Impact of urinary calcium excretion on kidney, bone, and cardiovascular systems in patients with bone biopsy proven osteoporosis: a longitudinal long-term follow-up study.

The impact of urine calcium on kidney, bone, and cardiovascular systems in osteoporosis is not well-known. In this 7-year-follow-up study, high urine calcium did not affect kidney function but increased risk of kidney stones, while low urine calcium increased cardiovascular diseases. Maintaining normal urine calcium is beneficial for bone health. PURPOSE: Hypercalciuria is common in patients with osteoporosis. However, the long-term effect of urinary calcium excretion (UCaE) on patients' health is not well-examined. The current study aims to assess the impact of UCaE on kidney, bone, and cardiovascular outcomes in patients with bone biopsy proven osteoporosis. METHODS: Longitudinal study of all patients with osteoporosis who underwent bone biopsy and 24-h urine collection between 2008 and 2015 in the University of Kentucky. DXA scans, serum markers, kidney function, and cardiovascular events were recorded until last clinic visit in 2021. Exclusion criteria were secondary osteoporosis or conditions that might substantially impact UCaE. The significant results in univariate analysis were confirmed in multi-variable regression models involving clinically important covariates that might impact patients' outcomes. RESULTS: Study included 230 patients with mean follow-up of 7.2 ± 2.9 years. The mean age was 61 years, and the mean eGFR at baseline was 85 ± 19 ml/min/1.73 m2. Low bone turnover (LBT) was present in 57% and high bone turnover (HBT) in 43% of patients. Hypercalciuria was found in one-third of patients with no difference between LTB and HTB. UCaE correlated positively with eGFR but did not affect the rate of eGFR decline over time. Higher UCaE predicted kidney stones development. We observed U-shaped effect of UCaE on bone health. Hypercalciuria predicted loss of BMD at all sites, but also hypocalciuria was associated with higher loss in total hip BMD. Upper limb fractures were the most observed fractures, and their incidence was higher in patients with hyper- or hypo-calciuria. Lower UCaE independently predicted development of major adverse cardiac events (MACE) and cardiovascular disease (CVD). CONCLUSION: UCaE correlated with eGFR but it did not affect the change of eGFR over time. Patients with normal UCaE had lower incidence of upper limb fractures and less reduction in BMD. Low UCaE predicted MACE and CVD.

Redefining peripheral inflammation signature in schizophrenia based on the real-world FACE-SZ cohort.

BACKGROUND: Peripheral inflammation is associated with impaired prognosis in schizophrenia (SZ). Highly sensitive C-reactive protein (hs-CRP) is the most used inflammatory biomarker in daily practice. However, no consensual cut-off has been determined to date to discriminate patients with peripheral inflammation from those without. AIMS: To determine if patients with peripheral inflammation between 1 and 3 mg/L had poorer outcomes compared to those with undetectable CRP (<1 mg/L). METHOD: Consecutive participants of the FACE-SZ cohort with a hs-CRP < 3 mg/L were included in 10 expert academic centers with a national geographical distribution between 2010 and 2018. Potential sources of inflammation, socio-demographics, illness characteristics, current illness severity, functioning and quality of life and were reported following the FACE-SZ standardized protocol. RESULTS: 580 patients were included, of whom 226 (39%) were identified with low-grade inflammation defined by a hs-CRP between 1 and 3 mg/L. Overweight and lack of dental care were identified as potential sources of inflammation. After adjustment for these factors, patients with inflammation had more severe psychotic, depressive and aggressive symptomatology and impaired functioning compared to the patients with undetectable hs-CRP. No association with tobacco smoking or physical activity level has been found. CONCLUSIONS: Patients with schizophrenia with hs-CRP level between 1 and 3 mg/L should be considered at risk for inflammation-associated disorders. Lowering weight and increasing dental care may be useful strategies to limit the sources of peripheral inflammation. Hs-CRP > 1 mg/L is a reliable marker to detect peripheral inflammation in patients with schizophrenia.

Depressive symptoms and chronic peripheral inflammation are associated with impaired functional remission in schizophrenia independently of psychotic remission.

BACKGROUND: While psychotic remission in schizophrenia (SZ) has been defined by consensus and associated with a rank of clinical predictive factors, there is a lack of data of factors associated with functional remission. OBJECTIVES: To identify clinical and biological factors associated with impaired functional remission in a non-selected chronic stabilized SZ outpatients. METHODS: This study was a cross-sectional study carried out on all admitted SZ stabilized outpatients in an academic daily care psychiatric hospital. Functional remission was defined by a global assessment of functioning score ≥61. Psychotic remission was defined according to international criteria. Depression was assessed with the Calgary Depression Rating scale for Schizophrenia. Sociodemographic variables, tobacco status, clozapine treatment and obesity were reported. Chronic peripheral inflammation was defined by a highly sensitive C-reactive protein serum level ≥3 mg/L and metabolic syndrome according to international recommendations. RESULTS: 273 patients were included, among them 51 (18.7%) were classified in the functional remission group. In the multivariate analysis, higher rate of functional remission was associated with psychotic remission (adjusted Odd ratio = 18.2, p <0.001), lower depressive symptoms (aOR=0.8, p = 0.018) and lower peripheral inflammation (aOR=0.4, p = 0.046). No association of functional remission with age, gender, illness duration, second-generation antipsychotics, clozapine treatment, tobacco smoking, obesity or metabolic syndrome has been found. CONCLUSION: Depressive symptoms and chronic peripheral inflammation are associated with impaired functional remission in SZ independently of psychotic remission. Future intervention studies should determine if improving depressive symptoms and chronic peripheral inflammation may improve SZ patients reaching functional remission.

Abnormal C-reactive protein blood levels as a specific biomarker of major depression and non-remission under antidepressants in schizophrenia.

BACKGROUND: C-reactive protein (CRP) is a general marker of peripheral inflammation and has been shown to be a good marker of neuroinflammation. CRP has been found to be elevated in patients with mood disorders (especially unipolar disorders (UD) and in schizophrenia (SZ)) but also to be lowered by antidepressants. OBJECTIVE: The objectives were (i) to determine the prevalence of major depression, antidepressant prescription and remission under antidepressant in a stabilized population of SZ and UD patients consulting in a daily hospital, and (ii) to determine if CRP was a marker of major depression and remission under antidepressant in these SZ and UD populations. METHODS: Abnormal CRP was defined by a CRP blood level ≥ 3 mg/L. Depressive symptoms were assessed by the Calgary Depression Rating Scale score. The clinicians were blinded of the CRP status of the patient. RESULTS: 411 patients were included (272 SZ and 139 UD). 171 (41.6%) were diagnosed with current major depression (74 (27.2%) for SZ and 97 (69.8%) for UD). 86 SZ (31.6%) and 119 UD (85.6%) were treated by antidepressant. Only 28/74 (37.8%) of the SZ subjects with major depression were administered antidepressants vs. 87/97 (89.7%) for UD. The non-remission rate under antidepressant was 28/86(32.6%) for SZ and 87/119 (73.1%) for UD. Overall, 105 (40.1%) of SZ and 39 (28.1%) of UD patients were found to have abnormal CRP blood levels. Abnormal CRP levels were significantly associated with increased MDD and more strongly with increased rates of non-remission under antidepressants in SZ patients, independently of age, gender, psychotic symptomatology, functioning, tobacco smoking and metabolic syndrome. This result was not replicated in UD patients, which suggests that CRP may be a specific marker of major depression and remission under antidepressant in SZ patients. CONCLUSION: The development of biomarkers in psychiatry may orientate specific etiologic therapies in patients with mental disorders. The present findings suggest that major depression is frequent in SZ patients and that increased CRP levels are associated with non-remission under antidepressants in this population. Anti-inflammatory strategies may be particularly useful in this specific population.

Hypovitaminosis D is associated with negative symptoms, suicide risk, agoraphobia, impaired functional remission, and antidepressant consumption in schizophrenia.

Hypovitaminosis D has been associated with, respectively, major depressive disorder, schizophrenia (SZ), and cognitive disorders in the general population, and with positive and negative symptoms and metabolic syndrome in schizophrenia. The objective was to determine the prevalence of hypovitaminosis D and associated factors in a non-selected multicentric sample of SZ subjects in day hospital. Hypovitaminosis D was defined by blood vitamin D level < 25 nM. Depressive symptoms were assessed by the Calgary Depression Rating Scale Score and Positive and Negative Syndrome Scale Score. Anxiety disorders and suicide risk were evaluated by the Structured Clinical Interview for Mental Disorders. Functioning was evaluated with the Functional Remission of General Schizophrenia Scale. Hypovitaminosis D has been found in 27.5% of the subjects. In multivariate analysis, hypovitaminosis D has been significantly associated with, respectively, higher suicide risk (aOR = 2.67 [1.31-5.46], p = 0.01), agoraphobia (aOR = 3.37 [1.66-6.85], p < 0.0001), antidepressant consumption (aOR = 2.52 [1.37-4.64], p < 0.001), negative symptoms (aOR = 1.04 [1.01-1.07], p = 0.04), decreased functioning (aOR = 0.97[0.95-0.99], p = 0.01), and increased leucocytosis (aOR = 1.17 [1.04-1.32], p = 0.01) independently of age and gender. No association with alcohol use disorder, metabolic syndrome, peripheral inflammation, insulin resistance, or thyroid disturbances has been found (all p > 0.05). Despite some slight abnormalities, no major cognitive impairment has been associated with hypovitaminosis D in the present sample (all p > 0.05 except for WAIS similarities score). Hypovitaminosis D is frequent and associated with suicide risk, agoraphobia and antidepressant consumption in schizophrenia, and more slightly with negative symptoms. Patients with agoraphobia, suicide risk and antidepressant consumption may, therefore, benefit in priority from vitamin D supplementation, given the benefit/risk profile of vitamin D. Further studies should evaluate the impact of vitamin D supplementation on clinical outcomes of SZ subjects.

High C-reactive protein levels are associated with depressive symptoms in schizophrenia.

BACKGROUND: Depressive symptoms are frequently associated with schizophrenia symptoms. C - Reactive protein (CRP), a marker of chronic inflammation, had been found elevated in patients with schizophrenia and in patients with depressive symptoms. However, the association between CRP level and depressive symptoms has been poorly investigated in patients with schizophrenia. The only study conducted found an association between high CRP levels and antidepressant consumption, but not with depressive symptoms investigated with the Calgary Depression Rating Scale for Schizophrenia (CDSS). OBJECTIVES: The aim of this study was to evaluate CRP levels and depressive symptoms in patients with schizophrenia, and to determine whether high CRP levels are associated with depressive symptoms and/or antidepressant consumption, independently of potential confounding factors, especially tobacco-smoking and metabolic syndrome. METHODS: Three hundred and seven patients with schizophrenia were enrolled in this study (mean age = 35.74 years, 69.1% male gender). Depressive symptoms was investigated with the CDSS. Patients were classified in two groups: normal CRP level (≤ 3.0mg/L) and high CRP level (> 3.0mg/L). Current medication was recorded. RESULTS: 124 subjects (40.4%) were classified in the high CRP level group. After adjusting for confounding factors, these patients were found to have higher CDSS scores than those with normal CRP levels in multivariate analyses (p = 0.035, OR = 1.067, 95% CI = 1.004-1.132). No significant association between CRP levels and antidepressants consumption was found. LIMITATIONS: The size sample is relatively small. The cut-off point for high cardiovascular risk was used to define the two groups. CRP was the sole marker of inflammation in this study and was collected at only one time point. The design of this study is cross-sectional and there are no conclusions about the directionality of the association between depression and inflammation in schizophrenia. CONCLUSION: This study found an association between high rates of CRP levels and depressive symptoms in patients with schizophrenia, but no association with antidepressant consumption. Further studies are needed to investigate the impact of inflammation in schizophrenia.

Quality of life is associated with chronic inflammation in depression: A cross-sectional study.

BACKGROUND: Inflammation may play a crucial role in the pathophysiology of depression. However, the association between chronic inflammation and health outcomes in depression remains unclear, particularly for patient-reported outcomes. METHODS: The aim of this study was to investigate the relationship between quality of life (QoL) (physical and mental health, assessed by the SF-36) and chronic inflammation assessed using C-reactive protein (CRP) in patients with current major depressive disorder. RESULTS: One hundred eighty-one patients with depression were enrolled in this study. After adjusting for key socio-demographic, clinical and biological confounding factors, patients with high levels of CRP (> 3.0mg/L) had worse physical health than those with normal CRP levels (OR = 0.95, 95% CI = 0.92-0.99). Significant associations were found between a higher rate of metabolic syndrome (OR = 0.10, 95% CI = 0.02-0.41) and high CRP levels. LIMITATIONS: The cut-off point for high cardiovascular risk was used to define the two groups: normal CRP level and high CRP level. CRP was the sole marker of inflammation in this study and was collected at only one time point. The design of this study is cross-sectional and there are no conclusions about the directionality of the association between QoL and inflammation in depression. QoL was assessed only by SF-36 scores. CONCLUSION: This study found an association between SF-36 physical health score and CRP in patients with depression, thereby showing the need to consider physical well-being in depression. This paves the way for interventions to act both on inflammation and QoL in patients with depression.

Two-year cortical and trabecular bone loss in CKD-5D: biochemical and clinical predictors.

This prospective two-year study of patients on chronic dialysis measured changes in bone mineral density (BMD). Patients with higher baseline BMD and shorter dialysis vintage lost more bone. Treatment with anti-hypertensives acting on the central nervous system was protective against bone loss. Baseline serum levels of sclerostin and bone-specific alkaline phosphatase predicted bone loss. INTRODUCTION: This prospective 2-year study of chronic kidney disease on dialysis (CKD-5D) patients assessed trabecular and cortical bone loss at the hip and spine and examined potential demographic, clinical, and serum biochemical predictors of bone loss. METHODS: Eighty-nine CKD-5D patients had baseline, year 1, and year 2 bone mineral density (BMD) measurements using dual X-ray absorptiometry (DXA) and quantitative computed tomography (QCT); concurrent blood samples were drawn and clinical variables recorded. No study treatments occurred. RESULTS: The 2-year total hip BMD change was - 5.9% by QCT and - 3.1% by DXA (p < 0.001). Spinal BMD was unchanged. QCT total hip cortical mass and volume decreased (- 7.3 and - 10.0%); trabecular volume increased by 5.9% (ps < 0.001). BMD changes did not vary with age, BMI, race, diabetes, smoking, or exercise. Patients with higher baseline BMD and shorter dialysis vintage lost more bone (p < 0.05). Vitamin D analogs and phosphate binders were not protective against bone loss; cinacalcet was protective by univariate but not by multivariable analysis. CNS-affecting antihypertensives were protective against loss of BMD, cortical mass, cortical volume (ps < 0.05) and trabecular mass (p = 0.007). These effects remained after adjustment. BSAP correlated with changes in BMD, cortical mass, and volume (p < 0.01) as did sclerostin (inversely). CONCLUSIONS: There was severe cortical bone loss at the hip best recognized by QCT. Patients with shorter dialysis vintage and less pre-existing bone loss lost more bone, while treatment with CNS-acting antihypertensives was protective. BSAP and sclerostin were useful markers of bone loss.

Quality of life is associated with chronic inflammation in schizophrenia: a cross-sectional study.

Inflammation may play a crucial role in the pathogenesis of schizophrenia. However, the association between chronic inflammation and health outcomes in schizophrenia remains unclear, particularly for patient-reported outcomes. The aim of this study was to investigate the relationship between quality of life (QoL) and chronic inflammation assessed using C -Reactive Protein (CRP) in patients with schizophrenia. Two hundred and fifty six patients with schizophrenia were enrolled in this study. After adjusting for key socio-demographic and clinical confounding factors, patients with high levels of CRP (>3.0 mg/l) had a lower QoL than patients with normal CRP levels (OR = 0.97, 95% CI = 0.94-0.99). An investigation of the dimensions of QoL revealed that psychological well-being, physical well-being and sentimental life were the most salient features of QoL associated with CRP. Significant associations were found between lower educational level (OR = 4.15, 95% CI = 1.55-11.07), higher body mass index (OR = 1.16, 95% CI = 1.06-1.28), higher Fagerström score (OR = 1.22, 95% CI = 1.01-1.47) and high levels of CRP. After replications with longitudinal approaches, the association between QoL and chronic inflammation may offer interesting interventional prospects to act both on inflammation and QoL in patients with schizophrenia.

The SATISPSY-22: development and validation of a French hospitalized patients' satisfaction questionnaire in psychiatry.

OBJECTIVE: The aim of our study was to develop a specific French self-administered instrument for measuring hospitalized patients' satisfaction in psychiatry based on exclusive patient point of view: the SATISPSY-22. METHODS: The development of the SATISPSY was undertaken in three steps: item generation, item reduction, and validation. The content of the SATISPSY was derived from 80 interviews with patients hospitalized in psychiatry. Using item response and classical test theories, item reduction was performed in 2 hospitals on 270 responders. The validation was based on construct validity, reliability, and some aspects of external validity. RESULTS: The SATISPSY contains 22 items describing 6 dimensions (staff, quality of care, personal experience, information, activity, and food). The six-factor structure accounted for 78.0% of the total variance. Each item achieved the 0.40 standard for item-internal consistency, and the Cronbach's alpha coefficients were>0.70. Scores of dimensions were strongly positively correlated with Visual Analogue Scale scores. Significant associations with socioeconomic and clinical indicators showed good discriminant and external validity. INFIT statistics were ranged from 0.71 to 1.25. CONCLUSIONS: The SATISPSY-22 presents satisfactory psychometric properties, enabling patient feedback to be incorporated in a continuous quality health care improvement strategy.

"All that glitters is not alone". Congruity effects in highly and less predictable sentence contexts.

CONTEXT: Using natural connected speech, the aim of the present study was to examine the semantic congruity effect (i.e. the difference between semantically incongruous and congruous words) in sentence contexts that generate high or moderate final word expectancies. METHODS: We used sentences with two levels of word expectancy in the auditory modality: familiar proverbs (that generate high final word expectancy), and unfamiliar sentences (that generate only moderate final word expectancy). RESULTS: Results revealed an early congruity effect (0-200 ms) that developed across all scalp sites for familiar proverbs but not for unfamiliar sentences. By contrast, typical centro-parietal N400 and Late Positivity Component congruity effects developed later (200-500 ms and 600-900 ms ranges) for both familiar proverbs and unfamiliar sentences. DISCUSSION: We argue that the early congruity effect for proverbs comprises both a Phonological Mismatch Negativity, reflecting the processing of the acoustic/phonological mismatch between the expected (congruous) and unexpected (incongruous) sentence completions and a typical N400 semantic congruity effect with an unusual short latency because final words can be predicted from the unusually high contextual constraints of familiar proverbs. These results are considered in the light of current views of anticipation and prediction processes in sentence contexts.

[Electrophysiology and schizophrenic vulnerability: the N400 component as endophenotype candidate?]. / Électrophysiologie et vulnérabilité schizophrénique: la composante N400 comme endophénotype candidat?

Research on early stages of schizophrenia aims to provide early, objective, and stable markers of vulnerability. In this review, we first briefly describe the notion of such markers, or endophenotypes, notably in terms of stability, specificity and heritability. Among other empirical approaches, event-related potentials (ERPs) have been recently considered as putative endophenotypes. The N400 component is an event-related brain potential classically elicited during semantic processing, as suggested by a growing body of empirical studies with a large variety of paradigms. We provide here a short account of its typical descriptions and the interpretations of its functional significance. Then we describe the main current results about schizophrenic alterations of the N400 component. Two levels of semantic processing (automatic spreading and controlled mechanisms) are disturbed in schizophrenia, even if the underlying mechanisms remain unclear or discussed. Several controversial issues may also need further research, such as the influence of symptomatology and evolution of schizophrenia. Another crucial topic concerns the putative schizophrenic specificity, and only little is known about possible alterations of N400 in affective disorders. We discuss the notion of heritability, mainly explored in current literature among people with schizotypal personality. Finally, even if N400 studies contribute to a better understanding of linguistic disturbances in schizophrenia, it appears difficult to consider the N400 component as a relevant schizophrenic endophenotype, given the current paucity of results on its stability, its heritability (clinical and genetic vulnerability) and its schizophrenic specificity.

Femoral bone mineral density reflects histologically determined cortical bone volume in hemodialysis patients.

UNLABELLED: We evaluated the associations between dual energy X-ray absorptiometry (DXA) and histologically determined cancellous and cortical bone volume by controlling for vascular calcifications and demographic variables in hemodialysis (HD) patients. Femoral bone mineral density (f-BMD) was associated with cortical porosity. INTRODUCTION: Assessment of bone mass in chronic kidney disease patients is of clinical importance because of the association between low bone volume, fractures, and vascular calcifications. DXA is used for noninvasive assessment of bone mass whereby vertebral results reflect mainly cancellous bone and femoral results reflect mainly cortical bone. Bone histology allows direct measurements of cancellous and cortical bone volume. The present study evaluates the association between DXA and histologically determined cancellous and cortical bone volumes in HD patients. METHODS: In 38 HD patients, DXA was performed for assessment of bone mass, anterior iliac crest bone biopsies for bone volume, and multislice computed tomography for vascular calcifications. RESULTS: While lumbar bone mineral density (l-BMD) by DXA was not associated with histologically measured cancellous bone volume, coronary Agatson score showed a borderline statistically significant association (P = 0.055). When controlled for age and dialysis duration, f-BMD by DXA was associated with cortical porosity determined by histology (P = 0.005). CONCLUSIONS: The usefulness of l-BMD for predicting bone volume is limited most probably because of interference by soft tissue calcifications. In contrast, f-BMD shows significant association with cortical porosity.

The five most commonly used intact parathyroid hormone assays are useful for screening but not for diagnosing bone turnover abnormalities in CKD-5 patients.

BACKGROUND/AIMS: Assessment of bone turnover for management of renal osteodystrophy is part of routine care in chronic kidney disease Stage 5 (CKD-5) patients. Measurement of intact parathyroid hormone (iPTH) is the most commonly used surrogate marker for bone turnover in these patients. The current study was conducted to evaluate the predictive value of the five most commonly used iPTH assays for bone turnover. METHODS: In a cross-sectional study, 84 CKD-5 patients underwent bone biopsy and blood drawings for determination of iPTH and total serum alkaline phosphatase (AP). RESULTS: Histologically, patients presented with a broad range of bone turnover abnormalities as determined by activation frequency and bone formation rate/bone surface. Results of the five iPTH assays in each patient correlated but were significantly different. There were also significant differences between iPTH measurements at the same bone turnover level. Using Kidney Disease Outcome Quality Initiative recommended iPTH ranges, all assays showed comparably poor diagnostic performance. At 80% specificity, cut-off values of the 5 iPTH assays for low bone turnover varied from 165 to 550 pg/ml and for high bone turnover from 404 to 1,003 pg/ml. Sensitivities at these cutoffs remained below acceptable standards. Addition of AP measurements to iPTH did not improve diagnostic accuracy. CONCLUSIONS: Precise assessment of bone turnover will require utilization of established and novel bone markers reflecting effects of bone turnover rather than measuring only iPTH or other effectors.

Absence of adynamic bone disease in African-Americans with CKD stage 5 after 3 years of vitamin D therapy guided by iPTH and the PTH-(1-84)/N-terminally truncated PTH fragments ratio.

BACKGROUND: Secondary hyperparathyroidism is a frequent complication of chronic kidney disease (CKD). The goal of treatment is to achieve circulating levels of parathyroid hormone (PTH) associated without oversuppression of bone turnover. This is commonly achieved by treatment with vitamin D analogs. Doses of vitamin D compounds are usually monitored by measurement of circulating levels of PTH. STUDY DESIGN: To prospectively assess the effects on bone histology of two different protocols for dosing vitamin D. SETTING AND PARTICIPANTS: African-American patients from the same geographic area, managed by the same team of physicians in three dialysis clinics were studied. Patients were treated with vitamin D for 3 years and underwent bone biopsies for assessment of bone turnover. Dosing of vitamin D during the 3 years prior to the biopsy was done following two different guidelines. One group was treated following K/DOQI guidelines adapted to the bio-intact PTH assay (Protocol A), the other group was managed (Protocol B) following K/DOQI guidelines for intact PTH and/or the ratio of PTH-(1-84)/N-terminally truncated fragments (PTH ratio). PREDICTOR: Levels of circulating PTH and/or PTH ratio. OUTCOME: Prevalence of low bone turnover. MEASUREMENTS: Qualitative and quantitative assessment of bone histology after tetracycline labeling. RESULTS: 7 out of 22 patients managed following Protocol A were found to have low bone turnover (32%) by bone histology. None of the 21 patients managed by Protocol B for guidance of vitamin D therapy, had low bone turnover. LIMITATIONS: Lack of bone biopsy at the beginning of study. CONCLUSIONS: This report indicates that the additional information provided by the PTH ratio represents a distinct advantage in avoiding low bone turnover over the use of a single PTH assay to guide vitamin D dosing in African-American patients with CKD Stage 5 on dialysis.

Improvements in renal osteodystrophy in patients treated with lanthanum carbonate for two years.

AIMS: To investigate the evolution of renal osteodystrophy in patients on maintenance dialysis, treated with lanthanum carbonate (LC) vs. standard phosphate-binder therapy (Stx). MATERIALS AND METHODS: This was a 2-year, randomized, prospective, open-label study during which patients on dialysis received LC titrated to a maximum of 3,000 mg/day or their previous phosphate binder treatment with the aim to achieve target phosphorus levels of < or = 5.9 mg/dl. Paired bone biopsy samples for histomorphometric analysis were available at baseline and 1 year (LC 32, Stx 33), and at baseline and 2 years (LC 32, Stx 24). RESULTS: With similar phosphorus control, Stx was associated with numerically higher serum calcium levels at most visits. Results of osteocalcin and bone-specific alkaline phosphatase in LC patients were higher throughout the study and correlated with parameters of bone formation; however, the differences were not significant. Histological changes in bone turnover and volume were analyzed with respect to normal ranges. There was an improvement in bone turnover in the LC group, which was significant in the 1-year group, and an improvement in bone volume which was significant in the 2-year group. No significant changes in bone turnover or bone volume were observed in the Stx groups. In the 2-year LC group, 1 patient had osteomalacia at baseline and end of therapy, and a mineralization defect developed in 2 other patients. Several possible factors for a mineralization defect were present in these patients, but no single cause could be clearly identified. Histomorphometric parameters of bone, including formation and mineralization, did not correlate with bone lanthanum. No mineralization defect was observed in the Stx groups. CONCLUSION: These findings show that similar phosphorus control with Stx and LC results in higher bone turnover after 1 year and higher bone volume after 2 years with LC.

An assessment of cinacalcet HCl effects on bone histology in dialysis patients with secondary hyperparathyroidism.

AIMS: Cinacalcet lowers plasma parathyroid hormone (PTH) levels in patients with secondary hyperparathyroidism (sHPT), but the bone histologic response has not been described. This prospective, double-blind, placebo-controlled trial assessed the effects of cinacalcet on bone histology and serum markers of bone metabolism in dialysis patients with sHPT. METHODS: Patients with intact PTH (iPTH) > or = 300 pg/ml were randomly assigned 2:1 to receive cinacalcet or placebo with concurrent vitamin D and/or phosphate binder therapy. Cinacalcet (30 - 180 mg/day) was used to achieve iPTH levels < or = 200 pg/ml. Bone biopsies were performed before and after one year of treatment. RESULTS: Baseline and end-of-study data were available from 32 patients (19 cinacalcet, 13 placebo). Baseline bone turnover was elevated in 27, reduced in 3 and normal in 2 patients. Serum bone-specific alkaline phosphatase (BSAP) and N-telopeptide (NTx) were elevated. Cinacalcet treatment decreased PTH and diminished activation frequency, bone formation rate/bone surface, and fibrosis surface/bone surface. Adynamic bone was observed in three patients receiving cinacalcet; in two of these, PTH levels were persistently low (< 100 pg/ml). The histomorphometric parameter changes in bone corresponded to PTH, BSAP and NTx reductions. Bone mineralization parameters remained normal. CONCLUSIONS: Treatment with cinacalcet lowered PTH and reduced bone turnover and tissue fibrosis among most dialysis patients with biochemical evidence of sHPT.

Influence of the parathyroid glands on bone metabolism.

Bone is a classic target tissue for parathyroid hormone (PTH), whose calciotropic effect is mediated largely via catabolic actions on this tissue. Paradoxically, PTH also exerts anabolic actions, with intermittent injections of PTH or its amino-terminal fragments causing an increase in bone formation and bone mass, actions that form the basis for the use of PTH in the treatment of osteoporosis. Besides vitamin D, PTH is the only other known bone anabolic agent. High-affinity PTH receptors (PTH-1R) have been detected on osteoblasts and osteoclasts (albeit in lower numbers). Bone turnover, which includes activation of osteoclasts and osteoblasts, appears to be best reflected not by absolute concentrations of PTH (which can vary based on the assay and antibody used) but by a balance of circulating full-length PTH-(1-84) and amino-terminally truncated C-PTH fragments. When PTH-(1-84) is predominant, bone turnover is promoted. Among PTH fragments, PTH-(7-84) appears to be the most potent antagonist of PTH-(1-84). The mechanisms involved in these effects are unclear although mediation via unique C-terminal receptors has been suggested. We propose that, within the range of total PTH (100-1000 pg mL(-1)), the ratio of PTH-(1-84)/C-PTH fragment is a valuable tool for diagnosis of bone turnover. Data indicate that at PTH levels < 100-150 pg mL(-1) and > 1000 pg mL(-1), the ratio looses its predictive power. Assay type, patient characteristics (race, underlying renal disease) and treatment attributes (vitamin D, corticosteroids, phosphate binders) have an impact on the PTH ratio, and care should be used in interpreting assay results and making subsequent treatment decisions.

Renal osteodystrophy: what's in a name? Presentation of a clinically useful new model to interpret bone histologic findings.

Renal osteodystrophy begins early in the course of chronic kidney disease and occurs almost without exception in all patients with Stage 5 disease (CKD-5). Bone biopsies and evaluation of mineralized bone sections after double tetracycline-labeling are currently considered the gold standard for diagnosis and classification of renal osteodystrophy. Nevertheless, bone biopsies are rarely employed. This is, at least in part, related to the paucity of nephrologists trained in performance of the procedure and the fact that reports of the histologic results are not easily translatable to clinical practice. Results are usually given qualitatively, using non-uniform classifications or by histomorphometric evaluations which are esoteric to most nephrologists. We suggest here that histomorphometric evaluation can be reserved for research and special situations. Also, the customarily used qualitative classification should be replaced by a clinically useful nomenclature, provided the interpretation is done by an individual with sufficient experience in bone pathology. We present a new interactive nomenclature for renal osteodystrophy that addresses abnormalities of turnover, abnormalities of bone balance, and abnormalities of mineralization. The new nomenclature, thus, includes disorders of high- and low-turnover with consideration of the interrelation with positive or negative bone balance with or without mineralization defect. In this schema, changes in bone status are described as deviations from a norm, and treatment is geared toward normalizing values rather than creating any absolute change in one direction or another. It is hoped that such a classification will be easily usable, clinically more relevant, and more amenable to individualized treatment guidance.

Parathyroid hormone assays--evolution and revolutions in the care of dialysis patients.

Renal osteodystrophy may present with low, normal, or high bone turnover. An ideal parathyroid hormone (PTH) assay should discriminate between the bioactive whole PTH-(1-84) molecule and PTH fragments, including the PTH-(7-84) fragment. Most dialysis patients have "intact" PTH (iPTH) levels between 65 and 450 pg/ml, which are poorly predictive of bone turnover state, making the iPTH test of limited value for bone turnover prediction. iPTH levels higher than 500 pg/ml can be observed in some dialysis patients with low bone turnover, while iPTH levels as low as 100 pg/ml have been found in patients with bone turnover above normal, indicating the standard second generation iPTH assay is not a reliable sole indicator of bone turnover. The whole PTH immunoradiometric assay, a third generation assay, uses a detection antibody that recognizes antigenic determinants at the extreme amino-terminal (1-4) end of the PTH molecule, making the assay specific for biologically active whole PTH-(1-84). Comparing results using the whole PTH and iPTH assays, the PTH-(7-84) level is indirectly determined and the PTH-(1-84)/PTH-(7-84) ratio can be calculated. It was shown that PTH-(7-84) inhibits the calcemic effect of PTH-(1-84) and its stimulatory effect on bone turnover. In the interpretation of results using the PTH-(1-84)/PTH-(7-84) ratio, it must be taken into consideration that second generation "intact" PTH assays have different cross-reactivity with PTH-(7-84). Therefore, when comparing or analyzing PTH-(1-84)/PTH-(7-84) ratios, the employed PTH assays must be identical. The whole PTH assay and the PTH-(1-84)/PTH-(7-84) ratio allow more meaningful interpretation of PTH trends, and offer a non-invasive means to more accurately diagnose bone disease in this population.