Bone, 12, pp. 47-56, (1991) Printed in the USA. All rights reserved.
8756-3282/91 $3.00 + .OO Copyright 0 1991 Pergamon Press plc
Evaluation of Bone Resorption and Renal Tubular Reabsorption of Calcium and Phosphate in Malignant and Nonmalignant Hypercalcemia B. BUCHS,
R. RIZZOLI*
and J. P. BONJOUR
Division of Clinical Pathophysiology, Department of Medicine, University Hospital of Geneva, CH-1211 Geneva 4, Switzerland Address for correspondence and reprints: Hospital, CH-1211 Geneve 4, Switzerland.
Rene Rizzoli, M.D., Division of Clinical Pathophysiology,
Abstract
of a Max Cloetta career development
of Medicine,
University
Increased TRCaI is restricted to some types of tumor, whereas decreased TmPYGFR is observed in all types except prostate carcinoma. In nonmalignant hypercalcemia, a sig nificant increase in mean TRCaI was only observed in PI-IP, of which individual cases can be fully discriminated from other conditions by using a new index taking into account alteration in the renal transport capacity of both Ca and Pi.
Tubular reabsorption of calcium (Ca) is becoming recognixed as a determinant of malignant hypercalcemia. However, its importance as compared to increased bone resorption has not yet been widely investigated. We determined Ca fluxes of bone resorption and tubular reabsorption in 141 rehydrated patients with hypercalcemia of malignant or benign origin, before any specitIc treatment. Bone resorp tion (BRI) was evaluated by fasting urinary Ca excretion and Ca tubular reabsorption using an index (TRCaI) calculated from a nomogram relating fasting urinary Ca excretion and calcemia. The relationship between alterations in TRCaI and in the tubular capacity to reabsorb inorganic phosphate (Pi), as judged by TmPi/GFR, was also examined for each cause of hypercalcemia. Among 101 cases with malignancy, 67% had overt bone metastases, but all displayed increased BRI. Calcemia was highest in breast cancer and lowest in prostate carcinoma. BRI was markedly increased in breast cancer, lymphoma, and multiple myeloma, whereas it was slightly elevated in lung squamous cell, renal, and liver carcinomas. TRCaI was increased in 49% of malignant hypercalcemia, particularly in epidermoid (above the upper normal limit in 71% of the cases), renal, and liver carcinomas. It was elevated in 54% of breast cancer and normal in multiple myeloma and prostate cancer. In nomualignant hypercalcemia, BRI was markedly increased In vitamin D httoxlcatIon, sarcoidosis, and hnmobilixation. In primary hyperparathyroklism (PIIP), BRI was moderately increased. TRCaI was abnormally elevated in PIIP, but normal in vitamin D intoxication, sarcoidosis, and immobilixabion. In maligmmt hypercalcemia, TmPVGFR was low in 77% of patients and in all types of tumors, except in prostate carcinoma. The index ratio [TRCaI/(TmPi/GFR)] gave a better discrimination of PI-IP from other causes of nonmalignant hypercalcemia than the use of either TRCaI or TmPl/GFR taken alone. Thus, in malignant hypercalcemia, increased bone resorption is associated with an elevation ln tubular Ca reabsorption in halfthe patients surveyed, whereas low tubular Pi reabsorption is observed in more than 75%.
*Dr.R. Rizzoli is a recipient
Department
Key Words: Malignant hypercalcemia-Primary hyperparathyroidism-Tubular reabsorption of calcium-Tubular reabsorption of phosphate-Bone resorption.
Introduction Hypercalcemia is a frequent complication of malignant disease (Fisken et al. 1980; Mundy and Martin 1982; Mundy et al. 1984). The increased level of plasma calcium (Ca) in malignancy has been ascribed to enhanced bone resorption caused either by bone metastases or by diffnse skeletal destruction due to tumor-produced circulating factors that stimulate bone resorption (Mundy and Martin 1982; Mundy et al. 1984; Insogna and Broadus 1987). Evidence has been provided, however, in certain types of cancer, of increased renal tubular reabsorption of Ca (Ralston et al. 1984a,b; Percival et al. 1985; Heller and Hosking 1986; Bonjour et al. 1987, 1988; Harinck et al. 1987). This concept has received considerable support by the recent isolation and characterization of a protein showing a structural homology with parathyroid hormone (PTH), and displaying similar effects in vitro as well as in vivo (Moseley et al. 1987; Horiuchi et al. 1987; Martin 1988; Broadus et al. 1988; Yates et al. 1988; pizurki et al. 1988; Rizzoli et al. 1989 a,b). In particular, the infusion to thyroparathyroidectomized rats of a synthetic aminoterminal fragment of this parathyroid hormonerelated protein (PTHrP) produced an increase in both bone resorption and tubular Ca reabsorption (Rizzoli et al. 1989a). In this model, the renal effect appeared to be the main determinant of PTHrP-induced hypercalcemia. The prevalence of increased renal tubular reabsorption of Ca in malignant hypercalcemia, whether due to PTHrP or to another tumoral factor(s), is not known. In the present work, we determined quantitative indices of Ca flux for both bone resorption and tubular reabsorption in 101 rehydrated patients with malignant hypercalcemia. These parameters were also evaluated
award.
41
B. Buchs et al.: Calcium and phosphate reabsorption
48
Table I. Indices of bone resorption
(BRI) and of tubular reabsorption
Number of subjects
Types of tumors
Bone invasion (% of cases)
of calcium (TRW)
in 101 patients with malignant hypercalcemia.
BRI (mmol/mmol)
Plasma Ca (mmoU1)
in hypercalcemia
TRCaI (mmol/l GFR)
Breast
35
100
3.61kO.66***
2.82k1.51***
2.96iO.56**
Epidetmoid b,
21
48
3.18iO.32***
1.33m71***
3.10&0.36***
Myeloma
13
100
3.17kO.24***
1.65ti.84***
2.46kO.53
Lymphoma
6
14
3.41ko.45***
2.16+0.93***
2.88i0.44
Kidney
7
0
3.29kO.20***
1.57*1.05**
3.13kO.24**
Liver
3
33
3.47nl.34***
1.63iO.7 I*
3.37fo.61**
Ptostate
3
100
2.8 lH.09
1.17ko.15
2.53zt0.23
13
58
3.19fo.35***
1.77kO.82***
2.95m.33*
2.25-2.62
0.10-0.50
2.40-2.88
Miscellanous ‘) Normal range
Values are mean f SD Bone resorption index (BRI) and tubular reabsorption index (TWX) were determined as described in “Methods” in rehydrated patients with malignant hypemalcemia before any antiosteolytic therapy. ***P
8756-3282/91 $3.00 + .OO Copyright 0 1991 Pergamon Press plc
Evaluation of Bone Resorption and Renal Tubular Reabsorption of Calcium and Phosphate in Malignant and Nonmalignant Hypercalcemia B. BUCHS,
R. RIZZOLI*
and J. P. BONJOUR
Division of Clinical Pathophysiology, Department of Medicine, University Hospital of Geneva, CH-1211 Geneva 4, Switzerland Address for correspondence and reprints: Hospital, CH-1211 Geneve 4, Switzerland.
Rene Rizzoli, M.D., Division of Clinical Pathophysiology,
Abstract
of a Max Cloetta career development
of Medicine,
University
Increased TRCaI is restricted to some types of tumor, whereas decreased TmPYGFR is observed in all types except prostate carcinoma. In nonmalignant hypercalcemia, a sig nificant increase in mean TRCaI was only observed in PI-IP, of which individual cases can be fully discriminated from other conditions by using a new index taking into account alteration in the renal transport capacity of both Ca and Pi.
Tubular reabsorption of calcium (Ca) is becoming recognixed as a determinant of malignant hypercalcemia. However, its importance as compared to increased bone resorption has not yet been widely investigated. We determined Ca fluxes of bone resorption and tubular reabsorption in 141 rehydrated patients with hypercalcemia of malignant or benign origin, before any specitIc treatment. Bone resorp tion (BRI) was evaluated by fasting urinary Ca excretion and Ca tubular reabsorption using an index (TRCaI) calculated from a nomogram relating fasting urinary Ca excretion and calcemia. The relationship between alterations in TRCaI and in the tubular capacity to reabsorb inorganic phosphate (Pi), as judged by TmPi/GFR, was also examined for each cause of hypercalcemia. Among 101 cases with malignancy, 67% had overt bone metastases, but all displayed increased BRI. Calcemia was highest in breast cancer and lowest in prostate carcinoma. BRI was markedly increased in breast cancer, lymphoma, and multiple myeloma, whereas it was slightly elevated in lung squamous cell, renal, and liver carcinomas. TRCaI was increased in 49% of malignant hypercalcemia, particularly in epidermoid (above the upper normal limit in 71% of the cases), renal, and liver carcinomas. It was elevated in 54% of breast cancer and normal in multiple myeloma and prostate cancer. In nomualignant hypercalcemia, BRI was markedly increased In vitamin D httoxlcatIon, sarcoidosis, and hnmobilixation. In primary hyperparathyroklism (PIIP), BRI was moderately increased. TRCaI was abnormally elevated in PIIP, but normal in vitamin D intoxication, sarcoidosis, and immobilixabion. In maligmmt hypercalcemia, TmPVGFR was low in 77% of patients and in all types of tumors, except in prostate carcinoma. The index ratio [TRCaI/(TmPi/GFR)] gave a better discrimination of PI-IP from other causes of nonmalignant hypercalcemia than the use of either TRCaI or TmPl/GFR taken alone. Thus, in malignant hypercalcemia, increased bone resorption is associated with an elevation ln tubular Ca reabsorption in halfthe patients surveyed, whereas low tubular Pi reabsorption is observed in more than 75%.
*Dr.R. Rizzoli is a recipient
Department
Key Words: Malignant hypercalcemia-Primary hyperparathyroidism-Tubular reabsorption of calcium-Tubular reabsorption of phosphate-Bone resorption.
Introduction Hypercalcemia is a frequent complication of malignant disease (Fisken et al. 1980; Mundy and Martin 1982; Mundy et al. 1984). The increased level of plasma calcium (Ca) in malignancy has been ascribed to enhanced bone resorption caused either by bone metastases or by diffnse skeletal destruction due to tumor-produced circulating factors that stimulate bone resorption (Mundy and Martin 1982; Mundy et al. 1984; Insogna and Broadus 1987). Evidence has been provided, however, in certain types of cancer, of increased renal tubular reabsorption of Ca (Ralston et al. 1984a,b; Percival et al. 1985; Heller and Hosking 1986; Bonjour et al. 1987, 1988; Harinck et al. 1987). This concept has received considerable support by the recent isolation and characterization of a protein showing a structural homology with parathyroid hormone (PTH), and displaying similar effects in vitro as well as in vivo (Moseley et al. 1987; Horiuchi et al. 1987; Martin 1988; Broadus et al. 1988; Yates et al. 1988; pizurki et al. 1988; Rizzoli et al. 1989 a,b). In particular, the infusion to thyroparathyroidectomized rats of a synthetic aminoterminal fragment of this parathyroid hormonerelated protein (PTHrP) produced an increase in both bone resorption and tubular Ca reabsorption (Rizzoli et al. 1989a). In this model, the renal effect appeared to be the main determinant of PTHrP-induced hypercalcemia. The prevalence of increased renal tubular reabsorption of Ca in malignant hypercalcemia, whether due to PTHrP or to another tumoral factor(s), is not known. In the present work, we determined quantitative indices of Ca flux for both bone resorption and tubular reabsorption in 101 rehydrated patients with malignant hypercalcemia. These parameters were also evaluated
award.
41
B. Buchs et al.: Calcium and phosphate reabsorption
48
Table I. Indices of bone resorption
(BRI) and of tubular reabsorption
Number of subjects
Types of tumors
Bone invasion (% of cases)
of calcium (TRW)
in 101 patients with malignant hypercalcemia.
BRI (mmol/mmol)
Plasma Ca (mmoU1)
in hypercalcemia
TRCaI (mmol/l GFR)
Breast
35
100
3.61kO.66***
2.82k1.51***
2.96iO.56**
Epidetmoid b,
21
48
3.18iO.32***
1.33m71***
3.10&0.36***
Myeloma
13
100
3.17kO.24***
1.65ti.84***
2.46kO.53
Lymphoma
6
14
3.41ko.45***
2.16+0.93***
2.88i0.44
Kidney
7
0
3.29kO.20***
1.57*1.05**
3.13kO.24**
Liver
3
33
3.47nl.34***
1.63iO.7 I*
3.37fo.61**
Ptostate
3
100
2.8 lH.09
1.17ko.15
2.53zt0.23
13
58
3.19fo.35***
1.77kO.82***
2.95m.33*
2.25-2.62
0.10-0.50
2.40-2.88
Miscellanous ‘) Normal range
Values are mean f SD Bone resorption index (BRI) and tubular reabsorption index (TWX) were determined as described in “Methods” in rehydrated patients with malignant hypemalcemia before any antiosteolytic therapy. ***P
