Bone turnover markers in the management of postmenopausal osteoporosis.

Osteoporosis is the most common cause of fragility fractures. Bone remodelling is essential for repairing damaged areas within bone to preserve bone strength and for assisting in mineral homeostases. In young adults, bone remodelling is usually balanced with approximately as much bone replaced as is removed during each remodelling cycle. However, when remodelling becomes accelerated in combination with an imbalance that favours bone resorption over formation, such as during menopause, precipitous losses in bone mass occur. Bone turnover markers (BTMs) measure the rate of bone remodelling allowing for a dynamic assessment of skeletal status and hold promise in identifying those at highest risk of rapid bone loss and subsequent fracture. Further, the use of BTMs to monitor individuals administered osteoporosis therapy is attractive as monitoring anti-fracture efficacy with bone mineral density has significant limitations. This review details remodelling biology, pre-analytical and analytical sources of variability for BTMs, describes the most commonly used resorption and formation markers, and offers some guidelines for their use and interpretation in the laboratory and the clinic.

Mechanisms of renal phosphate loss in liver resection-associated hypophosphatemia.

OBJECTIVE: To determine precisely the role of parathyroid hormone (PTH) and of phosphatonins in the genesis of posthepatectomy hypophosphatemia. BACKGROUND: Posthepatectomy hypophosphatemia has recently been related to increased renal fractional excretion of phosphate (FE P). To address the cause of hypophosphatemia, we measured serum concentrations of PTH, various phosphatonins, and the number of removed hepatic segment in patients with this disorder. METHODS: Serum phosphate (PO4), ionized calcium (Ca++), HCO3-, pH and FE P, intact PTH (I-PTH), carboxyl-terminal fibroblast growth factor 23 (C-FGF-23) and intact fibroblast growth factor 23 (I-FGF-23), FGF-7, and secreted frizzled related-protein-4 (sFRP-4) were measured before and on postoperative (po) days 1, 2, 3, 5, and 7, in 18 patients undergoing liver resection. The number of removed hepatic segments was also assessed. RESULTS: Serum PO4 concentrations decreased within 24 hours, were lowest (0.66 +/- 0.03 mmol/L; P < 0.001) at 48 hours, and returned to normal within 5 days of the procedure. FE P peaked at 25.07% +/- 2.26% on po day 1 (P < 0.05). Decreased ionized calcium concentrations (1.10 +/- 0.01 mmol/L; P < 0.01) were observed on po day 1 and were negatively correlated with increased I-PTH concentrations (8.8 +/- 0.9 pmol/L; P < 0.01; correlation: r = -0.062, P = 0.016). FE P was positively related to I-PTH levels on po day 1 (r = 0.52, P = 0.047) and negatively related to PO4 concentrations (r = -0.56, P = 0.024). Severe hypophosphatemia and increased urinary phosphate excretion persisted for 72 hours even when I-PTH concentrations had returned to normal. I-FGF-23 decreased to its nadir of 7.8 +/- 6.9 pg/mL (P < 0.001) on po day 3 and was correlated with PO4 levels on po days 0, 3, 5, and 7 (P < 0.001). C-FGF-23, FGF-7 and sFRP-4 levels could not be related to either PO4 concentrations or FE P. CONCLUSION: Posthepatectomy hypophosphatemia is associated with increased FE P unrelated to I-FGF-23 or C-FGF-23, FGF-7, or sFRP-4. I-PTH contributes to excessive FE P partially on po day 1 but not thereafter. Other yet defined factors should explain post hepatectomy hypophosphatemia.

Fifty years of development in the endocrinology laboratory.

The hormone assay laboratory has seen incredible changes over the last 50 years. In this historical review, we describe how the evolution of fundamental concepts in endocrinology and in hormone assay technology have faceted the laboratory as we know it today. The discovery of neurohormones, hormone receptors and the evolution of the concept of free hormones had a very significant impact on our understanding of the mechanisms of hormone action in health and disease and therefore on how physicians currently prescribe endocrine tests. In the analytical field, modern hormone assays rapidly replaced crude colorimetric methods and bioassays. Starting with the pioneering work of Yalow and Berson, hormone assays have gradually evolved through improvements in all aspects of assay design. This is best exemplified by the evolution of thyroid and parathyroid hormone assays. After reviewing some of the limitations of actual hormone immunoassays, we present some reflections on what the future of the hormone laboratory may look like considering all the developments in automation, point-of-care testing, molecular biology and array technologies.

Measurement of testosterone and its sub-fractions in Canada.

Interest in measuring bioactive testosterone in aging males has increased considerably in the last 5 years in Canada. Emerging andropause clinics have submerged our laboratories with requests for bioavailable testosterone (BAT) testing in replacement or addition to the traditional total testosterone (TT) and direct free testosterone (FT) assays. Beginning with a brief explanation of the bioavailability concept of Pardridge, this review examines the technical characteristics of various approaches currently available to measure TT and its sub-fractions. First, limitations in the measurement of TT, SHBG, and particularly direct (analog) FT assays are extracted from the scientific literature and recent external and internal QC reports. It is concluded that the free direct T assay is useless in the clinical context of andropause. The impact of the observed limitations of TT and SHBG measurements on calculated FT and BAT or BAT obtained by precipitation with ammonium sulfate is then discussed. A comparative evaluation of the advantages and disadvantages of calculated FT or BAT vs. precipitated BAT is presented before concluding that doing a TT as a first line test remains overall the most cost-effective measurement in the diagnosis of hypogonadism in males, and that this sole determination will be sufficient in over 75% of the cases.

When is bioavailable testosterone a redundant test in the diagnosis of hypogonadism in men?

OBJECTIVES: Total testosterone (TT) is frequently prescribed with an SHBG and/or free or bioavailable testosterone measurement. Our objective was to identify a TT range for which subsequent SHBG measurement/calculation adds no additional clinical information. DESIGN AND METHODS: Study data were composed of 3955 sets of TT, SHBG and calculated bioavailable testosterone (cBAT) results from unscreened ambulatory male subjects, aged 18-99. RESULTS: 90% of mismatches between TT and cBAT were observed with TT levels between 6.5 and 13.0 nmol/L, with only slight age variation and no important change with albumin level. SHBG measurement restricted to male patients with TT between 6.5 and 13.0 nmol/L should enable reagent cost savings of over 55%. CONCLUSION: We suggest that a TT level below 6.5 nmol/L or above 13.0 nmol/L provides sufficient useful information for ruling out hypogonadism in ambulatory adult males. This strategy of BAT testing should lead to significant time and cost savings.

Profile of endothelin isopeptides and markers of oxidative stress alongside the onset of streptozotocin-type I diabetes in rats.

Type I diabetes is associated with vascular endothelial abnormalities. Vasoactive mediators such as endothelins and reactive oxygen species are modulated in diabetic patients. We studied the hemodynamic profile and the release of mediators alongside the onset of streptozotocin-induced type I diabetes in rats. Arterial plasma samples were collected from chronically instrumented, unrestrained and conscious normotensive versus streptozotocin-diabetic rats. Streptozotocin-diabetic rats developed severe hypoinsulinemia and subsequent hyperglycemia within 5 days. Mean arterial blood pressure and heart rate decreased from 107 to 87 mmHg (19%) and from 386 to 282 beats per minute (bpm) (27%), respectively over 21 days. On day 20 post-streptozotocin administration, markers of oxidative stress (reactive oxygen species: hydrogen peroxide, total peroxides) and related vasodilatory nitric oxide metabolites, increased. Plasma concentrations of atrial natriuretic peptide were not affected, while vasocontractile endothelin-1 and big endothelin-1 increased in streptozotocindiabetic rats versus chronically instrumented, unrestrained and conscious normotensive rats. In addition, the ratios of endothelin-1 : big endothelin-1 and nitric oxide : endothelin-1 were increased. The depressed hemodynamic profile may result from an imbalance between vasocontracting and relaxing factors. Their interactions with reactive oxygen species may affect vascular tone and lead to vascular complications prevalent in this pathological condition. Defining the complex regulation and roles of these factors merits further investigations, especially in the later endstages of vascular complications, because the development of these complications is linked to the duration of the diabetic state.