Role of bone and kidney in tumor-induced hypercalcemia and its treatment with bisphosphonate and sodium chloride

Harinck, H. I. J.; Bijvoet, O. L. M.; Plantingh, AndréS.T.; Body, Jean‐Jacques; Elte, J.W.F.; Sleeboom, Harm; Wildiers, J.; Neijt, J.P.

doi:10.1016/0002-9343(87)90215-4

Cited by 87 publications

(12 citation statements)

References 21 publications

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“…This conclusion has been strengthened recently by observations that synthetic peptides of PTH-rP increase renal tubular calcium reabsorption in vivo (9), and Leydig tumor cells are known to produce a PTH-rP (35). A different mechanism for increasing renal tubular calcium reabsorption has been proposed by Bijvoet and his colleagues (36). This group has gained enormous experience over the years with the agent 3 amino-l-hydroxypropylidine-1,1-bisphosphonate (APD), a bisphosphonate that specifically inhibits bone resorption.…”

Section: Relative Roles Ofthe Kidney and Bone In Humoral Hypercalcemiamentioning

confidence: 97%

Hypercalcemia of malignancy revisited.

Mundy¹

1988

J. Clin. Invest.

171

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In the three years since the last Perspectives article in the Journal of Clinical Investigation on this topic (1), there have been major advances in our understanding of the heterogeneous mechanisms responsible for the hypercalcemia of malignancy. Reports of many of these advances have appeared in the pages of the Journal of Clinical Investigation. These advances include discovery and characterization of the PTH-related protein (PTH-rP)' produced by many solid tumors, demonstration of tumor-derived transforming growth factor-alpha (TGF-alpha) as a bone-resorbing factor that can cause hypercalcemia, identification of lymphotoxin as thie major mediator of bone destruction in myeloma, and definitive demonstration of increased renal tubular reabsorption of calcium in hypercalcemia associated with solid tumors.One concept that has not changed in these last three years is that the mechanisms responsible for hypercalcemia ofmalignancy are heterogeneous. Different patterns of disturbances in calcium homeostasis occur in different types of malignancy. A simple diagram illustrating some of these different patterns is shown in Fig. 1. In all of the examples provided, increased bone resorption is an important feature. However, the importance of the net fluxes of calcium that occur across the other two major organs that guard calcium homeostasis (gut and kidney) depend on the type of tumor. PTH-related protein (PTH-rP) and solid tumorsIn the last 12 months, a succession of papers has described a protein isolated from solid tumors that has significant sequence homology in the NH2-terminal region to PTH. It was first suggested by Albright almost 50 years ago that hypercalcemia of malignancy could be related to PTH or a PTH-like peptide, but it was not appreciated just how PTH-like this factor was until it was purified from a variety of tumor cell lines and molecularly cloned (2)(3)(4)(5)(6) ceptor (3). Synthetic peptides that correspond to the NH2-terminal end of PTH-rP have now been tested in vitro and in vivo; these peptides appear to have effects essentially identical to those of PTH on the kidney and bone (7-12). Synthetic peptide analogues of PTH-rP enhance osteoclastic bone resorption in vitro (7, 9, 10), enhance renal tubular calcium reabsorption (7, 9), and cause hypercalcemia in vivo (8-10). Differences in potency with PTH have been suggested (7), although these have not been found by other workers (8-10). These observations provoke obvious questions about the normal physiologic role of this protein and its relationship to PTH and to the PTH receptor. The immediate question is whether this protein explains all of the manifestations of hypercalcemia of malignancy in patients with solid tumors. Based on current data, this is unlikely. The syndrome of humoral hypercalcemia of malignancy associated with solid tumors is quite distinct from that of primary hyperparathyroidism, and cannot be explained simply by what is known of the effects of synthetic peptides of PTH-rP on kidney, bone, and gut. For example, osteoclastic bo...

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Section: Relative Roles Ofthe Kidney and Bone In Humoral Hypercalcemiamentioning

confidence: 97%

Hypercalcemia of malignancy revisited.

Mundy¹

1988

J. Clin. Invest.

171

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“…Thus, many cancer patients have increased renal tubular reabsorption of calcium (1)(2)(3)(4), increased urinary excretion of cAMP (5,6), and increased bone resorption (7)(8)(9). However, circulating concentrations of immunoreactive PTH are usually normal or suppressed in patients with hypercalcemia of malignancy (5,10), and tumor tissues iso-lated from such patients have not been found to express significant amounts of messenger RNA for PTH (11).…”

Section: Introductionmentioning

confidence: 99%

Effects of a synthetic peptide of a parathyroid hormone-related protein on calcium homeostasis, renal tubular calcium reabsorption, and bone metabolism in vivo and in vitro in rodents.

Yates¹,

Gutiérrez²,

Smolens³

et al. 1988

J. Clin. Invest.

257

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A synthetic peptide corresponding to the first 34 amino acids of the parathyroid hormone-related protein (PTH-rP) produced by a human tumor associated with hypercalcemia was examined for skeletal and renal effects on calcium metabolism in vivo and in vitro. These effects were compared with those of human parathyroid hormone (1-34), hPTH (1-34). Equal doses of PTH-rP(1-34) and hPTH(1-34) produced equivalent stimulation of adenylate cyclase in vitro in bone cells and kidney cells and tubules. Subcutaneous injection of PTH-rP(1-34) in mice caused a significant dose-related increase in blood ionized calcium similar to that seen with hPTH(1-34) at equivalent doses. Repeated injections of equal doses of both peptides caused sustained hypercalcemia which was significantly greater in PTH-rP(1-34)-treated mice, although each induced comparable increases in histomorphometric indices of osteoclastic bone resorption. PTH-rP(1-34) and hPTH(1-34) also caused similar increases in bone resorption when incubated with fetal rat long bones in organ culture. Infusion of either peptide into thyroparathyroidectomized rats suppressed urinary calcium excretion and increased urinary excretion of cyclic AMP. PTH-rP appears to have similar effects to those of PTH on the skeleton, the kidney, and overall calcium homeostasis.

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“…This was not feasible in the present study, and furthermore there may be major problems with interpre¬ tation of data derived from calcium infusion, since such a procedure induces considerable urinary sodium excredon (21). Therefore, these persons are not in a steady state.…”

Section: Clearance Measurementsmentioning

confidence: 77%

Renal tubular reabsorption of calcium and sodium in primary hyperparathyroidism

Kristiansen

Brøchner‐Mortensen²,

Pedersen³

et al. 1990

Acta Endocrinologica

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Nine patients with primary hyperparathyroidism were studied to investigate the renal tubular reabsorption of calcium and sodium. Fasting serum and urine samples were analysed, and the glomerular filtration rate and the renal plasma clearance of lithium were determined simultaneously. Comparison was made with 9 ageand sex-matched normocalcemic controls. In the proximal tubule, there was a significantly higher absolute reabsorption of calcium in patients than in controls, whereas the fractional reabsorption rate of calcium did not differ between the two groups. In the distal tubule, the absolute calcium reabsorption rate was significantly higher in the patients, whereas the fractional reabsorption rate of calcium was significantly lower than in controls. In the patient group there was a significantly positive linear correlation between the increased tubular capacity for calsium reabsorption and the absolute proximal calcium reabsorption rate, but not between the increased capacity and the absolute distal calcium reabsorption rate. No significant differences were found in the renal tubular handling of sodium between patients and controls. Our results suggest that the increased capacity for tubular calcium reabsorption in primary hyperparathyroidism mainly is localized in the proximal tubule, and that the renal tubular handling of calcium and sodium in this disease differs from that in familial hypocalciuric hypercalcemia.Primary hyperparathyroidism is a disease charac¬ terized biochemically by hypercalcemia, hypophosphatemia, and elevated level of immunoreactive parathyroid hormone (PTH). The hypercalcemia in primary hyperparathyroidism can be accounted for by the enhancing effect of PTH on flux of cal¬ cium from gut and bone and an increased capacity for renal tubular reabsorption of calcium (1), the latter apparently playing the major role (1,2).Another hypercalcémie disorder which biochem¬ ically have much in common with primary hyper¬ parathyroidism is familial hypocalciuric hypercal¬ cemia (3). However, several studies have estab¬ lished that aspects of the pathophysiology of famil¬ ial hypocalcimic hypercalcemia differ from those of typical primary hyperparathyroidism (4-9).Recently we investigated the nephron site of the enhanced tubular calcium reabsorption in familial hypocalcimic hypercalcemia by means of combined determination of the glomerular filtration rate (GFR) and lithium clearance (10). Compared with normal healthy controls, the results suggested that the increased tubular calcium reabsorption in fa¬ milial hypocalcimic hypercalcemia took place ex¬ clusively in the proximal tubule. Furthermore, the same study revealed a difference in renal handling of sodium between familial hypocalcimic hypercal¬ cemia and controls (11).As an extension of that study we have attempted to elucidate the renal tubular function in primary hyperparathyroidism with special reference to:1. Estimation of the increased capacity for renal tubular reabsorption of calcium.2. Determination of fractional and absolute reabsorptio...

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Role of bone and kidney in tumor-induced hypercalcemia and its treatment with bisphosphonate and sodium chloride

Cited by 87 publications

References 21 publications

Hypercalcemia of malignancy revisited.

Hypercalcemia of malignancy revisited.

Effects of a synthetic peptide of a parathyroid hormone-related protein on calcium homeostasis, renal tubular calcium reabsorption, and bone metabolism in vivo and in vitro in rodents.

Renal tubular reabsorption of calcium and sodium in primary hyperparathyroidism

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