal range for 53.57 % of the patients, and 46.43 % had elevated values according to the normal ranges. Only taking into account the normal values at (T0), the average Pyrilinks for control group (T0) were 5.75± 1.20 nM/mM, (T1): 6.02±3.00 nM/mM. For experimental group, (T0) was 5.71± 0.72, and it was 6.63± 0.73 in (T1).There were no significant differences in the Pyrilinks changes. (p= 0.75). In the experimental group levels raised statistically significant (p = 0.009). LLLT on patients starting orthodontic treatment with normal Pyrilinks levels have a statistically significant increment on their levels 5 days post irradiation.

El objetivo de este trabajo fue evaluar si la aplicación de la terapia láser de bajo nivel (TLBN) durante la primera etapa del tratamiento ortodóncico tiene un efecto sobre la resorción ósea local y es detectable a nivel sistémico midiendo los niveles de desoxipiridinolina en la orina. Se trató de un ensayo aleatorizado (1:1), doble ciego, controlado de forma activa y paralelo. 28 pacientes adultos que iban a iniciar el tratamiento de ortodoncia se dividieron al azar en el grupo control (n: 13) y el grupo experimental (n: 15), el último de los cuales recibió TLBN. Todos los sujetos fueron sometidos a pruebas de muestras de orina: la primera en el día anterior al inicio del tratamiento ortodóncico (T0) y la segunda 5 días después de la colocación del bracket para medir los valores de Pyrilinks (Dpd / Cr) en la orina. Las diferencias grupales se evaluaron con la prueba t de Student pareada. Al inicio del estudio, los Pyrilinks estaban en el rango normal para 53,57 % de los pacientes, y 46,43 % tenían valores elevados según los rangos normales. Sólo teniendo en cuenta los valores normales en (T0), los Pyrilinks medios para el grupo de control (T0) fueron 5,75 ± 1,20 nM / mM, (T1): 6,02 ± 3,00 nM / mM. Para el grupo experimental, (T0) fue de 5,71 ± 0,72, y fue de 6,63 ± 0,73 en (T1). No hubo diferencias significativas en los cambios de Pyrilinks. (P = 0,75). En el grupo experimental los niveles aumentaron estadísticamente (p = 0,009). LLLT en los pacientes que comienzan el tratamiento ortodóncico con niveles normales de Pyrilinks tienen un incremento estadísticamente significativo en sus niveles 5 días después de la irradiación.

Reduced bone resorption by intake of dietary vitamin D and K from tailor-made Atlantic salmon: A randomized intervention trial.

Suboptimal vitamin D status is common among humans, and might increase bone resorption with subsequent negative effects on bone health. Fatty fish, including Atlantic salmon, is an important dietary vitamin D source. However, due to a considerable change in fish feed composition, the contribution of vitamin D from salmon fillet has been reduced. The main objective was to investigate if intake of vitamin D3 enriched salmon or vitamin D3 tablets decreased bone biomarkers (urinary N-telopeptides, deoxypyridinoline, serum bone-specific alkaline phosphatase, and osteocalcin) compared to a low vitamin D3 intake. The 122 healthy postmenopausal women included in this 12 weeks intervention trial were randomized into four groups: three salmon groups (150 grams/two times/week) and one tablet group (800 IU vitamin D and 1000 mg calcium/day). The salmon groups also received calcium supplements. The salmon had three different vitamin D3/vitamin K1 combinations: high D3+high K1, low D3+high K1, or high D3+low K1. Increased intake of salmon containing high levels of vitamin D3 (0.35-0.38 mg/kg/fillet) and supplements with the same weekly contribution had a positive influence on bone health as measured by bone biomarkers in postmenopausal women. Consequently, an increased level of vitamin D3 at least to original level in feed for salmonids will contribute to an improved vitamin D3 status and may improve human bone health.

Urinary N-telopeptide and Rate of Bone Loss Over the Menopause Transition and Early Postmenopause.

The purpose of this study was to assess the ability of urinary N-telopeptide (U-NTX) to gauge rate of bone loss across and after the menopause transition (MT). U-NTX measurement was measured in early postmenopause in 604 participants from the Study of Women's Health Across the Nation (SWAN). We examined the association between U-NTX and annualized rates of decline in lumbar spine and femoral neck bone mineral density (BMD) across the MT (1 year before the final menstrual period [FMP] to time of U-NTX measurement), after the MT (from time of U-NTX measurement to 2 to 4 years later), and over the combined period (from 1 year before FMP to 2 to 4 years after U-NTX measurement). Adjusted for covariates in multivariable linear regression, every standard deviation (SD) increase in U-NTX was associated with 0.6% and 0.4% per year faster declines in lumbar spine and femoral neck BMD across the MT; and 0.3% (lumbar spine) and 0.2% (femoral neck) per year faster declines over the combined period (across and after the MT) (all p < 0.01). Each SD increase in U-NTX was also associated with 44% and 50% greater risk of fast bone loss in the lumbar spine (defined as BMD decline in the fastest 16% of the distribution) across the MT (p < 0.001, c-statistic = 0.80) and over the combined period (across and after the MT) (p = 0.001, c-statistic = 0.80), respectively. U-NTX measured in early postmenopause is most strongly associated with rates of bone loss across the MT, and may aid early identification of women who have experienced fast bone loss during this critical period. © 2016 American Society for Bone and Mineral Research.