Objectives: To identify evidence for the role of bisphosphonates in malignancy for the treatment of hypercalcaemia, prevention of skeletal morbidity and use in the adjuvant setting. To perform an economic review of current literature and model the cost effectiveness of bisphosphonates in the treatment of hypercalcaemia and prevention of skeletal morbidity Data sources: Electronic databases (1966-June 2001). Cochrane register. Pharmaceutical companies. Experts in the field. Handsearching of abstracts and leading oncology journals (1999-2001). Review methods: Two independent reviewers assessed studies for inclusion, according to predetermined criteria, and extracted relevant data. Overall event rates were pooled in a meta-analysis, odds ratios ( OR) were given with 95% confidence intervals (CI). Where data could not be combined, studies were reported individually and proportions compared using chi- squared analysis. Cost and cost-effectiveness were assessed by a decision analytic model comparing different bisphosphonate regimens for the treatment of hypercalcaemia; Markov models were employed to evaluate the use of bisphosphonates to prevent skeletal-related events (SRE) in patients with breast cancer and multiple myeloma. Results: For acute hypercalcaemia of malignancy, bisphosphonates normalised serum calcium in >70% of patients within 2-6 days. Pamidronate was more effective than control, etidronate, mithramycin and low-dose clodronate, but equal to high dose clodronate, in achieving normocalcaemia. Pamidronate prolongs ( doubles) the median time to relapse compared with clodronate or etidronate. For prevention of skeletal morbidity, bisphosphonates compared with placebo, significantly reduced the OR for fractures (OR [95% CI], vertebral, 0.69 [0.57-0.84], non-vertebral, 0.65 [0.54-0.79], combined, 0.65 [0.55-0.78]) radiotherapy 0.67 [0.57-0.79] and hypercalcaemia 0.54 [0.36-0.81] but not orthopaedic surgery 0.70 [0.46-1.05] or spinal cord compression 0.71 [0.47-1.08]. However, reduction in orthopaedic surgery was significant in studies that lasted over a year 0.59 [0.39-0.88]. Bisphosphonates significantly increased the time to first SRE but did not affect survival. Subanalyses were performed for disease groups, drugs and route of administration. Most evidence supports the use of intravenous aminobisphosphonates. For adjuvant use of bisphosphonates, Clodronate, given to patients with primary operable breast cancer and no metastatic disease, significantly reduced the number of patients developing bone metastases. This benefit was not maintained once regular administration had been discontinued. Two trials reported significant survival advantages in the treated groups. Bisphosphonates reduce the number of bone metastases in patients with both early and advanced breast cancer. Bisphosphonates are well tolerated with a low incidence of side-effects. Economic modelling showed that for acute hypercalcaemia, drugs with the longest cumulative duration of normocalcaemia were most cost-effective. Zoledronate 4 mg was the most costly, but most cost-effective treatment. For skeletal morbidity, Markov models estimated that the overall cost of bisphosphonate therapy to prevent an SRE was pound250 and pound1500 per event for patients with breast cancer and multiple myeloma, respectively. Bisphosphonate treatment is sometimes cost-saving in breast cancer patients where fractures are prevented. Conclusions: High dose aminobisphosphonates are most effective for the treatment of acute hypercalcaemia and delay time to relapse. Bisphosphonates significantly reduce SREs and delay the time to first SRE in patients with bony metastatic disease but do not affect survival. Benefit is demonstrated after administration for at least 6-12 months. The greatest body of evidence supports the use of intravenous aminobisphosphonates. Further evidence is required to support use in the adjuvant setting.

/pdf/a-systematic-review-of-the-role-of-bisphosphonates-in-o1merva1fv.pdf

A systematic review of the role of bisphosphonates in metastatic disease.

https://www.tpbin.com/Uploads/Subjects/cb210f6b-b28e-4704-9f8d-adaefa600e01.pdf

Current views on calcium phosphate osteogenicity and the translation into effective bone regeneration strategies

The Evaluation of Measurement Data - Guide to the Expression of Uncertainty in Measurement (usually referred to as the GUM) provides general rules for evaluating and expressing uncertainty in measurement When a measurand, y, is calculated from other measurements through a functional relationship, uncertainties in the input variables will propagate through the calculation to an uncertainty in the output y The manner in which such uncertainties are propagated through a functional relationship provides much of the mathematical challenge to fully understanding the GUMThe aim of this review is to provide a general overview of the GUM and to show how the calculation of uncertainty in the measurand may be achieved through a functional relationship That is, starting with the general equation for combining uncertainty components as outlined in the GUM, we show how this general equation can be applied to various functional relationships in order to derive a combined standard uncertainty for the output value of the particular function (the measurand) The GUM equation may be applied to any mathematical form or functional relationship (the starting point for laboratory calculations) and describes the propagation of uncertainty from the input variable(s) to the output value of the function (the end point or outcome of the laboratory calculation) A rule-based approach is suggested with a number of the more common rules tabulated for the routine calculation of measurement uncertainty

Uncertainty of measurement: A review of the rules for calculating uncertainty components through functional relationships

OBJECTIVES: To evaluate a new formula for glomerular filtration rate (GFR), derived from the Modification of Diet in Renal Disease (MDRD) study in older people. DESIGN: An observational study of the performance of the MDRD formula compared with other formulae and creatinine clearance (ClCr) as measures of the GFR. SETTING: Volunteers were recruited via outpatient clinics. PARTICIPANTS: Fifty-two patients (27 men, 25 women: mean age 80, range 69-92) with a variety of medical diagnoses. Mean GFR was 53.3 mL/min/1.73 m 2 (range 15.9-100.2). Exclusion criteria included renal replacement therapy/renal transplantation and cognitive impairment. MEASUREMENTS: 51 Chromium ethylenediaminetetraacetic acid ( 51 Cr EDTA) was used as the reference method against which the formulaic estimates of GFR were compared using bias plot and regression analyses. RESULTS: The MDRD and Cockcroft and Gault formulae (both coefficient of determination (R 2 ) = 0.84) gave the best fit with GFR, followed by the Jelliffe formula (R 2 = 0.81), ClCr (R 2 = 0.73) and the Baracskay formula (R 2 = 0.56). ClCr (-1.2%) demonstrated minimal bias compared with the MDRD (8.0%) and Cockcroft and Gault (-10.4%) formulae. However, imprecision compared with 51 Cr EDTA was lowest for the Cockcroft and Gault formula, with 50% of estimates lying between -9.5 and -0.5 mL/min/1.73 m 2 of measured 51 Cr EDTA clearance. This compares with -6.7 and 10.1 mL/min/1.73 m 2 for ClCr and 0.0 and 12.7 mL/min/1.73 m 2 for the MDRD formula. CONCLUSION: Calculated estimates of GFR are an improvement over ClCr estimation. On balance, the MDRD formula does not improve the estimate of GFR compared with the Cockcroft and Gault formula in older Caucasian patients with chronic renal insufficiency.

Estimation of glomerular filtration rate in older patients with chronic renal insufficiency: is the modification of diet in renal disease formula an improvement?

background Studies indicate that gastrectomy might alter calcium and bone metabolism, resulting in bone disorders No data are currently available on the prevalence of bone disorders after gastrectomy methods Sixty gastrectomy patients were investigated for serum parameters of calcium and bone metabolism 5 to 20 years postoperatively and compared to an age- and sex-matched healthy control population Forty patients agreed to a radiological investigation of the spine by anterior-posterior and lateral radiographs of the thoracic and lumbar spine and by computed tomography (CT) osteodensitometry results Serum calcium and 25-(OH)-vitamin D were decreased in gastrectomized patients, while parathyroid hormone and 1,25-(OH) 2 -vitamin D were increased Serum parameters of calcium metabolism were altered in as many as 68% of patients We found 31 vertebral fractures in 13 patients, 30 grade 2 vertebral deformities in 18 patients, and osteopenia in 15 patients, corresponding to a prevalence of 33%, 45%, and 37% in gastrectomized patients, respectively The overall rate of gastrectomy patients having vertebral fractures and/or osteopenia was 55% The risk of having a vertebral deformity was increased by more than sixfold after gastrectomy Our study is the first report evaluating vertebral deformities in gastrectomized patients, and the largest series of gastrectomized patients investigated by CT osteodensitometry conclusion We found a high prevalence of bone disorders in gastrectomized patients, possibly resulting from disorders in calcium metabolism Postgastrectomy bone disease might derive from a calcium deficit, which increases calcium release from bone and impairs calcification of newly build bone matrix

High prevalence of bone disorders after gastrectomy

Serum total calcium was measured in 1693 patients during a four-month period. We examined the effects of adjustment for albumin concentration on the interpretation of single measurements of serum total calcium and on the variation of series of measurements in individual patients. Markedly abnormal total calcium concentrations--2.75 mmol/l (11.0 mg/100 ml) or more, or 2.00 mmol/l (8.0 mg/100 ml) or less--were found in 115 patients, but only 24 (21%) remained markedly abnormal after adjustment for albumin. Three patients, two with malignant disease and one with primary hyperparathyroidism, had significant hypercalcaemia which was masked by hypoalbuminaemia. The serum total calcium measured on a subsequent occasion had changed 0.15 mmol/l (0.6 mg/100 ml) or more in 60 patients, but after adjustment for albumin this number was reduced to 27 (45%). The within-person standard deviation for serum total calcium was calculated in 26 patients with normal mean adjusted calcium concentrations who had had six or more sequential measurements. The mean standard deviation was 0.148 mmol/1 (0.59 mg/100 ml) and, after adjustment for albumin, this was reduced to 0.100 mmol/1 (0.40 mg/100 ml). We conclude that adjustment of serum total calcium concentration for albumin is essential to detect abnormal values and to assess changes in a value.

https://jcp.bmj.com/content/jclinpath/32/1/56.full.pdf

Interpretation of serum total calcium: effects of adjustment for albumin concentration on frequency of abnormal values and on detection of change in the individual.

We examined the plasma urea and creatinine concentrations and the ratio between them according to diagnosis in 100 unselected and 31 selected adult hospital patients with a plasma urea concentration greater than or equal to 10 mmol/l (60mg/100ml). We also examined plasma urea and creatinine concentrations in 350 unselected consecutive patients, but found no useful relation between the two values. Congestive heart failure was the most common identifiable cause of a raised plasma urea concentration in the 100 unselected patients (36%). Among these 100 patinets the plasma creatinine concentration was a more useful discriminant between prerenal uraemia and intrinsic renal failure than was the urea:creatinine ratio or the plasma urea concentration. A plasma creatinine concentration greater than 250 mumol/1 (2-8 mg/100ml) indicated intrinsic renal failure with a 90% probability.

https://www.bmj.com/content/bmj/2/6092/929.full.pdf

M E Carver

Papers

Interpretation of serum total calcium: effects of adjustment for albumin concentration on frequency of abnormal values and on detection of change in the individual.

Plasma creatinine and urea: creatinine ratio in patients with raised plasma urea