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).

Renal shear wave elastography and urinary procollagen type III amino-terminal propeptide (uPIIINP) in feline chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is one of the most common diseases occurring in cats. It is characterized by renal fibrosis, which is strongly correlated with impairment of renal function. Since renal biopsy is not performed routinely in clinical practice, the non-invasive method of ultrasonographic shear-wave elastography (SWE) was used to determine renal parenchymal stiffness. Currently, urinary procollagen type III amino-terminal propeptide (uPIIINP) is a renal fibrosis biomarker in humans. Moreover, PIIINP is increasingly applied for identification of fibrosis in various organs in animals. RESULTS: The Young's modulus (E) value on SWE, uPIIINP, and renal function were evaluated in 23 CKD cats and 25 healthy cats (HC). The renal cortical E values were significantly higher than those of the renal medulla in both groups (P < 0.001). The E values of the renal cortex and medulla were significantly higher in CKD cats than in HC (P < 0.001 and P < 0.01, respectively). The E values, especially of the cortex, showed a significant positive correlation with concentrations of plasma creatinine (P < 0.001), blood urea nitrogen (P < 0.05), while they had a negative correlation with urine specific gravity (P < 0.001) and urine osmolality per plasma osmolality ratio (P < 0.01). The uPIIINP to creatinine ratios (uPIIINP/Cr) were significantly higher in CKD cats than in HC (P < 0.01) and were highly correlated with renal cortical E values (P < 0.001). CONCLUSIONS: SWE might be an additively useful and non-invasive diagnostic imaging tool to evaluate renal parenchymal stiffness, which correlates with renal functional impairment in CKD cats. Moreover, the uPIIINP/Cr might be a promissing biomarker for adjunctive assessing the renal fibrosis in feline CKD.

Urinary procollagen III aminoterminal propeptide and ß-catenin - New diagnostic biomarkers in solitary functioning kidney?

PURPOSE: We aimed at evaluating urinary levels of procollagen III aminoterminal propeptide (PIIINP) and ß-catenin and the relationship between these markers and clinical and laboratory variables in children with a solitary functioning kidney (SFK). PATIENTS AND METHODS: The study group consisted of 98 (M/F: 62/36) children with an SFK with a median age of 8 years. An age-matched control group contained 54 healthy peers. Urinary levels of procollagen III aminoterminal propeptide and ß-catenin were measured using a commercially available immunoassay kit. RESULTS: The urinary values of PIIINP (UPIIINP) were significantly increased in patients with SFK versus controls (p < 0.01). Our analysis revealed no significant differences in urinary ß-catenin levels between the SFK patients and control subjects (p > 0.05). Only urinary PIIINP levels were correlated to renal function tests, such as serum creatinine, urea, uric acid, and estimated glomerular filtration rate (p<0.05). CONCLUSIONS: An increased urinary level of PIIINP may indicate early kidney impairment in children with SFK. Urinary ß-catenin does not seem to play any important role as a marker of renal function in children with SFK. Further long-term studies are required in order to evaluate the clinical usefulness of these markers and their predictive value of chronic kidney disease (CKD) progression.

Abatacept might increase bone mineral density at femoral neck for patients with rheumatoid arthritis in clinical practice: AIRTIGHT study.

We investigated the influence of abatacept (ABT) on bone mineral density (BMD) and bone metabolic markers (BMMs) in patients with rheumatoid arthritis (RA) compared to other biologic disease-modifying anti-rheumatic drugs (bDMARDs). This prospective, comparative, non-randomized study (the AIRTIGHT study; UMIN000005570) investigated the effects of ABT and other bDMARDs on bone metabolism. A total of 165 RA patients were divided into ABT (n = 50) and non-ABT (n = 115). We evaluated percentage changes in BMD (%ΔBMD) at the lumbar spine and femoral neck using dual-energy X-ray absorptiometry. Urinary levels of cross-linked N-telopeptide of type I collagen (uNTx) and bone-specific alkaline phosphatase (BAP) were used as markers of bone resorption and formation, respectively. No significant differences in 1-year completion rates were seen between ABT (64%) and non-ABT (72%; p = 0.387). The %ΔBMD at the femoral neck was significantly higher in the ABT group (0.97%) than in the non-ABT group (- 2.19%; p = 0.026). Whereas, no significant difference in %ΔBMD at the lumbar spine was observed between groups (ABT, - 0.40%; Non-ABT, - 1.67%; p = 0.524). No significant differences were observed in changes to uNTx or BAP. ABT treatment was significantly associated with increased BMD at the femoral neck (odds ratio (OR) 8.84; 95% CI 1.08-72.4; p = 0.04), and baseline lumbar osteoarthritis was significantly associated with BMD at the lumbar spine (OR 2.97; 95% CI 1.23-7.13; p = 0.02). The efficacy of ABT for increasing BMD at the femoral neck was superior to that of other bDMARDs. ABT may offer good efficacy for improving BMD at the femoral neck in patients with RA.

Can exercise suppress tumour growth in advanced prostate cancer patients with sclerotic bone metastases? A randomised, controlled study protocol examining feasibility, safety and efficacy.

INTRODUCTION: Exercise may positively alter tumour biology through numerous modulatory and regulatory mechanisms in response to a variety of modes and dosages, evidenced in preclinical models to date. Specifically, localised and systemic biochemical alterations produced during and following exercise may suppress tumour formation, growth and distribution by virtue of altered epigenetics and endocrine-paracrine activity. Given the impressive ability of targeted mechanical loading to interfere with metastasis-driven tumour formation in human osteolytic tumour cells, it is of equal interest to determine whether a similar effect is observed in sclerotic tumour cells. The study aims to (1) establish the feasibility and safety of a combined modular multimodal exercise programme with spinal isometric training in advanced prostate cancer patients with sclerotic bone metastases and (2) examine whether targeted and supervised exercise can suppress sclerotic tumour growth and activity in spinal metastases in humans. METHODS AND ANALYSIS: A single-blinded, two-armed, randomised, controlled and explorative phase I clinical trial combining spinal isometric training with a modular multimodal exercise programme in 40 men with advanced prostate cancer and stable sclerotic spinal metastases. Participants will be randomly assigned to (1) the exercise intervention or (2) usual medical care. The intervention arm will receive a 3-month, supervised and individually tailored modular multimodal exercise programme with spinal isometric training. Primary endpoints (feasibility and safety) and secondary endpoints (tumour morphology; biomarker activity; anthropometry; musculoskeletal health; adiposity; physical function; quality of life; anxiety; distress; fatigue; insomnia; physical activity levels) will be measured at baseline and following the intervention. Statistical analyses will include descriptive characteristics, t-tests, effect sizes and two-way (group × time) repeated-measures analysis of variance (or analysis of covariance) to examine differences between groups over time. The data-set will be primarily examined using an intention-to-treat approach with multiple imputations, followed by a secondary sensitivity analysis to ensure data robustness using a complete cases approach. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Human Research Ethics Committee (HREC) of Edith Cowan University and the Sir Charles Gairdner and Osborne Park Health Care Group. If proven to be feasible and safe, this study will form the basis of future phase II and III trials in human patients with advanced cancer. To reach a maximum number of clinicians, practitioners, patients and scientists, outcomes will be disseminated through national and international clinical, conference and patient presentations, as well as publication in high-impact, peer-reviewed academic journals. TRIAL REGISTRATION NUMBER: ACTRN 12616000179437.

Urinary Type III Procollagen Is Associated With Chronic Allograft Dysfunction and Predicts Graft Survival.

BACKGROUND: Chronic allograft dysfunction (CAD) is the most important clinical problem in solid organ transplantation. Interstitial fibrosis and tubular atrophy contribute to long-term renal allograft failure. Urinary type III procollagen N-terminal propeptide (PIIINP), has been shown to associate fibrotic processes. METHODS: One hundred sixty patients with CAD who underwent allograft biopsies were evaluated, and 52 patients with chronic or sclerosing allograft nephropathy were enrolled in the study. The subjects were divided into 2 groups according to the level of urinary PIIINP to creatinine (u-PIIINP-to-Cr): high procollagen group and low procollagen group. The association between u-PIIINP-to-Cr level at the time of biopsy and renal endpoints during 36 months of follow-up was assessed by multivariate Cox analysis. RESULTS: Interstitial fibrosis and proteinuria were higher in the high procollagen group compared with the low urinary procollagen group. Correlation analysis showed that levels of u-PIIINP-to-Cr were positively associated with fibrosis scores. During the follow-up, glomerular filtration rate (GFR) decreased in both study groups; however, GFR declined more in the high procollagen group than in low procollagen group. Cox regression model showed that the u-PIIINP-to-Cr levels, GFR, and proteinuria were independent risk factors associated with graft survival. CONCLUSION: u-PIIINP-to-Cr level is a potentially useful noninvasive marker for graft survival in patients with CAD.

New frontiers in fibrotic disease therapies: The focus of the Joan and Joel Rosenbloom Center for Fibrotic Diseases at Thomas Jefferson University.

Fibrotic diseases constitute a world-wide major health problem, but research support remains inadequate in comparison to the need. Although considerable understanding of the pathogenesis of fibrotic reactions has been attained, no completely effective therapies exist. Although fibrotic disorders are diverse, it is universally appreciated that a particular cell type with unique characteristics, the myofibroblast, is responsible for replacement of functioning tissue with non-functional scar tissue. Understanding the cellular and molecular mechanisms responsible for the creation of myofibroblasts and their activities is central to the development of therapies. Critical signaling cascades, initiated primarily by TGF-ß, but also involving other cytokines which stimulate pro-fibrotic reactions in the myofibroblast, offer potential therapeutic targets. However, because of the multiplicity and complex interactions of these signaling pathways, it is very unlikely that any single drug will be successful in modifying a major fibrotic disease. Therefore, we have chosen to examine the effectiveness of administration of several drug combinations in a mouse pneumoconiosis model. Such treatment proved to be effective. Because fibrotic diseases that tend to be chronic, are difficult to monitor, and are patient variable, implementation of clinical trials is difficult and expensive. Therefore, we have made efforts to identify and validate non-invasive biomarkers found in urine and blood. We describe the potential utility of five such markers: (i) the EDA form of fibronectin (Fn(EDA)), (ii) lysyl oxidase (LOX), (iii) lysyl oxidase-like protein 2 (LoxL2), (iv) connective tissue growth factor (CTGF, CCNII), and (v) the N-terminal propeptide of type III procollagen (PIIINP).

Reference intervals for bone turnover markers in Spanish premenopausal women.

BACKGROUND: The aims of this study were to establish robust reference intervals and to investigate the factors influencing bone turnover markers (BTMs) in healthy premenopausal Spanish women. METHODS: A total of 184 women (35-45 years) from 13 centers in Catalonia were analyzed. Blood and second void urine samples were collected between 8 a.m. and 10 a.m. after an overnight fast. Serum procollagen type I amino-terminal propeptide (PINP) and serum cross-linked C-terminal telopeptide of type I collagen (CTX-I) were measured by two automated assays (Roche and IDS), bone alkaline phosphatase (bone ALP) by ELISA, osteocalcin (OC) by IRMA and urinary NTX-I by ELISA. PTH and 25-hydroxyvitamin D (25OHD) levels were measured. All participants completed a questionnaire on lifestyle factors. RESULTS: Reference intervals were: PINP: 22.7-63.1 and 21.8-65.5 µg/L, bone ALP: 6.0-13.6 µg/L, OC: 8.0-23.0 µg/L, CTX-I: 137-484 and 109-544 ng/L and NTX-I: 19.6-68.9 nM/mM. Oral contraceptive pills (OCPs) influenced PINP (p=0.007), and low body mass index (BMI) was associated with higher BTMs except for bone ALP. Women under 40 had higher median values of most BTMs. CTX-I was influenced by calcium intake (p=0.010) and PTH (p=0.007). 25OHD levels did not influence BTMs. Concordance between the two automated assays for PINP and particularly CTX-I was poor. CONCLUSIONS: Robust reference intervals for BTMs in a Southern European country are provided. The effects of OCPs and BMI on their levels are significant, whilst serum 25OHD levels did not influence BTMs. Age, calcium intake, BMI and PTH influenced CTX-I. The two automated assays for measuring PINP and CTX-I are not interchangeable.

Urine Collagen Fragments and CKD Progression-The Cardiovascular Health Study.

Tubulointerstitial fibrosis is common with ageing and strongly prognostic for ESRD but is poorly captured by eGFR or urine albumin to creatinine ratio (ACR). Higher urine levels of procollagen type III N-terminal propeptide (PIIINP) mark the severity of tubulointerstitial fibrosis in biopsy studies, but the association of urine PIIINP with CKD progression is unknown. Among community-living persons aged ≥65 years, we measured PIIINP in spot urine specimens from the 1996 to 1997 Cardiovascular Health Study visit among individuals with CKD progression (30% decline in eGFR over 9 years, n=192) or incident ESRD (n=54) during follow-up, and in 958 randomly selected participants. We evaluated associations of urine PIIINP with CKD progression and incident ESRD. Associations of urine PIIINP with cardiovascular disease, heart failure, and death were evaluated as secondary end points. At baseline, mean age (±SD) was 78±5 years, mean eGFR was 63±18 ml/min per 1.73 m(2), and median urine PIIINP was 2.6 (interquartile range, 1.4-4.2) µg/L. In a case-control study (192 participants, 231 controls), each doubling of urine PIIINP associated with 22% higher odds of CKD progression (adjusted odds ratio, 1.22; 95% confidence interval, 1.00 to 1.49). Higher urine PIIINP level was also associated with incident ESRD, but results were not significant in fully adjusted models. In a prospective study among the 958 randomly selected participants, higher urine PIIINP was significantly associated with death, but not with incident cardiovascular disease or heart failure. These data suggest higher urine PIIINP levels associate with CKD progression independently of eGFR and ACR in older individuals.

Bone turnover markers in medicamentous and physiological hyperprolactinemia in female rats.

BACKGROUND/AIM: There is a lack of data on the effects of prolactin on calcium metabolism and bone turnover in hyperprolactinemia of various origins. The aim of this study was to compare the influence of medicamentous and physiological hyperprolactinemia on bone turnover in female rats. METHODS: Experimental animals (18 weeks old, Wistar female rats) were divided as follows: the group P - 9 rats, 3 weeks pregnant; the group M3-10 rats that were intramuscularly administrated sulpirid (10 mg/kg) twice daily for 3 weeks, the group M6 - 10 rats that were intramuscularly administrated with sulpirid (10 mg/kg) twice daily for 6 weeks, and age matched nulliparous rats as the control group: 10 rats, 18-week-old (C1) and 7 rats, 24 weeks old (C2). Laboratory investigations included serum ionized calcium and phosphorus, urinary calcium and phosphorous excretion, osteocalcin and serum procollagen type 1 N-terminal propeptide (P1NP). RESULTS: Experimental animals in the group P compared to the control group, displayed lower mean serum ionized calcium (0.5 +/- 0.2 vs 1.12 +/- 0.04 mmol/L; p < 0.001); higher mean serum phosphorus (2.42 +/- 0.46 vs 2.05 +/- 0.2 mmol/L; p < 0.05); increased urinary calcium (3.90 +/- 0.46 vs 3.05 +/- 0.58; p < 0.01) and significantly increased P1NP (489.22 +/- 46.77 vs 361.9 +/- 53.01 pg/mL; p < 0.001). Experimental animals in the group M3 had significantly decreased P1NP, compared to the contol group. Prolongated medicamentous hyperprolactinemia (the group M6) induced increased serum ionized calcium (1.21 +/- 0.03 vs 1.15 +/- 0.02 mmol/L; p < 0.001); decreased serum phosphorus (1.70 +/- 0.13 vs 1.89 +/- 0.32 mmol/L; p < 0.001); decreased osteocalcin and P1NP. CONCLUSIONS: Physiological hyperprolactinemia does not have such harmful effect on bone metabolism as medicamentous hyperprolactinemia. Chronic medicamentous hyperprolactinemia produces lower serum levels of bone formation markers. Assessment of bone turnover markers in prolongated medicamentous hyperprolactinemia provides an opportunity for earlier diagnosis of bone metabolism disturbances and should be considered as mandatory.

Relationships between age-related biochemical markers of bone turnover and OPG, TGF-ß1 and TGF-ß2 in native Chinese women.

Osteoprotegerin (OPG), transforming growth factor-ß1 (TGF-ß1) and TGF-ß2 are cytokines closely associated with bone metabolism. However, their association with bone turnover markers in native Chinese women remains unknown. The study aims to investigate the relationship between bone metabolism related cytokines including OPG, TGF-ß1, TGF-ß2 and bone turnover markers in native Chinese women. The cross-sectional study was conducted on 691 healthy Chinese women (20-80 years old). Levels of OPG, TGF-ß1, TGF-ß2, serum bone-specific alkaline phosphatase (BAP), osteocalcin (OC), cross-linked N-terminal telopeptides of type I collagen (sNTX), cross-linked C-terminal telopeptides of type I collagen (sCTX), urinary NTX (uNTX), urinary CTX (uCTX) and total urinary deoxypyridinoline (uDPD) were determined. The present study showed that OPG and TGF-ß2 had positive correlation with BAP, OC, uNTX, uCTX and uDPD, while TGF-ß1 showed negative correlation with BAP, OC, sCTX, uNTX and uCTX, and most of the coefficients of partial correlation remained significant after adjustments for age and body mass index (BMI). Multiple linear regression stepwise analysis showed that OPG and TGF-ß2 were positive determinative factors for BAP, sCTX, uNTX and uCTX, which could explain 0.6-16.6% of the variation in these markers. TGF-ß1 was a negative determinative factor for BAP, OC, sCTX and uCTX, which could explain 0.7-7.3% of the variation in these markers. This study suggested that measuring bone turnover indicators and serum cytokines simultaneously might help evaluating changes in bone turnover rate caused by aging or menopause in women.

The safety and effectiveness profile of daily teriparatide in a prospective observational study in Japanese patients with osteoporosis at high risk for fracture: interim report.

This postmarketing surveillance study assessed the safety and effectiveness of daily teriparatide treatment in patients with osteoporosis in a Japanese clinical setting. In this prospective, multicenter, observational study, patients with osteoporosis at high risk for fracture received subcutaneous injections of teriparatide (20 µg/day) for a maximum of 24 months. For this interim report, data from 1,671 patients were eligible for analysis at the cutoff date. The mean age was 75.3 years; 93% of patients (1,552/1,671 patients) were women. There were 117 adverse drug reactions (ADRs) reported in 101 of 1,671 patients (6.04%); the most common reported ADRs were nausea, dizziness, headache, and palpitations. No clinically significant safety issues were identified, although 5 serious ADRs were reported in 4/1,671 (0.24 %) patients. At 12 months, 71.9% of patients remained on teriparatide treatment. From 1 month, there were rapid increases in the biomarkers of bone formation P1NP and, to a lesser extent, BAP. In contrast, increases in the biomarkers of bone resorption, serum NTX, urinary NTX, and TRACP5b, were smaller. After 12 months of treatment, there was an increase in bone mineral density at the lumbar spine, femoral neck, and total hip, and a decrease in the Visual Analog Scale score for back pain. The incidence of new vertebral and nonvertebral fractures was 1.21% and 3.18%, respectively. In conclusion, the favorable safety profile and effectiveness of teriparatide observed in this population of Japanese patients with osteoporosis were accompanied by relatively high persistence with treatment, which is a key factor in the success of osteoporosis treatment.

The value of cartilage biomarkers in progressive knee osteoarthritis: cross-sectional and 6-year follow-up study in middle-aged subjects.

To determine the possible diagnostic and prognostic value of cartilage biomarkers in early-stage progressive and nonprogressive knee osteoarthritis (OA) in a population-based cohort of middle-aged subjects with chronic knee pain. Design tibiofemoral (TF) and patellofemoral (PF) radiographs were graded in 128 subjects (mean age at baseline, 45 ± 6.2 years) in 2002, 2005, and 2008. Cartilage degradation was assessed by urinary C-telopeptide fragments of type II collagen (uCTx-II), synthesis by serum type II A procollagen N-terminal propeptide (sPIIANP), and articular tissue turnover in general by cartilage oligomeric matrix protein (sCOMP). Several diagnostic associations were found between all studied biomarkers and progressive osteophytosis. COMP and CTx-II had a predictive value for subsequent progressive osteophytosis in multiple knee compartments and in case of CTx-II-also for progressive JSN. Over the first 3 years (2002-2005), significant associations were observed between COMP and progressive osteophytosis, whereas 3 years later (2005-2008) between CTx-II and progressive JSN. Thus, the associations between cartilage markers (COMP, CTx-II) and progression of radiographic OA features--osteophytes and JSN--were different between 2002-2005 and 2005-2008. Logistic regression revealed that for every unit increase in COMP level, there was 33 % higher risk for TF osteophyte progression. During early-stage OA, the presence and progression of osteophytosis is accompanied by increased level of cartilage biomarkers. This is the first study to demonstrate biochemical differences over the course of knee OA, illustrating a phasic nonpersistent character of OA with periods of progression and stabilization.

Cholecalciferol supplementation does not protect against renal allograft structural and functional deterioration: a retrospective study.

BACKGROUND: Apart from their important role in mediating calcium homeostasis, vitamin D derivatives regulate numerous vitamin D receptor-mediated renoprotective cellular functions including cell differentiation, negative regulation of inflammation, and fibrosis. Renal models of chronic kidney injury and clinical observational studies have suggested that vitamin D analogues may protect against the epithelial-to-mesenchymal transition (EMT), interstitial inflammation, and fibrosis. METHODS: The aim of this retrospective study is to test whether oral supplementation with cholecalciferol (vitamin D3) between 3 and 12 months posttransplantation confers a structural and functional nephroprotection in a population of 64 renal transplant patients, using historical controls. We analyzed glomerular filtration rates using iohexol clearance, urinary procollagen III aminoterminal propeptide excretion, and epithelial phenotypic changes as markers of the EMT and Banff scores at 3 and 12 months after transplantation in 64 renal transplant recipients with or without cholecalciferol supplementation between months 3 and 12. RESULTS: Cholecalciferol supplementation in stable renal transplant recipients did not prevent EMT, interstitial fibrosis, tubular atrophy, or renal function deterioration. CONCLUSION: Our results challenge the experimental data, suggesting that vitamin D-analog supplementation confers nephroprotection. These findings should be confirmed by randomized prospective studies.

Baseline RANKL:OPG ratio and markers of bone and cartilage degradation predict annual radiological progression over 11 years in rheumatoid arthritis.

OBJECTIVE: To determine to what extent baseline measurements of the ratio receptor activator of nuclear factor-kappaB ligand (RANKL):osteoprotegerin (OPG) and C-terminal cross linking of type-I and type-II (CTX-I and CTX-II), in addition to traditional markers of disease severity, could predict annual radiological progression. METHODS: A cohort of 155 patients with early, active, untreated rheumatoid arthritis (RA) who participated in the Combination Therapy in Early Rheumatoid Arthritis trial (COBRA trial) was followed up for 11 years. Urine was sampled at baseline and after 3 months from the start of treatment and analysed for CTX-I and CTX-II. Baseline serum samples were analysed for RANKL and OPG. Available traditional markers of disease severity included baseline measurements of erythrocyte sedimentation rate, rheumatoid factor and baseline radiological damage. A digital database of frequent radiographs was available, scored according to the Sharp/van der Heijde method. Individual annual progression rates were calculated and used as outcome variable. Multiple linear regression analyses identified the strongest predictors of annual radiological progression. RESULTS: In multivariable analyses the RANKL:OPG ratio and CTX-I or CTX-II proved to be independent predictors of annual radiological damage over 11 years. The prediction of annual radiological progression was strongest when the RANKL:OPG ratio and CTX-I or CTX-II were evaluated in the same model (36-39% explained variance). Adding the effect of treatment at 3 months to the baseline models improved the predictive ability of the models up to 44-46%. CONCLUSION: Unfavourable baseline levels of the RANKL:OPG ratio as well as CTX-I and CTX-II in patients with early, active, untreated RA are strong independent predictors of rapid and persistent damage progression over the 11-year follow-up. Early improvement in bone markers by treatment predicts a better outcome.

Possible beneficial effect of bisphosphonates in osteonecrosis of the knee.

UNLABELLED: Osteonecrosis (ON) in the knee occurs as a localized inflammatory disease in relation to spontaneous or non-traumatic ON. Conservative treatment possibilities are limited, and prognosis appears to be poor; in most cases, ON results in knee arthroplasty. Bisphosphonates are suggested to prevent bone resorption and collapse of necrotic bone. In this observational, prospective study we investigated the effect of bisphosphonate treatment in patients with spontaneous or arthroscopy-induced ON of the knee. Twenty-eight patients with osteonecrotic lesions and bone marrow oedema in the knee were included. In 22 patients (80%), ON was identified after arthroscopic surgery of the knee; six patients were diagnosed with spontaneous ON. Patients were initially given pamidronate 120 mg i.v. divided in 3-4 perfusions over 2 weeks, followed by oral bisphosphonate treatment with alendronate 70 mg weekly for 4-6 months. Bisphosphonate treatment resulted in a rapid pain relief, VAS decreasing from 8.2 ± 1.2 at baseline to 5.02 ± 0.6 after 4-6 weeks (p < 0.001). After 6 months, the VAS decreased by 80% (p < 0.001). At the 6-month follow-up, symptoms had resolved completely in 15 patients out of 28; in 6 patients, minimal symptoms (VAS 1-2) remained. In two patients, treatment effect was unsatisfactory, and surgical intervention was needed (arthroplasty). Bone marrow oedema on MRI resolved completely in 18 patients out of 28 with substantial reduction in the remaining. Furthermore, osteonecrotic area resolved completely or demarcation with sclerotic changes of the necrotic area could be observed. Bisphosphonate treatment in patients with osteonecrosis of the knee was associated with a rapid improvement in pain score and radiological consolidation of the area of osteonecrosis. Further randomized, controlled trials are warranted to confirm the potential beneficial role of bisphosphonates in the treatment of osteonecrosis of the knee. LEVEL OF EVIDENCE: observational study, level IV.

A longitudinal analysis of urinary biochemical markers and bone mineral density in STR/Ort mice as a model of spontaneous osteoarthritis.

OBJECTIVE: To investigate the longitudinal changes both in the urinary concentrations of biochemical markers and in bone mineral density (BMD) during disease progression in the STR/Ort mouse model of osteoarthritis (OA). METHODS: Male STR/Ort mice were studied, with CBA mice used as nonarthritic controls. Radiographic evaluation and grading of the knee and measurements of urinary C-terminal crosslinking telopeptide of type II collagen (CTX-II), pyridinoline (Pyr), and deoxypyridinoline were performed between 8 weeks and 40 weeks of age. The BMD of the femoral shaft was measured from 20 weeks to 40 weeks of age and adjusted for body weight. Histologic evaluation and grading were performed at 40 weeks of age. STR/Ort mice were divided into 2 subgroups (STR OA and STR non-OA) based on histologic grading. RESULTS: No significant differences between STR/Ort and CBA mice were observed for any biochemical marker or BMD at any time point. Urinary CTX-II levels and BMD in the STR OA subgroup were higher than those in the STR non-OA subgroup before radiographic changes of OA were apparent. Higher urinary Pyr levels in the STR OA subgroup were observed at the advanced stage of OA. CONCLUSION: Urinary CTX-II could be a useful marker in the early diagnosis and predicting the progression of OA, and urinary Pyr may be a potential marker to assess the severity of OA at an advanced stage. An increase in BMD prior to the establishment of radiographic OA may be related to the induction of OA.

Urinary procollagen III aminoterminal propeptide (PIIINP): a fibrotest for the nephrologist.

BACKGROUND AND OBJECTIVES: Kidney biopsy (KB), to date the only tool for the evaluation of renal fibrosis, carries specific risks, and its relevance is limited by the small size of renal parenchyma assessed. Thus, a noninvasive alternative to KB is required. Collagen type III amino-terminal propeptide (PIIINP) is a degradation product of collagen type III, the increase of which may reflect an ongoing fibrotic process. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a prospective study including 199 patients with various stages of chronic kidney disease (CKD), the association between urinary PIIINP/creatinine ratio (UPIIINP/Cr), patients' characteristics, and renal fibrosis was assessed. RESULTS: A total of 118 of the patients had UPIIINP/Cr measured simultaneously with the performance of a KB. In patients, median UPIIINP/Cr was 290 ng/mmol versus 93.7 ng/mmol in controls. In univariate analysis, UPIIINP/Cr was correlated with serum creatinine, estimated GFR, CKD stage, presence of coronary artery disease, and nephropathy type (glomerulonephritis versus other types). In multivariate analysis, only estimated GFR and nephropathy type were correlated with UPIIINP/Cr. UPIIINP/Cr was closely correlated with the extent of interstitial fibrosis in KB assessed using two different methods. Moreover, UPIIINP/Cr >800 ng/mmol had a negative predictive value of 94% to detect patients in whom KB will eventually prove "noninformative" (KB leading neither to a definite diagnosis of nephropathy nor to specific treatment). CONCLUSIONS: UPIIINP/Cr is a promising fibro-test for the kidney and may alleviate the need for KB in some patients with CKD. Its predictive value for CKD progression deserves evaluation in prospective studies.

Short-term high dietary calcium intake during bedrest has no effect on markers of bone turnover in healthy men.

OBJECTIVE: Immobilization and space flight are causes of disuse osteoporosis. Increasing calcium intake may counteract this disuse-induced bone loss. METHODS: We conducted two bedrest experiments (crossover design: bedrest versus ambulatory control) in a metabolic ward, studying the effect of 1000 mg/d of calcium intake (study A, length of intervention 14 d) compared with that of a high calcium intake of 2000 mg/d (study B, 6 d) on markers of bone turnover. Both studies were randomized, controlled studies with the subjects staying under well-controlled environmental conditions (study A, 9 male subjects, age 23.6+/-3.0 y; study B, 8 male subjects, age 25.5+/-2.9 y). Blood was drawn to analyze serum calcium, parathyroid hormone, procollagen type I C-terminal propeptide, and bone alkaline phosphatase. Urine (24-h) was collected for analysis of calcium, C-terminal telopeptide of collagen type I, and N-terminal telopeptide of collagen type I. RESULTS: In both studies, serum calcium levels remained unchanged. Procollagen type I C-terminal propeptide was lower (P=0.03) in the bedrest phase than in the ambulatory phase in study A and tended to be lower (P=0.08) in bedrest in study B, whereas bone alkaline phosphatase was not affected in either study. Urinary calcium excretion was greater during bedrest than during the ambulatory phase (study A, P=0.005; study B, P=0.002). C-terminal telopeptide of collagen type I excretion was also greater during bedrest in both studies (study A, P<0.001; study B, P<0.001). CONCLUSION: Doubling calcium intake to 2000 mg/d does not prevent increased bone resorption induced by bedrest.

[Progress of research in osteoarthritis. The evaluation of osteoarthritis with biological markers].

It is socially required to establish the correlation of some specific biomarkers and the clinical stage of osteoarthritis (OA). This study is to evaluate the usefulness of serum or urine biomarkers in OA in the large population cohort study of Japan. There are many reports to evaluate the usefulness of biological markers in OA, and the similar clinical results are supported in this study. The further follow-up study would be wished to be done.