Breast cancer outcome in relation to bone mineral density and bisphosphonate use: a sub-study of the DATA trial.

PURPOSE: The phase III DATA study compared 6 and 3 years of adjuvant anastrozole following 2-3 years of tamoxifen in postmenopausal breast cancer patients. This pre-planned side-study assessed the relationship between a reduced bone mineral density (BMD) and distant recurrence-free survival (DRFS), and evaluated the effect of bisphosphonates on DRFS. METHODS: We selected all patients with a BMD measurement within 3 years after randomisation (landmark) without any DRFS events. Kaplan-Meier methods and Cox proportional hazards models were used for analyses. RESULTS: Of 1860 eligible patients, 1142 had a DEXA scan before the landmark. The BMD was normal in 436 (38.2%) and showed osteopenia in 565 (49.5%) and osteoporosis in 141 (12.3%) patients. After a median follow-up of 5.0 years from the landmark, neither osteopenia nor osteoporosis (compared with normal BMD) were associated with DRFS in both the 6-year [osteopenia HR 0.82 (95% CI 0.45-1.49), osteoporosis HR 1.10 (95% CI 0.26-4.67)] and the 3-year arm [osteopenia HR 0.75 (95% CI 0.40-1.42), osteoporosis HR 1.86 (95% CI 0.43-8.01)]. Moreover, bisphosphonate use did not impact DRFS. CONCLUSION: No association was observed between a reduced BMD and DRFS. Neither did we observe an impact of bisphosphonates on DRFS.

Therapeutic interventions for chronic kidney disease-mineral and bone disorders: focus on mortality.

PURPOSE OF REVIEW: Chronic kidney disease-mineral and bone disorder (CKD-MBD) encompasses a broad spectrum of abnormalities related to bone and cardiovascular health. Many reports related to therapeutic interventions specifically aimed at these disorders describe an effect only on surrogate outcomes. This review will focus on recent literature pertaining to interventions directed at CKD-MBDs that emphasize the clinical outcome of mortality. RECENT FINDINGS: Higher levels of serum phosphorus (including those within the normal range) and its regulatory hormone, fibroblast growth factor 23 (FGF-23), are associated with increased mortality in patients with all stages of CKD. Reports investigating specific interventions that affect dietary intake of phosphorus, as well as serum levels of phosphorus, FGF-23, calcium, and parathyroid hormone have recently been published which support the hypothesis that abnormal mineral metabolism is directly linked to increased mortality. Unfortunately, with the exception of altered dialysis prescription, no intervention has been subject to the scrutiny of placebo-controlled randomized clinical trials. SUMMARY: Observational evidence continues to accumulate relating specific therapeutic interventions to improved survival in patients with kidney disease including phosphate binders, calcimimetics, and altered dietary and dialysis prescription patterns. It is time for randomized clinical trials to definitively establish whether or not interventions directed at CKD-MBD effect improvement in hard clinical outcomes in patients with kidney disease.

Serum iPTH, calcium and phosphate, and the risk of mortality in a European haemodialysis population.

BACKGROUND: A number of US observational studies reported an increased mortality risk with higher intact parathyroid hormone (iPTH), calcium and/or phosphate. The existence of such a link in a European haemodialysis population was explored as part of the Analysing Data, Recognising Excellence and Optimising Outcomes (ARO) Chronic Kidney Disease (CKD) Research Initiative. METHODS: The association between the markers of mineral and bone disease and clinical outcomes was examined in 7970 patients treated in European Fresenius Medical Care facilities over a median of 21 months. Baseline and time-dependent (TD) Cox regression were performed using Kidney Disease Outcomes Quality Initiative (KDOQI) target ranges as reference categories, adjusting for demographics, medical history, dialysis parameters, inflammation, medications and laboratory parameters. Fractional polynomial (FP) models were also used. RESULTS: Hazard ratio (HR) estimates from baseline analysis for iPTH were U-shaped [>600 pg/mL, HR = 2.10, 95% confidence interval (CI) 1.62-2.73; <75 pg/mL, HR = 1.46, 95% CI 1.17-1.83]. TD analysis confirmed the results for iPTH. Baseline analysis showed that calcium >2.75 mmol/L increased risk of death (HR = 1.70, 95% CI 1.19-2.42). TD analysis showed that both low (HR = 1.19, 95% CI 1.04-1.37) and high calcium (HR = 1.74, 95% CI 1.30-2.34) increased risk of death. Baseline analysis for phosphate showed a U-shaped pattern (<1.13 mmol/L, HR = 1.18, 95% CI 1.01-1.37; >1.78 mmol/L, HR = 1.32, 95% CI 1.13-1.55). TD analysis confirmed the results for phosphate <1.13 mmol/L. HR estimates were higher in patients with diabetes versus those without diabetes for baseline analysis only (P-value = 0.014). FP analysis confirmed the results of baseline and TD analyses. CONCLUSION: Patients with iPTH, calcium and phosphate levels within the KDOQI target ranges have the lowest risk of mortality compared with those outside the target ranges.

[CKD-MBD (Chronic Kidney Disease-Mineral and Bone Disorder). The impact of CKD-MBD on mortality].

The final goal of CKD-MBD (chronic kidney disease, mineral and bone disorder) is to reduce the risk of death in uremic patients. To achieve this objective, it is of importance to manage laboratory abnormalities, bone abnormalities, and vascular calcification appropriately. Many observation studies suggested that the good control of serum phosphate, calcium, and PTH concentration would lead to the lower risk of death. Fracture and vascular calcification would increase the risk for mortality. In addition, some randomized clinical trials have shown that the use of CKD-MBD related drugs, e.g. vitamin D, phosphate binder, might lead to reductions in the risk of death.

Consistent control of mineral and bone disorder in incident hemodialysis patients.

BACKGROUND AND OBJECTIVES: In 2003, the National Kidney Foundation introduced guidelines for the control of parathyroid hormone, calcium, and phosphorus in hemodialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A cohort study was conducted of 22,937 incident hemodialysis patients who were identified from a large national provider between July 1, 2000, and June 30, 2002, and followed through June 30, 2004. Consistent achievement was determined (1) as the simultaneous control of multiple markers over time and (2) as the time in target for each marker during the first year of dialysis. Mortality risk was assessed with Cox proportional hazards models. RESULTS: In the simultaneous control analysis, patients who achieved target for none of the markers had a 51% greater risk for death than those who achieved target for all three markers (reference group). Patients who achieved any target for any single marker had a 35 to 39% higher risk for death, and patients who achieved target for any two of the three markers had a 15 to 21% higher risk for death compared with the reference group. In the time in target analysis, patients with parathyroid hormone in target for 4 quarters had a 25% lower risk for death compared with those who did so for

MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover.

MT1-MMP is a membrane-bound matrix metalloproteinase (MT-MMP) capable of mediating pericellular proteolysis of extracellular matrix components. MT1-MMP is therefore thought to be an important molecular tool for cellular remodeling of the surrounding matrix. To establish the biological role of this membrane proteinase we generated MT1-MMP-deficient mice by gene targeting. MT1-MMP deficiency causes craniofacial dysmorphism, arthritis, osteopenia, dwarfism, and fibrosis of soft tissues due to ablation of a collagenolytic activity that is essential for modeling of skeletal and extraskeletal connective tissues. Our findings demonstrate the pivotal function of MT1-MMP in connective tissue metabolism, and illustrate that modeling of the soft connective tissue matrix by resident cells is essential for the development and maintenance of the hard tissues of the skeleton.