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Plasma concentrations of parathyroid hormone-related protein (PTHrP), parathyroid hormone, alkaline phosphatase, osteocalcin and albumin-adjusted calcium were measured along with nephrogenous cyclic adenosine monophosphate (NcAMP) in 10 normal women longitudinally through pregnancy. In addition, an assessment of bone resorption was made in these same subjects by the measurement in true fasting urine specimens of the calcium/creatinine ratio (Ca/Cr), hydroxyproline/creatinine ratio (HP/Cr), pyridinoline/creatinine ratio (Pyr/Cr) and deoxypyridinoline/creatine ratio (Dpyr/Cr). The PTHrP level rose through pregnancy from (mean +/- SEM) 0.8 +/- 0.2 pmol/l in the first trimester to 2.7 +/- 0.2 pmol/l 6 weeks postpartum (p < 0.0001). Serum alkaline phosphatase rose from 94 +/- 8 U/l (first trimester) to 347 +/- 25 U/l at term (p < 0.0001). A significant positive correlation was evident between PTHrP and alkaline phosphatase up to term (r = 0.44, p < 0.005). Parathyroid hormone concentrations remained unchanged during pregnancy but rose significantly postpartum from 1.8 +/- 0.2 pmol/l (first trimester) to 3.1 +/- 0.5 pmol/l (p < 0.0001). Similarly, osteocalcin, a marker of bone formative activity, remained unchanged through pregnancy but rose significantly at 6 weeks after delivery to 0.38 +/- 0.05 nmol/l from 0.19 +/- 0.03 nmol/l (first trimester) (p = 0.019). No significant change was noted in serum-adjusted calcium or NcAMP, either through pregnancy or at the postpartum assessment. Fasting urinary Ca/Cr fell through pregnancy from 0.70 +/- 0.11 (first trimester) to a nadir of 0.19 +/- 0.04 6 weeks postpartum (p = 0.007).(ABSTRACT TRUNCATED AT 250 WORDS)

In this study we retrospectively reviewed results of the first 9 days of treatment with pamidronate at doses of 30 mg (n = 13), 45 mg (n = 9), and 90 mg (n = 13) in an attempt to see what factors influenced the response of serum calcium to pamidronate. The nadir of serum calcium obtained post treatment was correlated with pretreatment levels of nephrogenous cyclic adenosine monophosphate (NcAMP), the renal tubular threshold for phosphate reabsorption (TmPO4), and the renal tubular threshold for calcium reabsorption (TmCa). Using the post treatment serum calcium levels, patients were divided into "good" and "poor" responders depending on whether a normal serum calcium was obtained. Pretreatment NcAMP was significantly correlated with the magnitude of the response of serum calcium (r = 0.45, P = 0.0001). Pretreatment NcAMP was significantly higher in the poor responders (mean +/- SEM): 65.0 +/- 9.4 nmol/liter GF (poor responders) versus 29.6 +/- 6.3 (good responders), P = 0.004. NcAMP as a predictor of the acute response of serum calcium showed a sensitivity of 93% and a specificity of 72%. Pretreatment TmPO4 was negatively correlated with the serum calcium response post treatment (r = -0.41, P = 0.003). However, though TmPO4 tended to be lower in the poor responders, this was not statistically significant [0.65 mmol/liter GF +/- 0.09 (poor responders) versus 0.76 mmol/liter GF +/- 0.06 (good responders)]. As a predictor of the acute response of serum calcium, TmPO4 was less good with a sensitivity of 70% and specificity of 58%. No significant correlation was present between TmCa and the serum calcium response.(ABSTRACT TRUNCATED AT 250 WORDS)

Several aspects of calcium metabolism were studied in five patients during the surgical exploration of malignant tumours associated with humorally-mediated hypercalcaemia. Before operation in all patients the renal tubular threshold for calcium reabsorption was raised and the threshold for renal tubular phosphate reabsorption depressed. On removal of the primary tumour in three cases, serum calcium returned to normal, renal calcium threshold fell, renal phosphate threshold rose, but urinary hydroxyproline excretion did not change. In two patients where the tumour proved inoperable, serum calcium remained elevated and no changes in renal calcium threshold or phosphate threshold occurred. Histomorphometry carried out on biopsy specimens from four patients showed normal bone resorption in three, and slightly increased resorption in one, without depression of osteoblastic bone formation. It is suggested that hypercalcaemia in these patients resulted mainly from an alteration in renal calcium threshold caused by a humoral substance released by tumour cells. Correction of hypercalcaemia on removal of the primary tumour was achieved rapidly and could be explained principally by a reduction in renal calcium threshold with increased loss of calcium into the urine. These data contrast with those of many previous studies which have emphasised the predominant role of accelerated osteoclastic bone resorption as the principal cause of hypercalcaemia in malignancy and suggest that a renal effect of the putative humoral agent may predominate in some cases.

A simple procedure is described for the preparation of a stable precision quality control material for use in the measurement of level of ionised calcium in serum at or near the reference range. Repeat analyses on a Nova 2 ionised calcium analyser of serum pools stored at different temperatures over a period of three months showed coefficients of variation less of less than 4%.

The renal handling of calcium was examined in 31 patients with hypercalcaemia of malignancy. Results were compared with those from patients with primary hyperparathyroidism, and normal controls rendered hypercalcaemic by calcium infusion. On relating the urinary calcium excretion indices to serum calcium values, inappropriately low rates of urinary calcium excretion were generally found in patients with malignancy associated hypercalcaemia. Further, the pattern of urinary calcium excretion in these subjects was similar to that found in patients with primary hyperparathyroidism. These observations suggest that, in many solid tumours, the development of hypercalcaemia may be attributable to a humoral mediator with a parathyroid hormone-like effect on renal tubular calcium reabsorption. The relatively frequent occurrence of hypercalcaemia in malignant disease thus may be partially explained by the presence of this humoral agent, which may impair the renal excretion of an increase in filtered calcium load, whether due to bone metastases, or humorally mediated osteolysis.

The relation between urinary sodium excretion (NaE) and renal tubular calcium reabsorption (TmCa/GFR) was assessed in patients with hypercalcaemia associated with malignancy and primary hyperparathyroidism. On acute saline loading of seven normally hydrated patients with primary hyperparathyroidism and five patients with malignancy, raised values of TmCa/GFR were reduced to normal in most cases, in association with increases in NaE. The reduction in TmCa/GFR, which occurred, may have been due to a reduction in proximal tubular calcium reabsorption associated with sodium: this would have obscured the effect of humorally mediated increases in distal tubular calcium reabsorption, which are stimulated either by parathyroid hormone or by a putative humoral mediator in hypercalcaemia of malignancy. In patients who were normally hydrated NaE and TmCa/GFR were not significantly correlated. When data were included from patients who were dehydrated and from those undergoing acute saline loading, significant inverse correlations between NaE and TmCa/GFR were observed both in primary hyperparathyroidism (r = -0.49; p less than 0.02) and malignancy (r = -0.60; p less than 0.001). In clinical practice changes in TmCa/GFR associated with sodium seem to be of minor importance under normal circumstances, but they become evident at the upper and lower extremes of urinary sodium excretion. In clinical studies of renal calcium handling urinary sodium excretion must also be assessed, as interpreting TmCa/GFR data is difficult in states of excessive sodium loading or depletion.