Critical R&ens in Oncol~)~~lHemurolo~~, 1991; 11:l-27 ,iT 1991 Elsevier Science Publishers B.V. 1040-8428/91/$3.50

ONCHEMOOOOI

Hypercalcemia of malignancy: pathophysiology, Leif Mosekilde,

diagnosis and treatment

Erik Fink Eriksen and Peder Charles

ofEndocrinology und Metabolism, Aarhus Amtssqyhus. Aarhus C. Denmurk

Universitr Deparfmenr

Contents I.Abstract

.............................................................................

II.Introduction

z

.........................................................................

................................................................. ........................................................ ........................................ B. The role of the skeleton in calcium homeostasis. C. Calciotropic hormones. .............................................................

III. Calcium

homeostasis

A. Normal

calcium

homeostasis

D. Locallyactingagents IV. Calcium

...............................................................

homeostasis

A. Humeral

in hypercalcemic

states.

............................................

................................................ of malignancy in HHM .........................................................

hypercalcemia

B. Renal mechanisms

.................................... . . ............... ................. D. Bone metastases and hypercalcemia of malignancy. E. Hypercalcemia and hematologic malignancies, .........................................

C. Gut.

1.25(OH)2D3 and hypercalcemia

V.Symptomsofhypercalcemia A. Differential VI. Treatment

of hypercalcemic

of hypercalcemia

B. Symptomatictreatment C. Medicalmanagement

states

..........................................

..............................................

of malignancy

...................................................

12 12 12 13

14 17 17 17

.............................................................

17

............................................................... . ...............................

.............................................

IO

13

............................................................

diagnosis

A. Tumorablationandchemotherapy

References

of malignancy

10

21

L. Mosekilde received an M.D. and Ph.D. from the University hus. Aarhus.

Denmark

ciate Professor

and is currently

of Internal

logy and Metabolism

Medicine

Professor

and Metabolism

of Medicine

tabolism

and

Denmark.

University

and is at present

and is currently

in the Department

As-

of Endocrinology an M.D. and

Assistant

of Endocrinolgy

Profesand Me-

of this university.

Correspondence: logy

Medicine

of Endocrino-

P. Charles received

of Aarhus

of Aar-

L. Mosekilde.

Metabolism,

Aarhus

University

Department

Amtssygehus.

of Endocrino-

DK-8000

I. Abstract

and Asso-

E.F. Eriksen received an

in the Department

at this university.

Ph.D. from the University sor of Internal

in the Department

of the same university.

M.D. and Ph.D. degree from Aarhus sistant

Senior Consultant

Aarhus

C.

Malignancy is the most frequent cause of hypercalcemia in hospitalized patients. The pathophysiology of hypercalcemia of malignancy (HM) is complex. Increased bone resorption is involved in most cases caused either by extensive local bone destruction or by humoral factors. Tumor extracts from patients with humoral hypercalcemia of malignancy (HHM) often contain PTH-like bioactivity. Recently, cDNAs coding for a PTH-related protein (PTH-rP) has been cloned. The N-terminal amino acid sequence of this protein show a considerable

2

homology with human PTH. However, other bone resorbing factors including prostaglandins, transforming growth factors, colony stimulating factors, leucocyte cytokines and 1,25dihydroxyvitamin D may be involved in different types of malignancy. HM is usually progressive with troublesome symptoms and a high mortality. Several treatment alternatives are available including rehydration, bisphosphonates, calcitonin, plicamycin, phosphate, and glucocorticoids. Others are under investigation. Treatment should be individualized taking into account the pathophysiological mechanisms involved, the extent of hypercalcemia and renal failure, and the prognosis related to the malignant disease. II. Introduction Hypercalcemia and ectopic calcifications in patients with malignant bone metastases were first described in 1855 by Virchow [l]. Later, hypercalcemia was recognized as a frequent and often severe complication of malignant tumours with bone secondaries [2,3]. It was generally accepted that the expanding metastases provoked mobilization of skeletal calcium leading to hypercalcemia when the renal capacity for calcium excretion was exceeded [4]. However, in 1936 Gutman et al. [3] first described a patient with tumour-induced hypercalcemia without bone metastases and in 1941 Albright [5] proposed production of a parathyroid hormone (PTH) like substance by the tumour as a possible explanation for the hypercalcemia in some cases of malignancy without significant bone metastases. It was later demonstrated that patients with hypercalcemia of malignancy often exhibit features similar to those in primary hyperparathyroidism [6-S]. Furthermore, it has been shown that tumor extracts and serum from patients with hypercalcemia of malignancy often contain a biological active substance which in many systems mimic PTH [9-l I]. Recently, cDNAs coding for such a factor, called PTH-related protein (PTH-rP) [ll] or PTH-like peptide [12], were cloned, and the amino acid sequence of the protein was determined, demonstrating a considerable amino acid sequence homology with human PTH in the first 13 amino acids [12-141. Synthesized N-terminal fragments of this protein have effects similar to those of PTH such as stimulation of CAMP, enhancement of bone resorption, suppression of renal phosphate transport, and elevation of serum 1,25_dihydroxyvitamin D levels [14-l 71. The pathophysiology of hypercalcemia of malignancy, however, is complex and heterogenous. In most cases increased bone resorption, dehydration and reduced renal calcium clearance are of importance. Varying bone re-

sorbing factors may be involved in different types of malignancy including PTH-rP, prostaglandins, transforming growth factors, colony stimulating factors, leucocyte cytokines and 1,25_dihydroxyvitamin D [ 1S-201. Furthermore, in some cases of lymphoma and Hodgkin’s disease an increased production of 1,25-dihydroxyvitamin D can increase intestinal calcium absorption [21,22]. Knowledge of the various mechanisms of tumour-induced hypercalcemia is essential in order to select the most effective treatment. Since routine determination of serum calcium has been introduced hypercalcemia is increasingly recognized in patients with malignant diseases. Malignancy is probably the most frequent cause of hypercalcemia in hospitalized patients [23]. However, the incidence rate in the general population, which has been estimated to about 150 new cases per million per year [20], is not as high as that of primary hyperparathyroidism (approximately 250 new patients per million per year [24,25]). About 10-20 % of all patients suffering from malignancy experience episodes of hypercalcemia during their disease [26-281. The risk of developing hypercalcemia, however, varies between the different types of malignancy. Among the solid tumors the common lung and breast cancers, squamous cell carcinomas of the head and neck and the rare cholangiocarcinomas are relatively often complicated by hypercalcemia, whereas common tumors like carcinomas of colon and the female genital tract rarely are associated with hypercalcemia [20,29]. Among the hematological disorders multiple myelomas and lymphomas are most often associated by hypercalcemia. Hypercalcemia in malignant diseases usually cause symptoms ranging from gastrointestinal complaints to dehydration and abnormal mental status depending on the rapidity and extent of the increase in serum calcium. Symptomatic hypercalcemia should therefore be effectively treated. Severe hypercalcemia is rare but places patients at high risk of death from cardiovascular complications, renal failure, shock or coma and demands immediate, rapidly effective treatment [30,3 11. The choice of final treatment is often determined by the specific disease causing hypercalcemia. However, the etiology is not always easy to identify and may not be amenable to rapid and effective treatment. In most cases, therefore, the emergency treatment of hypercalcemia aims at an acute reduction of the elevated serum calcium irrespective of its cause. Various methods, either singly or in combination, have been used for this purpose. The treatment schedules mainly comprise rehydration and a drug which reduce bone resorption, including calcitonin, bisphosphonates and plicamycin. Other drugs with more complex actions like glucocorticoids, prostaglan-

din-synthetase

inhibitors

and phosphate

also been used. The aim of the present and pathological calcium

III-A.1.

have, however,

survey is to describe normal homeostasis with special at-

tention to the influence of systemic tors involved in the pathophysiology

and paracrine facof hypercalcemia

of malignancy. Symptoms, differential diagnoses and treatment modalities will be described and discussed in detail and an attempt will be done to outline a treatment strategy

for symptomatic

hypercalcemia.

III-A. Normul calcium homeostasis

calcium

kinetic

and calcium

bal-

ance studies normal calcium fluxes between organs have been established [32] (Fig. I). In this study based on 17 individuals picked from a Danish population with a habitual high dietary intake of calcium due to dairy products the daily calcium intake was 31 mmol with a net calcium absorption of 5 mmol/day. From the plasma pool 250 mmol/day is excreted through glomerular filtration. Another 4.5 mmol/day is excreted in the intestine as digestive juice calcium, 1.6 mmol/day is lost through the skin and 4.9 mmol/day is incorporated into the skeleton through active mineralization. Of the 250 mmol filtered in the glomeruli per day, 245 mmol is reabsorbed in the renal tubules. A total of 26 mmol/day is lost in feces and 5.5 mmol/day in urine.

CALCIUM

calcium

absorption

can be divided

into (I)

an active, saturable portion, which is mediated by vitamin D and calcium binding protein [33,34] and (2) a passive portion, which is mediated by simple diffusion and possible facilitated (carrier mediated) diffusion. With increasing dietary intake of calcium the passive absorption will increase. However, due to the saturability of the active transport system, the fraction of dietary calcium absorbed will go down [33]. The active transport across the intestinal epithelium is regulated mainly by 1,25_dihydroxyvitamin D (1,25(OH)zD). Other hormones like PTH, glucocorticoids, calcitonin, thyroid

III. Calcium homeostasis

Based on combined

Intestinal calcium absorption

Intestinal

FLUXES IN 17 NORMAL MMOL/DAY

DANES

hormones, estrogen, gestagen and growth hormone indirectly play a regulatory role by modulating the renal production of 1,25_dihydroxyvitamin D. For illustration calcium absorption adapts to a high calcium intake through a putative PTH-mediated mechanism by reducing fractional intestinal calcium absorption [35]. III-A.2.

Renal calcium excretion

Only 60% of the calcium present in serum is ultrafilterable [36]. With a normal glomerular filtration capacity of 180 liters/day about 250 mmol will be filtered per day. More than 96% is reabsorbed in the renal tubules, leaving less than 10 mmol for urinary excretion. The main part of reabsorption takes place in the proximal tubules, where calcium is reabsorbed together with sodium and water [37]. This process is mainly regulated by changes in extracellular volume (ECV). Residual, PTH sensitive, reabsorptive capacity resides, however, in the loop of Henle, the distal tubules and the collecting duct [37]. In a steady state situation with regard to serum and skeletal calcium renal calcium excretion mainly reflects intestinal absorbed calcium [33]. The fasting renal calcium excretion, on the other hand, reflects the difference between bone resorption and bone formation (the skeletal balance) [33]. III-A.3.

Dermal calcium loss

The existence of calcium in sweat was first reported in 1931 [38]. The mechanism by which calcium is lost through the skin is, however, still unknown. III-A.4.

Fig.

I. Schematic

ish individuals.

representation Figures

of calcium

arc converted 40.

fluxes in a 17 normal

to mg/day

by multiplication

Danby

Bone remodelling

and calcium homeostasis

Bone is continuously renewed (remodelled) throughout life [39] in order to secure the viability of the cells and the biomechanical competence of the skeleton. Bone remodelling takes place at localized sites in cortical and trabecular bone. In cortical bone following activation (i.e., recruitment of osteoclast precursors at the given resorptive site) a group of osteoclasts creates a ‘cutting cone’. which erodes a canal through existing

bone without any notice of the previous formed osteons [40]. When resorption is completed the osteoblasts start forming new concentric layers of lamellar bone - the ‘closing cone’. At the individual site bone resorption lasts for approximately one month and formation for about 3 months, after which a new completed osteon (Bone Structural Unit (BSU)) has been formed at the site of previous resorption. In cortical bone the BSU’s form typical patterns of several generations of osteons, which in cross section are nearly circular structures with concentric lamellae surrounding a central canal [40]. During the last few years it has become evident that trabecular bone is renewed in the same way as cortical bone. Trabecular bone consists of BSU’s (or packets or walls), which in sections present as crescent shaped structures with parallel lamellae outlined by the trabecular bone surface and the cement line [41,42]. These BSU’s are, like the osteons of cortical bone, renewed by osteoclastic resorption followed by osteoblastic formation (Fig. 2) [42]. Following activation osteoclasts and later mononuclear cells erode from the bone surface to a mean depth of about 65 pm, the final resorption depth [43]. The osteoblasts proceed to form bone and during this process they gradually become more and more pyknotic and end up as inactively looking flat lining cells or surface osteocytes [44]. The amount of bone resorbed by osteoclasts and not yet reformed by osteoblasts form the remodelling space. The size of this space depends on the number of current remodelhng processes, the final resorption depth, and the average duration of the remodelling cycle. During remodelling the coupling between bone resorption and bone formation secures the preservation of bone mass in spite of large interindividual variations in bone turnover [45,46]. Uncoupling, which in-

BONE

Fig. 2. Schematic

representation

sors and subsequent sorption

is followed

normals

(Mosekilde,

by formation,

lasting

sequence

in trabe-

of osteoclast

approximately Ciba-Geigy

1989, ISBN 87-983055514)

TURNOVER

Fig. 3. Effect of variation

precur-

30 days.

which lasts for about

L.. Bone Biology,

III-B.1. The remodelling system The temporal and spatial coupling between resorption and formation usually secures skeletal integrity and reduces the ability of the remodelling system to participate in serum calcium regulation. The remodelling system, however, allows several mechanisms by which bone may be lost and calcium mobilized under pathological conditions [42,48,49]. Some of these mechanisms have been studied in detail in primary hyperparathyroidism [50] and hyperthyroidism [51] using quantitative histomorphometry. It is important to distinguish between reversible and irreversible bone losses. The reversible bone changes are induced by variations in the remodelling space, typically because of an increased activation of new remodelling cycles, whereas irreversible changes are caused by an imbalance between the thickness of bone resorbed and formed per remodelling cycle or by a decoupling between the two processes (trabecular perforations). Reversible bone loss. Fig. 3 illustrates the effect of increased activation frequency on cortical and trabecu-

and number

of the remodelling

starts with recruitment

resorption

M-B. The role of the skeleton in calcium homeostasis

NORMAL

REMODELING

FORMATION PERIOD

cular bone. Remodelling

dicates that resorption is not followed by formation or that formation starts without previous resorption may however, occur at the periosteal and endosteal surfaces. Uncoupling has to be distinguished from imbalance between the amount of bone resorbed and formed during one remodelling cycle [47]. In normal individuals bone resorption will liberate 7.1 mmol of calcium per day, while 4.9 mmol will be reincorporated during bone formation, leading to net negative calcium balance of 2.2 mmol/day [32].

A/S.

Re-

140 days in Denmark.

turnover; porosity

in activation

of Howship’s

right

panel:

with many remodelling

high

The bone loss is reversible. Biology. Ciba-Geigy

lacunas

frequency

in trabecular

turnover).

TURNOVER

on cortical

porosity

bone (left panel: low

A high activation

frequency

cycles going on results in an increased

and a high density

result in a decrease

HIGH

of resorptive

cavities

A reduction

in activation

in porosity

bone.

frequency

and bone gain (Mosekilde,

A/S. Denmark,

cortical

in trabecular

1989, ISBN 877983055

will

L.. Bone

14).

REVERSIBLE

BONE

LOSS

lar bone

as seen in primary

Due to the increased

number

hyperparathyroidism of newly activated

[50]. remo-

delling cycles, where bone is resorbed but not yet reformed, the bone will show increased porosity (right panel). The increased porosity is of course followed by mobilization of bone mineral and a temporary reduction in bone mass. Following normalization of the activation frequency (after parathyroidectomy), resorption will decrease before formation and the holes will be refilled with bone (left panel). Irreversible bone loss. A negative balance per remodelling cycle between the amount of bone resorbed and later formed will create an irreversible bone loss IRREVERSIBLE

b

CORTICAL

BONE LOSS

BONE

(Fig. 4). If the activation frequency is also increased, as in hyperthyroidism [51], the remodelling space will expand and the irreversible bone loss will accelerate. Trabecular bone may also be lost irreversibly by trabecular perforations. This process which by its nature is related to the activation of osteoclasts is probably of major importance for the normal age-related loss of trabecular bone [49]. The average resorption depth in trabecular bone is 65 pm, but can amount to several hundred micrometres in some lacunae [43]. The average trabecular thickness is around 150 urn, but shows great scatter from close to zero and up to several hundred pm. Therefore, the possibility exists that a deep resorption lacuna hits a thin trabeculum or two lacunae meet each other midway through a trabeculum and thus perforates the structure. This will result in the removal of the structural basis for subsequent bone formation (uncoupling), and the final result will be a hole in the trabecular network with reduced mechanical competence of the bone affected. The risk of trabecular perforations depend on activation frequency, final resorption depth and trabecular plate thickness.

LOSS

C

TaA TaB

III-B.Z.

1

Fig. 4. Possible malignancy:

bone loss mechanisms

(a) A reversible

in humoral

bone loss: In HHM

hypercalcemia

of

bone the activation

of new remodelling cycles is enhanced due to osteoclast activating factors (OAF’s) leading to a reversible bone loss. (b) A irreversible trabecular bone loss: Bone formation net balance structures

per remodelling

is suppressed

cycle and a gradual

(A). Due to osteoclast

bone is also lost because versible cortical

activation

of trabecular

bone loss: Cortical docorticai

leading to a net negative thinning

of trabecular

and increased

perforations

turnover,

(B). (c) A Irre-

bone is lossed due to enhanced resorption.

en-

The osteocyte-lining

cell system

All quiescent surfaces are covered with a fenestrated membrane of lining cells that exhibit osteocytic properties and communicate with deeper osteocytes (Fig. 5). The participation of these cells in calcium homeostasis was first proposed by Talmage [52]. The deep osteocytes inside bone and the lining cells on the bone surface seems to interact in a rapid manner to regulate a threshold system for calcium at the bone surface. As shown in Fig. 5. a passive transport of calcium takes place from extraosseous extracellular fluid (ECF) ([Ca2+] = 1.25 mmol/l) to the intraosseous ECV ([Ca’+] = 0.4 mmol/l). In order to balance this influx of calcium an active PTH and CT sensitive transport mechanism located in lining cells pumps Ca’+ from the intraosseous ECF to the extraosseous ECF [52-561. The capacity of this systems has been estimated to l-6 g of calcium per day [57]. The

b

+ + Fig. 5. Functional

similarities

between

extracellular

fluid (ECV) is followed

in ECF

.25 mmol/l);

=

= 0.4 mmol/l):

the threshold

systems

by a PTH mediated

E.

in bone and kidney.

active transport

in exchange

is there10

of calcium

It has

serum

with the threshold

system in

of An increase in serum to increased of Ca2+ an increased of Ca’+. in of Ca?+

in Cal+ rium has been formed transport systems in

between

a new equilibthe passive and active by Parfitt in a recent

paper

on results to circadian in the

III-C. Calciotropic

PTH

stimulated

A passive,

in the other direction

in calcium to this to alterations in the in the of renal

hormones

In the relevant target organs (bone, kidney, um transport is regulated by both systemic

process

concentration

dependent

(for further

explanation

transport

away from the

see text). A, vessel (Ca’+

H, intraosseous H;

of calcium

- together ~ is serum

active

of lining

F,

- 100 versus

passive movement

gut) calciand local

C. renal

D, collecting

factors. The calciotropic hormones of interest are: calcitonin (CT), parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D - all hormones that are regulated by the calcium concentrations in the extracellular fluid. Our knowledge on local factors operating in the microenvironment of bone has increased tremendously over the last years and the number of factors identified is still increasing. The general picture is further complicated by the fact that relative concentrations of systemic and local factors may modulate the magnitude and direction of the response at the cell level [50].

III-C.I. Calcitonin Calcitonin (CT) is synthesized and secreted by the parafollicular cells of the thyroid gland [61]. The secretion is regulated by extracellular calcium, food intake and certain gastric hormones (gastrin, glucagon, secretin and cholecystokinin-pancreozymin) [62,63]. Increases in extracellular Ca2+ leads to increased CT secretion, while lowering extracellular Ca2+ inhibits secretion. The gene for CT undergoes tissue specific RNA processing [64,65]; in the thyroid this leads to preferential expression of CT, while calcitonin gene-related peptide (CGRP) is the primary transcriptional product in the brain. CT is secreted as a larger propeptide (17.5 kDa), which later is split to form the circulating peptide of 32 amino acids.

Endogenous CT has a complex which is still not well understood.

physiological function The principal role of

CT is to enhance the capability of the body to deal with a calcium load or calcium depletion. CT also, however, controls the movements of other ions, such as phosphate, magnesium and sodium. The prime target organs are bone and kidney. In bone CT acts directly on the osteoclast through specific receptors and increases in-

phosphate and water [88]. The renal production of 1,25dihydroxyvitamin D is enhanced by CT, which increase the activity of the renal 1-c+hydroxylase in the proximal straight tubule [89]. This effect may explain the elevated serum levels of 1,25-dihydroxyvitamin D found in patients with medullary thyroid carcinoma and endogenous excess [90].

tracellular CAMP levels [66]. The hormone decreases osteoclastic number and mobility and causes depression of

III-C.2. Parathyroid hormone Parathyroid hormone (PTH)

cellular function [67-691. Following larger doses of CT the osteoclasts rapidly lose their brush border and move away from the resorption surface [70,71] In vivo, exo-

cells of the parathyroid sized as a 115 amino

genous CT inhibits

the increased

bone resorption

found

is secreted

by the chief

gland. The hormone is syntheacid precursor (pre-pro-PTH),

which is later cleaved down to the 90 amino acid proPTH [91]. The final processing takes place in the secre-

in hyperparathyroidism, hyperthyroidism and Paget’s disease as well as the normal bone resorption in healthy

tory granules where the active. circulating peptide is formed. The biological activity

volunteers [72-741. However, in chronic endogenous CT excess (e.g., medullary thyroid carcinoma) an increase in resorption surface and osteoid surface has been observed [75]. This apparent high turnover state is a surprising finding, because decreased osteoclastic number and activity should lead to a fall in bone turnover. Such a fall in bone turnover has been demonstrated in studies employing continuous CT administration in order to increase bone mass [76]. During prolonged continuous treatment with CT, cells exhibit ‘escape’ from the effects of the hormone [77]. The mechanisms underlying this phenomenon is still unknown, but may involve receptor down-regulation or antibody formation [78]. Besides the inhibitory effect on osteoclast function CT apparently reduces the osteocyte-lining cell mediated 2+ from intraosseous to extraosseous transport of Ca ECF resulting in a changed blood-bone equilibrium [55,56]. This effect which is followed by morphological changes [79] begins within minutes and may in some cases completely block the effect of PTH on the system. CT receptors have also been demonstrated on osteoblasts [80-821, but so far no direct action on the osteoblast or bone formation has been described. Whether these receptors play a role in the regulation of osteoclast function as is the case for parathyroid hormone (PTH) is still unknown [83]. CT receptors have been demonstrated in the human kidney [84]. In the nephron they are located in the ascending limb of the loop of Henle, in the proximal end of the distal convoluted tubule and in the cortical segment of the collecting tubule [85,86]. A single injection of CT results in an increased renal excretion of calcium because of a reduced tubular reabsorption [87]. Continuous CT infusion will also initially increase renal calcium excretion but later on the excretion may go down because of reduced bone resorption [87]. CT also increases the renal excretion of sodium, potassium, chloride,

ing intact hormone is confined to the amino terminal 34 amino acids. The secretion of PTH is primarily regulated by fluctuations in extracellular Ca’+[92], but other factors such as prostaglandins, adrenergic agonists, magnesium and vitamin D metabolites also affect secretion [93]. The system responsible for transmitting the changes in extracellular Ca’+ levels to the chief cell is still poorly characterized. The secreted intact PTH is cleaved in the liver and the kidney releasing biologically inactive C-terminal and mid-region fragments [94]. The biological half-life of the C-terminal fragments, which are cleared by glomerular filtration, is longer than that of the intact hormone. Therefor the principal circulating immunoreactive form of PTH (iPTH) is different C-terminal fragments [95]. Despite the variation with kidney function the C-terminal fragments formed the basis for most PTH-assays until the emergence of the Irma-assay for intact PTH [96,97], which has revolutionized PTH assays and the diagnosis of PTH-related disorders including hypercalcemia of malignancy. PTH stimulates recruitment and attraction of osteoclasts to bone surfaces (activation) and induces bone resorption at tissue and organ level [32.50.70,98-IOO]. The mechanism behind the activation of bone resorption is still largely unknown, but PTH mediated changes in lining cell size and structure causing retraction and subsequent access of osteoclasts to a naked’ bone surface have been invoked [lo!]. Osteoclasts possess no PTH receptors and isolated osteoclast do not react to PTH [102]. The effect of PTH on osteoclasts seems to be mediated indirectly by binding of the peptide to receptors located on neighboring osteoblasts [ 1031 or immune cells [ 1041. Histomorphometric studies indicate that the cellular activity of the osteoclasts actually is reduced somewhat in primary hyperparathyroidism [50,100]. At the tissue and organ level this effect is however offset by

84 amino acid of the circulat-

ti the pronounced activation of new resorptive sites [50], leading to increased turnover at tissue [50,100] as well as organ level [32]. In vitro studies have demonstrated a general inhibition of osteoblasts with reduced synthesis of alkaline phosphatase, matrix proteins and collagen Type I when exposed to PTH [105]. These findings are corroborated by histomorphometric

studies showing

reduced

mineral

apposition in primary hyperparathyroidism [SO,lOO]. Due to the increase in recruitment of new remodelling sites, however, tissue level bone formation hanced. In primary hyperparathyroidism

rate is enthe balance

Apart

from its actions

on bone, PTH exerts powerful

effects on the threshold system for calcium in the kidney, where it increases reabsorption of calcium in the distal convoluted tubule [106]. This effect seems to be enhanced by 1,25_dihydroxyvitamin D [ 1071. Moreover, the fractional excretion of bicarbonate and phosphate is increased due to a reduced reabsorption in the proximal convoluted tubule. PTH also stimulate the renal l-c+ hydroxylase

activity and thereby

the production

dihydroxyvitamin D [108,109]. PTH has no direct effect on the intestine. calcium absorption is indirectly increased

of 1.25However, by excess

between resorbed and reformed bone per remodelling cycle is essentially unchanged [50] and the loss of bone and bone mineral is in most cases unremarkable

PTH [32] due to its stimulation vitamin D formation.

[32,100]. The increased activation frequency will, however, induce a moderate reversible bone loss due to an expansion of the remodelling space. As previously described, PTH enhance the active osteocyte-lining cell mediated outward transport of calciurn over the blood-bone barrier from the intraosseous to the extraosseous ECF.[52,57]

III-C.3. Vitamin D metabolites 1,25_Dihydroxyvitamin D is the vitamin D analogue with the highest affinity for the vitamin D-receptor [l lo]. The synthesis of 1,25_dihydroxyvitamin D is outlined in Fig. 6. On exposure to ultraviolet light the precursor in the skin, 7-dehydrocholesterol. forms cholecalciferol, which through a hydroxylation step in the liver [l 1 l] forms 25-hydroxyvitamin D. This compound is further hydroxylated in the kidney [112] to 1,25-dihydroxyvitamin D, the hormonal form of the vitamin. Even though the affinity of 25-hydroxyvitamin D for vitamin D receptor is three orders of magnitude lower than 1,25_dihydroxyvitamin D the metabolite may still have some direct effects on its own due to the lOO-fold higher concentration in the circulation. The vast majority of I-a-hydroxylase activity resides in the kidney. It is primarily stimulated by PTH [ 108,109] and low phosphate levels in the extracellular fluid [113], while CT. hypocalcemia, estrogen, growth hormone, prolactin and hypovitaminosis D may also exert stimulatory effects. The enzyme is inhibited by its product and by high serum phosphate and calcium levels.

Dietary intake

7- dehydrochole-

sterol \p

Vitamin

D

pool.

Vitamin D 25hydroxylase

metabolites

3

of renal 1,25-dihydroxy-

A major

D is

- hydroxylasa

D has

Fig. 6. Vitamin hydrocholesterol

D metabolism. UV light leads to formation of 7-dein the skin. This compound is further transformed

into cholecalciferol, and

kidney

is

which

through

transformed

into

two hydroxylation

steps in liver

1.25-dihydroxycholecalciferol

(t,25(OH)zD,).

regulators of cell differentiation in bone marrow. It promotes fusion of mononuclear osteoclast precursors into the osteoclastic syncytium [ 1151, increases the extension of osteoclastic ruffled border with bone contact[ 1161and enhances bone resorption at tissue level[ll7]. Furthermore, it exerts stimulatory effects on osteoblastic syn-

thesis (BGP),

of alkaline

phosphatase

an osteoblast

and

specific matrix

Bone Gla protein

Protein

[118-1201.

Moreover the hormone seems to affect the immune system, where it increases the secretion of certain lymphokines (interleukin 1 and 2) [ 1211.

effects on osteoblast-like synthesis

cells, but in-

[ 1361.

111-0.4. Tumor necrosis factor

( TNF) and iymphotoxin

(LTI Tumor necrosis factor and lymphotoxin are both produced by activated macrophages and exert the same ef-

III-D. Locally acting agents

III-D.I. Prostaglandins The prostanoids acting

exerts mitogenic hibits collagen

fects on osteoclasts as IL- 1 [ 1371. TNF produced by the immune system is also responsible for the cachexia assoon bone

are mainly

prosta-

glandins of the E series. Bone cells produce large amounts of PGE2 and are also able to respond to the prostanoid by binding of the hormone to membrane receptors. The main effect of PGE? is stimulation of bone resorption at the tissue level [ 122,123]. However, when isolated osteoclasts are subjected to PGEl they react with contraction of cytoplasmatic processes much like the reaction observed after calcitonin exposure [124]. It is therefore puzzling how the genera1 increase in bone resorption is brought about. Bone formation is also stimulated by PGE2 but the effects are dose dependent. Low doses stimulate collagenand matrix protein-synthesis. while larger doses seem to inhibit protein synthesis, resulting in depressed longitudinal and radial growth of long bones [125]. In vivo increased periosteal bone formation has been observed in infants treated with PGEz for persistent ductus arteriosus [126]. Intracelluarly PGE? leads to stimulation of adenyl cyclase and increased levels of CAMP [127]. The prostaglandins have been associated with some states of hypercalcemia associated with malignancy [29,128] and with bone destruction in chronic inflammatory diseases (e.g., rheumatoid arthritis) [129]. III-0.2. Osteoclast activating factors The term ‘osteoclast activating factor’ (OAF) was first used in the early seventies based on experiments showing increased bone resorption in fetal rat calvariae subjected to conditioned medium from lymphocyteor monocyte cultures exposed to phytohemagglutinin [ 130.13 11. In recent years research conducted mainly by the group around Mundy has demonstrated that OAF is a mixture of many different lymphokines [ 1321. Interleukin 1. tumor necrosis factor. lymphotoxin, gammainterferon have been identified as OAF constituents. 111-0.3. Inter~eak~n-I (IL-I) Interleukin-I is produced by monocytes and its primary action is to stimulate thymocyte proliferation [ 1331. It is probably the most active component of OAF. It stimulates osteoclastic bone resorption, IL-l-a being more potent than IL-I-/3 [I 34,135]. The compound also

ciated with malignant III-D.5.

disease [ 1381.

Gamma-interferon

The role of gamma

activation

remains

interferon in relation to osteoclast to be established. In vitro it seems to

have effects opposite to those of IL-I, TNF and LT. When added alone to culture systems it inhibits differentiation and fusion of osteoclast precursors, and in fetal rat calvariae it inhibits bone resorption induced by IL- 1, TNF and LT [139,140].

111-0.6. Transforminggrowth.factors (TGF-ct,TGF-b) andplatelet- derivedgrowth factor (PDGF) Transforming growth factors (TGF-a and TGF-p) are defined by their ability to stimulate anchorage independent growth of certain cell lines (e.g., fibroblasts) in soft agar [141]. TGF-a (5600 Da) stimulates cell proliferation in general and bone resorption [142]. The latter effect arises from stimulation of osteoclast precursor recruitment as well as stimulation of the fully differentiated osteoclast. The cellular effects of the compound all seem to be mediated through the EGF-receptor and a marked homology exists between the two compounds. TGF-P is present in virtually all tissues. but exists in particularly high concentrations in bone, platelets and placenta. Despite its name it acts primarily as an inhibitor of cell growth in most tissues. The substance is liberated from bone matrix during bone resorption, and has been implicated as a ‘coupling factor‘ securing the matching of resorption and formation. It inhibits osteoclast formation and stimulates osteoblast recruitment [143,144]. During bone resorption the peptide is protected from degradation through binding to a larger peptide, which binds the peptide at low pH values and liberates it at the higher pH-values present. when resorption has terminated [ 1451. Platelet derived growth factor (PDGF) is also abundant in bone. It stimulates bone resorption and osteoblastic collagen synthesis [I 46.1471 and has been implicated as a primary growth factor in certain osteosarcoma cell lines, where it is related to the sisproto-oncogenes.

10

III-D.7. Hematopoietic colony stimulating factors These important growth regulatory peptides affect osteoclast-recruitment and function [

steady hypercalcemia can persist for years without any signs of renal impairment or progressive loss of bone mineral. This kind of hypercalcemia is typical of moderate primary

hyperparathyroidism

hypocalciuric hypercalcemia HHM due to PTH-rP [155].

[32,58,153],

[154] and certain

Disequilibrium hypercalcemia Disequilibrium hypercalcemia

familial kinds

is characterized

of

by

progressive hypercalcemia and renal impairment. it is often induced by a massive loss of bone mineral, as seen in myeloma or rapidly progressive bone metastases from solid tumors, or by enhanced intestinal calcium absorption. Severe primary hyperparathyroidism manifest itself as disequilibrium hypercalcemia

can also [58]. The

underlying mechanism is a circulus vitiosus with severe hypercalcemia causing progressive renal impairment and thus compromising renal excretion of calcium [58].

IV. Calcium homeostasis in hypercalcemic states Clinically equilibrium

the hypercalcemic and disequilibrium

states can be divided into hypercalcemia [58].

Equilibrium hypercalcemia In equilibrium hypercalcemia

a slight

to moderate

A model for serum calcium homeostasis A simple pool model may facilitate the perception of serum calcium homeostasis (Fig. 7). The serum calcium level is symbolized by the water level, which is balanced by input (net intestinal calcium absorption and net release of calcium from bone) and output (renal calcium excretion). The output is regulated through a threshold system, which in steady state determines the water level (serum calcium). If input exceeds output. either through enhanced bone resorption or increased intestinal absorbed calcium, a state of overflow hypercalcemia ensues. A reduction in the size of the outlet (renal impairment) will further accentuate the hypercalcemia (disequilibrium hypercalcemia). However, in this type of hypercalcemia the increase in serum calcium (water level) will only last as long as the input is increased. Equilibrium hypercalcemia, on the other hand, is caused by a steady increase in the renal threshold for calcium (and an altered blood-bone barrier). IV-A. Humeral hypercalcemia of malignancy

Fig. 7. A simple pool (J) model

for serum calcium

water level (K) in the pool (S-Ca2+) is dependent tween influx (I) of water bone resorption) um threshold).

(i.e., net intestinal

and the threshold The threshold

of the kidney

is caused by an increased

release of calcium caused

(Mosekilde,

be-

calcium

absorption,

is symbolized

net

absorption

equilibrium

87-983055-14).

hy-

and/or

net

hypercalcemia

is

in the renal (and skeletal) threshold

L., Bone Biology, Ciba-Geigy

by boards

the water level. Overflow

intestinal

from bone, whereas

by an increase

The

for the outlet (L) (i.e., renal calci-

placed in the outlet in order to increase percalcemia

homeostasis. on the balance

A/S, Denmark,

for calcium 1989, ISBN

Humoral hypercalcemia of malignancy (HHM) is caused by circulating factors produced by solid tumors. These factors elicit changes in calcium absorption, bone remodelling and/or calcium excretion (Fig. 8) leading to increases in extracellular fluid calcium levels. Most often the syndrome is associated with suppressed serum PTH and changes in the renal phosphate and calcium handling. Most cases bear in them an element of increased bone resorption. IV-A.1. Pathophysiology of increased bone resorption The factors currently considered primarily responsi-

11

ABNORMALITIES OF CALCIUM HOMEOSTASIS IN DIFFERENT FORMS OF HYPERCALCEMIA

TABLE

1

Calciotropic resorption PTH-like

factors condidered

responsible

for increased

bone

in HHM factors

TGF-I Prostaglandins Cytokines

(OAF’s)

I ,WOH)zD~

-+

Ca++ L-l

PTH-,P

(LUNG

CANCER)

OR TUMOR CELL (BREAST CANCER) YEDIITED INCREASED BONE RESORPTlON

INCREASED BONE RESORPTlON DUE TO CYTOKINES

Fig. 8. Abnormalities percalcemia creased

of calcium

of malignancy.

bone resorption

myelomas

in combination

due to impaired direct resorbing breast cancer).

activity

with a reduced

factors.

In certain

of tumor

(typically

hypercalcemia

increased

mediated

from

of calcium

lung cancer)

mediated

factors

by inor other

of calcium

D paired

or

(typically

is potentiated by PTH-rP

gut absorption

of 1.25-dihydroxyvitamin

creased cytokine

is in-

(OAF’s)

renal filtration

cells or paracrine

of calcium

lymphomas

production

forms of hydefect

In lung and breast cancer bone resorp-

In both conditions

renal reabsorption

in different the primary

of cytokines

due to either PTH-rP

creased

to increased

due to liberation

renal function.

tion is also increased

homeostasis

In myeloma

due

with in-

bone resorption.

ble for increased bone resorption are shown in Table 1. Lafferty [6] was the first to describe the clinical findings characteristic for HHM: renal phosphate wasting, increased renal tubular reabsorption of calcium, increased bone resorption and hypercalcemia. In the early eighties it was recognized that tumor extracts from patients with HHM increased nephrogenic CAMP by binding to the PTH-receptor [9]. The PTH-like factor responsible for these effects was later cloned from a human lung cancer cell line and further characterized [ 12,156]. Other groups

have reported similar results from analysis of factors derived from breast cancer and renal carcinoma [ 14,1.57]. The factors now called PTHPTH-related peptides related peptides (PTH-rP) share 80% homology with the first thirteen amino acids of PTH in the region responsible for binding to the PTH receptor (Fig. 9) [156,157]. Whether PTH-rP has a physiological role is still uncertain, but the compound seems to be primarily associated with epithelium. Very high concentrations have been found in breast milk, and immunocytochemical studies have demonstrated high concentrations of the peptide in mammary epithelium [ 1581 It is also abundant in skin, and most squamous cell carcinomas contain the peptide [ 1591. A specific PTH-rP receptor has been characterized in breast tissue and it has been hypothesized that the peptide in normal physiological states regulate calcium transport in the breast [160]. In HHM, however, it exerts its action primarily by crosstalking with the PTHreceptor [ 1601. The effects of synthetic PTH-rP are similar to those of PTH, although differences in potency may exist [15]. The peptide stimulates renal reabsorption of calcium [ 15,16,16 1] and increases bone resorption in vitro and in vivo [161]. Despite the homology with PTH and the binding to PTH receptors in kidney and bone many aspects of PTH-rP action in these tissues show differences to the action of PTH. In bone a negative balance due to increased bone resorption and profound depression of bone formation develops in most cases of HHM [162]. This picture is different from the normal balance between resorption and formation observed in most cases of primary hyperparathyroidism [32,50,100]. Another difference is the suppression of renal I-a-hydroxylase by PTH-rP [ 171 In primary hyperparathyroidism the production of 1.25(OH)*Ds is most often increased [7.163]. Finally alkalosis is prominent in HHM rather than the slight hyperchloremic acidosis of primary hyperparathyroidism [ 1641. The mechanisms behind these differences are still elusive. but may involve binding to different domains of the PTH-receptor or modification of PTH-rP action by other factors.

I2

IV-B. Renal mechanisms -20

-30

-10

I

PTH-rP

VOOWSVAVFLLSYADPSCGRSVEGLSRRLKRAVSEHQLLHD

PTH

MIPAKDMAKVMIVMLAICFLTKSDGKSVKKRSVSEIQLMHN

PTH-rP

KGKSI

PTH

LEKHLNSMERVEWLRKKLODVHNFVALGAPLAPRDAGSORP

PTH-rP

NTKNHPVRFGSDDEGRYLTOETNKVETYKEOPLKTPGKKK

PTH

RKKEDNVLVESHEKSLGEADKADVNVLTKAKSQ

PTH-rP

KGKPGKRKEOEKKKRRTRSALD

Several studies indicate that the renal set point for reabsorption of calcium is altered in HHM leading to 50

30

ODLR:

RF FLHHLI

80

100

AEI HTAEI

RATYEVSP-

NSKPSP

80

70

in HHM

10

90

110

Fig. 9. N terminal sequences for PTH( l-84) and PTH-rP.

IV-A.2. Transforming growth factor-x (TGF-cl) TGF-cr increases bone resorption in vitro [165-1671. The peptide increases plasma calcium in mice [168] and has been linked to HHM associated with several tumors (e.g., rat Leydig cell tumor, squamous cell carcinoma of the lung). [ 18,169]. and EGF, which shows homology to TGF-a, can also elicit hypercalcemia, but it is less potent [ 1671. EGF has not been demonstrated so far in any tumor. IV-A.3. Colony stimulating factors (CSF) Certain squamous cell carcinomas of the lung and other tissues produce a humoral factor that induces leukocytosis and hypercalcemia [ 150,170.17 11. The substance responsible for these changes possessed properties similar to CSF [ 1501. The simultaneous development of leukocytosis and hypercalcemia has also been demonstrated in a mouse mammary tumor transplanted onto nude mice [172]. That CSFs are associated with HHM corroborates recent research demonstrating the ability of GM-CSF to increase the formation of osteoclasts in vitro [ 1481. IV-A.4. Other resorption stimulating agents Interleukin-1 (11-l) has been implicated as a pathogenetic factor in HHM associated with certain solid tumors [173,174]. IV-AS. Prostaglandins Five to ten years ago prostaglandins were considered important in the pathogenesis of HHM [123]. Certain rare tumors may produce large quantities of prostaglandins that could increase bone resorption. However, cyclooxygenase inhibitors - although effective in rare cases of HHM - lack effectivity in decreasing serum calcium in the vast majority of cases [ 1751.

increased

tubular

reabsorption

(Fig. 8) [ 176,177]. It has

been argued that the increased reabsorption is an obligatory consequence of increased sodium reabsorption in the proximal tubule [178]. Studies on the rat Leydig tumor have, however, definitely demonstrated the existence of a substance responsible for increased calcium reabsorption. PTH-rP is a possible candidate, and recent studies have demonstrated that this peptide is able to increase renal tubular It has been computed

calcium reabsorption [ 1611. that an increase in serum calci-

um from 2.50 mmol to 3.00 mmol would demand an extra flow of calcium of 250 mmol (lg) per day to and from the extracellular phase [57]. In moderate primary hyperparathyroidism the intestinal absorption of calcium only goes up by 170 mg/day [32]. If the hypercalcemia was sustained by increased influx to extracellular fluid the remaining 830 mg would have to come from the skeleton. A negative calcium balance of this magnitude has never been reported and is far away from the calculated balance estimates [32]. Furthermore, it would indicate that the skeleton would vanish over a period of 47 years. Furthermore, hypercalcemia in primary hyperparathyroidism is not caused by increased intestinal absorption. Neither low calcium diet or resins inhibiting calcium absorption nor glucocorticoids are able to reduce the degree of hypercalcemia in this state [ 179,180]. Changes in the renal threshold are therefore of paramount importance in these hypercalcemic states. PTH as well as PTH-rP have been shown to change the threshold for calcium reabsorption [ 161,18 1.1821. IV-C. Gut, 1.25(OH)~Dj malignancy

and h.vpercalcemia

of

As previously mentioned, patients with HHM are generally characterized by depressed I-a-activity in the kidney. Therefore significant contribution from increased calcium absorption from the gut is unlikely. A few cases with increased 1,25(OH)zD~ involving tumors as lung cancer and a few cases of renal cell carcinoma have, however, been reported [ 183,184]. IV-D. Bone metastases

and hJ,percalcemia

qf‘malignancy

Widespread destruction of bone due to metastatic lesions from solid tumors may cause hypercalcemia due to increased resorption per se. However, most cases are associated with changes in renal reabsorption of calcium. Breast cancer constitutes a typical case demonstrating these mechanisms.

IV-D. 1. Breast cancer and hypercalcemia Bone metastases

are prevalent

in breast

TABLE

cancer

pa-

tients. 90% of patients dying from breast cancer have bone metastases. In a material comprising 127 patients, Galasko and Burn [185] reported 30% with progressive symptomatic hypercalcemia, 30% with asymptomatic hypercalcemia and the rest having hypercalciuria. Several different mechanisms operate in relation to hypercalcemia of breast cancer (Fig. 8). Direct bone resorption by tumor cells has been demonstrated and constitutes a process teoclastic bone

that operates resorption

independently [ 186,187].

from osOsteoclast

activation by TGF-r, TGF-P. and possibly prostaglandins play a significant role [l88,189]. The role of lymphokines and other locally acting agents remains to be established. Finally increased tubular reabsorption has been demonstrated in breast cancer patients [l90]. I V-E. H>,perculcemia and hematologic malignancies The classical case of hypercalcemia in hematology is of course myeloma. Bone pain is the dominant symptom in more than 80% of patients, and the vast majority of patients present bone lesions as well. The dominant mechanism is increased bone resorption mediated by osteoclast activating lymphokines liberated from myeloma cells stimulating adjacent resorptive foci (Fig. 8) [l91]. In a few cases an osteoblastic growth factor has been implicated. and on rare occasions osteosclerosis may develop in a myeloma patient. Often the patients with osteosclerotic lesions fulfil the criteria for having the POEMS syndrome characterized by: Progressive polyneuropathy, Organomegaly, Endocrine dysfunction, Gynecomastia. M-component and spinal fluid proteins [192]. The most important mediator of increased bone resorption in myeloma seems to be lymphotoxin, but also interleukin- I. and TNF may play a role. In a few lymphomas hypercalcemia seems to be mediated by 1.25(OH)2DA formed by I -x-hydroxylation of 25(OH)D3 in the lymphomas themselves [I931 (Fig. 8, see below). Different lymphokines are, however. also thought to participate. Hypercalcemia is fairly common in Burkitt’s lymphoma, while rare in Hodgkin lymphomas [l94]. In the leukemias hypercalcemia is uncommon. V. Symptoms of hypercalcemia

The clinical features of hypercalcemia related to malignancy are listed in Table 3. Contraction of the extracellular volume (ECV) contributes significantly to the symptomatology of the hypercalcemic syndrome. The symptoms are often very troublesome and unpleasant

2

Pathogenetic

mechanisms underlying

I. Osteoclast

activation

hypercdlcemia

in breast cancer

2. Direct resorption of hone by tumor cells 3. Increased renal tubular calcium reabsorption __~__.__

for the patient with persistent nausea and vomiting. confusion and disturbing nightmares.They vary considerably from patient to patient and it is often difficult to differentiate

between

symptoms

caused

by

advancing

malignant disease, cytotoxic drug therapy or radiation therapy and those induced by complicating hypercalcemia. The neuro-psychiatric symptoms in hypercalcemia may mimic cerebral metastases [ 1951. Anorexia and vomiting often complicates chemotherapy or the malignant disease per se and bed rest, inactivity, anorexia and dehydration promotes constipation. Impaired glomerular function may be explained by other causes than hypercalcemia such as Bence-Jones nephropathy in myeloma or obstructive uropathy. Symptoms, however, are often most prominent in patients with the highest serum calcium levels or in those with the most rapid increase in serum calcium and correction of hypercalcemia and accompanying dehydration often dramatically improve the clinical state of the patient and reduce mortality (30.311. From a clinical point of view it is important to notice that calcium and digoxin have a synergistic effect on the heart [l96]. Moreover. the elimination of digoxin is often reduced in hypercalcemic states due to a reduced renal function. Digoxin should therefore be administered with caution in hypcrcalcemic patients. Hypercalcemia reduce the ability of the kidney to concentrate the urine probably due to inhibition of the effect of ADH [197]. The resulting polyuria often induces dehydration with reduced ECV. renal perfusion and glomerular filtration rate (GFR) [58]. Nephrocalcinosis. which is mainly seen in patients with concomitant hyperphosphatemia due to massive bone destruction (myeloma, breast cancer) or increased intestinal absorption of calcium and phosphate (lymphoma) further impairs renal function. [l98,199]. These renal changes will tend to exacerbate the hypercalcemia through several vicious circles [S8]. The reduction in GFR will decrease the filtered load of calcium. Moreover. the contracted ECV will enhance the proximal tubular reabsorption of sodium and calcium [58.200]. The resulting increase in serum calcium will further compromise renal function. Based on these pathophysiological mechanisms. rehydration is a major tool in the treatment of hypercalcemia.

14 TABLE

V-A. D@erential

3

Symptoms

and signs of hypercalcemia

Neurological depression, irritability, lethargy,

confusion,

muscle weakness,

disturbed stupor,

in Table 4 lists the potential diagnostic possibilities to case of verified hypercalcemia grouped according parathyroid function. This separation is essential, since determination of serum intact parathyroid hormone (S-

sleep

coma

PTH( l-84)) today is an important calcemic states. The hypercalcemic

reflexes

Cardiovascular shortening

of T-wave

stressed that the pathophysiology most often is complex involving bone as well as intestine and kidney. Hyper-

heart block, asystole ventricular

arrhythmias

increased

sensitivity

calcemia of malignancy is separated from the other hypercalcemic states in this group because of the marked

to digoxin

Gastrointestinal anorexia,

vomiting,

gastric

variability

atony

acute pancreatitis Renal polydipsia

dehydration impaired

glomerular

filtration

nephrocalcinosis

TABLE

4

Differential

diagnosis

Hyperparathyroid

of hypercalcemia

hypercakemia

Primary

hyperparathyroidism

Tertiary

hyperparathyroidism

Lithium

treatment

hypercalcemia

(increased intestinal calcium absorption) Vitamin

D intoxication

Sarcoidosis Addison’s

and other granulomatous

diseases

disease

(increased bone resorption) Hyperthyroidism Immobilization Paget’s disease Vitamin

(Table 5).

acute situation renal function is important from a diagnostic point of view and to assess the indication for acute treatment. Renal function is often normal in slight to moderate primary hyperparathyroidism [32,58,163], humoral hypercalcemia of malignancy [ 1551, hyperthyroidism [202] and familial hypocalciuric hypercalcemia [ 1541, but may be severely affected in case of increased intestinal calcium absorption or enhanced bone tissue break down [58,198,199,201]. In many situations there is no single clinical test to separate between the different diagnostic possibilities. The clinician has to make his diagnosis based on symptoms and signs and available laboratory investigations. The most important of these will be discussed in the following.

Pheochromocytoma Hypoparathyroid

in pathophysiology

In most patients with hypercalcemia of malignancy, the presence of malignant disease is indisputable and the cause of hypercalcemia is evident. It is not often that a hypercalcemic patient has an occult malignancy. More frequently doubt exists whether the hypercalcemia in a patient with known malignancy is caused by the malignant disease or by some other coincidental disease or treatment. Immobilization, intoxication with vitamin D and A, treatment with lithium or thiazides and the milk alkali syndrome can most often be ruled out from the history. The most frequent causes of hypercalcemia are primary hyperparathyroidism and malignancy [20,23, 24,251. If these diagnoses are less likely from a clinical point of view or ruled out by investigations less frequent causes of hypercalcemia should be considered. In the

constipation

polyuria,

tool to classify hyperstates with function-

al hypoparathyroidism are further subdivided according to their main pathophysiology. It should, however, be

of QT interval

broadening

states

of malignancy

hypotonia

absent deep-tendon

diagnosis of hypercalcemic

A intoxication

(increased tubular reabsorption of calcium) Milk-alkali Thiazide

syndrome diuretics

(multiple mechanisms) Hypercalcemia

of malignancy

Normoparathyroid Familial

hypercalcemia

hypocalciuric

hypercalcemia

_

V-A.I. Serum immunoreactive parathyroid hormone (SiPTH) Until recently RIAs for PTH have not been ideal. The main objective has been to develop a method which clearly can separate between the two most frequent causes of hypercalcemia: primary hyperparathyroidism and hypercalcemia of malignancy. This has not been ac-

complished

for the conventional

or Mid-region

C-terminal,

N-terminal

RIAs [203,204]. PTH circulates

PTH(l-84) and fragments tivity and immunoreactivity.

as intact

with different biological acThis can explain the lack

of discriminative power of the conventional assays. Cterminal PTH RIAs tend to give false elevated values in patients with compromised renal function due to retention of biologically inactive C-terminal fragments and some N-terminal RIAs may cross-react with PTH-rP due to the marked

homology

in the N-terminal

region

[156,157]. Recently the development of immunoradiometric says (IRMA) for intact PTH( l-84) have drastically

asim-

proved the possibility to discriminate between the different causes of hypercalcemia [96,97,205]. In this type of assay the intact hormone forms a link between two antibodies directed specifically towards each end of the hormone. The IRMA assay is unaffected by impaired renal function. Fig. 10 compare S-PTH(l-84) in 23 patients with primary hyperparathyroidism and 25 patients with hypercalcemia and cancer [206]. In normal subjects SiPTH was in the range of 16-50 rig/l.. All of the patients with primary hyperparathyroidism had elevated SPTH( l-84). S-PTH( l-84) was below 16 rig/l in 24 of the 25 patients with hypercalcemia of malignancy and in the low normal range in one. The separation between normal individuals and patients with primary hyperparathyroidism was not very much different from that observed with conventional radioimmunoassays [203,204]. The advantage of the new assay is a better discrimination of reduced serum PTH values. The applicability of the radioimmunometric assay is supported by other studies [97,205]. S-PTH

. (603)

rig/l

(l-84)

l

(675)

loo/-

50_-----

I _@:

_-----

--,_-----~----*-

I

O-

I

I

2

, I I

.

.

_*-_____

9 ,:.*-

.. 4

3

S-Ca Fig. 10. Serum (V).

patients

PTH( l-84) with primary

with hypercalcemia

and serum calcium

.

in normal

hyperparathyroidism

of malignancy (0). (Laurberg, Lq, 150:2972. 1988).

(B)

mmolll

individuals and

patients

P., et al., Ugeskr

V-A.2. Maximum renal tubular reabsorption capacity for phosphorus (TMPIGFR) Serum phosphate and renal tubular phosphate reabsorption is decreased in primary hyperparathyroidism [3,32,106] and in most patients with HHM [5-71. The reabsorption is best expressed as the maximum tubular reabsorption capacity per volume glomerular filtrate (TMP/GFR)

[207], which in the clinical

determined

from serum levels and fasting

centrations

of creatinine

and phosphate

setting urinary

can be con-

[208]. Other in-

dices of renal phosphorus handling (phosphate clearance, TRP, IPE, PEI) do not describe the renal tubular handling of phosphorus, because they are influenced by the excretion rate of phosphorus and variations in GFR. TMP/GFR is decreased in most patients with primary hyperparathyroidism [209] and in some patients with hypercalcemia of malignancy [7], and increased in patients with hypoparathyroidism [209]. V-A.3. Urine CAMP Renal production of CAMP is increased by PTH [210] and by PTH-rP [8.9]. Urine CAMP is usually corrected for creatinine excretion or expressed per volume glomerular filtrate. A more exact measure is nephrogenous CAMP, which is calculated by subtracting the filtered amount of CAMP from the excreted amount [211]. Urinary CAMP is increased in primary hyperparathyroidism and in many patients with hypercalcemia of malignancy [7,209,2 11,212]. It is therefore not suitable for the differential diagnosis between primary hyperparathyroidism and hypercalcemia of malignancy, but it may identify those patients with known malignancy in whom PTH-rP is a causal factor. At present, low intact PTH and high nephrogenous CAMP is the most useful method for identifying humoral hypercalcemia of malignancy. V-A.4. Serum levels of vitamin D metabolites The two clinically relevant vitamin D metabolites are S-25hydroxyvitamin D, which reflect the patients vitamin D intake, and S-l ,25_dihydroxyvitamin D, the hormonal form of vitamin D normally produced in the kidney. The renal production of 1,25-dihydroxyvitamin D is stimulated by PTH [ 108,109] and N-terminal fragments of PTH-rP [ 161 and suppressed by high serum levels of phosphate [113] and probably calcium [213]. S1,25_dihydroxyvitamin D is of some significance in the investigation of hypercalcemic states. It is increased in about 1344% of all patients with primary hyperparathyroidism [163]. In the remaining patients the serum values are normal or subnormal because of reduced renal function or lack of the precursor, 25-hydroxyvitamin D [ 1631. S- 1,25_dihydroxyvitamin D may also be increased in patients with sarcoidosis and other granulomatous

16

diseases [214] and in occasional patients with T-cell lymphomas [2 1,093], Hodgkin’s disease [22,2 15,2 161, and even B-cell lymphomas [217]. In sarcoidosis 1,25-dihydroxyvitamin is produced in the granulomatous tissue [114]. A recent study have demonstrated that HTLVtransformed

lymphocytes

can convert

25-hydroxyvita-

min D to 1,25_dihydroxyvitamin D [218]. In hypercalcemia induced by solid tumors S-1,25-dihydroxyvitamin D is usually reduced in spite of normal S-25-hydroxyvitamin D levels, reflecting suppression of the parathyroid1,25_dihydroxyvitamin D axis [7,8]. In 50 patients with hypercalcemia of malignancy S- 1,25-dihydroxyvitamin D was undetectable in 25 [7]. The average serum value in the total group was 20 pg/ml compared with a normal range of 22 - 64 pg/ml. However, in I5 patients with malignancies without hypercalcemia S- 1.25-dihydroxyvitamin D was undetectable in all. This suggest that the renal production of 1,25_dihydroxyvitamin D is suppressed in these patients either because of approaching hypercalcemia or because of some inhibiting factor produced by the tumor [2 191. These results are supported by measurements of fractional intestinal calcium absorption by the double isotope technique in patients with malignancies [220,221]. Patients with hypercalcemia or bone metastases had lower fractional intestinal calcium absorption than normal controls. However, S- 1,25-dihydroxyvitamin D is not reduced in all patents with solid tumors and hypercalcemia. A recent study [ 1831 reported that of 18 hypercalcemic patients with renal cell carcinoma and hypercalcemia 14 had normal serum 1,25_dihydroxyvitamin D levels, two had clearly elevated and two suppressed levels. In contrast, low serum 1,25_dihydroxyvitamin D concentrations were found in most patients with hypercalcemia caused by hematological malignancies or malignancies with extensive bone metastases. The patients with renal cell carcinoma had lower serum phosphate levels than those with bone metastases or hematological malignancies. It was suggested that this was an effect of PTH-rP and that the low serum phosphate might be a stimulator of renal 1-a-hydroxylase in hypercalcemia associated with this malignancy.

V-AS. Urine calhm excretiott Renal calcium excretion should be corrected for creatinine excretion. Low values are diagnostic for familiar hypocalciuric hypercalcemia in asymptomatic patients with hypercalcemia and normal S-iPTH [ 1541. The 24-hurine calcium excretion is increased in primary hyperparathyroidism and in most cases of hypercalcemia of malignancy. It is therefore of no value in the differentiation between these two hypercalcemic states. Fasting urine

calcium/creatinine net bone resorption efficacy of treatment resorption.

ratio gives an indirect

estimation

of

[209] and can be used to assess the with drugs aiming at reducing bone

V-Ah. Bone markers Alkaline phosphatase

in serum (S-AP) consists

of sev-

eral isoenzymes derived mainly from bone and liver, but also from placenta and malignant tumors [222]. An elevated total S-AP, therefore, is not diagnostic for bone involvement. The different isoenzymes by heat inactivation, electrophoresis. say or lectin precipitation ase (S-BAP) is usually

can be separated radioimmunoas-

[223]. Bone alkaline phosphatincreased in patients with en-

hanced bone resorption because of the normal coupling between resorption and formation [45,46]. Consequently, SAP or S-BAP add little further information in the differential diagnosis between primary hyperparathyroidism and hypercalcemia of malignancy. In multiple myeloma there is often no evidence of an increase in new bone formation in spite of excessive bone resorption. Serum bone Gla protein (S-BGP) or osteocalcin is another marker of osteoblastic function which can be measured by radioimmunoassay [224]. It is degraded in the kidney and to give a better estimate of bone formation serum values should be corrected for variations in renal function. It is usually increased in primary hyperparathyroidism and other states of increased bone turnover, but decreased in hypercalcemia of malignancy [225]. However, at present determination of S-BGP mainly provides a scientific tool in the investigation of bone diseases. The renal excretion of hydroxyproline is usually measured on a gelatin restricted diet or collected in the fasting state and corrected for creatinine excretion [209]. In non-malignant diseases urinary hydroxyproline reflects bone resorption [223,224]. In malignant disease, however, it may be greatly influenced by tumor spread in soft tissues. Urinary hydroxyproline is increased in primary hyperparathyroidism and other states with increased bone resorption [209] and provides little useful information in the differential diagnosis of hypercalcemia. However, fasting urine hydroxyproline/creatinine ratio can be used to assess the efficacy of treatment with antiresorptive drugs.

V-A.7. Skeletal rudiology and hone scanning Skeletal radiology and bone scanning are important tools in the diagnosis of myeloma and metastatic bone disease. However, due to a suppressed osteoblastic activity, bone scan may be negative in patients with myeloma in spite of distinct radiological findings.

17

VI. Treatment of hypercalcemia

of malignancy

taking digitalis digitalis,

preparations

hypercalcemia,

since the combined

hypokalemia,

effect of

and hypomagne-

Hypercalcemia and contraction of ECV are the main features of tumor induced hypercalcemia, and treatment

semia on the myocardium is synergistic and may lead to fatal arrhythmias [ 1961. This clinical situation may even

must aim to relieve both elements. The actual serum calcium level is often not related to the clinical status of the patient. Other factors like the rapidity with which the

appear in patients not treated with digitalis. Therefore, unless hyperkalemia and hypermagnesemia are present

serum

calcium

rises, accompanying

renal

failure

and

electrolyte disturbances. cardiovascular status, and the general state of illness will modulate the clinical response to hypercalcemia. Furthermore, a patient with hypercalcemia may not recognize any symptoms at all until improvement by the treatment. All these factors must be taken into account when treating a patient with hypercalcemia

of malignancy.

potassium to prevent

and magnesium should be added to the saline depletion of these cations.

VI-B.2. Diuretics Loop-diuretics has been shown to induce calciuresis [228], and they might be needed in order to prevent congestive heart failure. Routine use of loop-diuretics may be harmful,

unless their administration

is delayed

until

VI-A. Tumor uhlation and chemotherap)

volume expansion is achieved. Thiazides decrease renal excretion of calcium and should be avoided in any hypercalcemic patient.

Of course, the most appropriate therapy in hypercalcemia of malignancy is removal of the tumor causing the hypercalcemia. In the humoral form of hypercalcemia of malignancy it is occasionally possible to remove the tumor surgically, and thereby successfully treat the patient. This can, however, not be achieved in metastatic disease and hematologic malignancies. In this case chemotherapy is a logical treatment if the clinical state of the patient and the serum calcium level allow it, and if the drug regime is expected to be rapidly effective. However. in most cases this is not the case and symptomatic treatment has to be initiated.

VI-B.3. Dietary restriction It may seem logical to reduce calcium intake. It is, however difficult to recommend a diet with a low calcium content. which at the same time should be palatable and sufficient in energy. Moreover, except in conditions where gastrointestinal absorption of calcium is excessive (e.g., sarcoidosis. vitamin D intoxication, and certain lymphomas), the absorption of calcium in the gut is reduced in patients with hypercalcemia due to regulatory mechanisms, nausea and vomiting [229]. We feel, therefore, that there is no indication for dietary restrictions in these patients.

VI-B. Symptomatic

VI-C. Medicul management

treatment

VI-B.1. Wuter and electrol~~te repletion The most important steps in the treatment of hypercalcemia are to restore adequate hydration and increase renal calcium output. This is best accomplished by giving the patient normal saline infusions. The amount of saline to be given depends on the degree of dehydration and the tolerance of the patients cardiovascular system to extracellular volume replacement. The administration of a few liters of saline will often be sufficient to break the previous described vicious cycles of polyuria, vomiting, dehydration, reduced ECV, reduced GFR, decreased urinary output, decreased renal calcium excretion and rising serum calcium. Isotonic sodium sulfate may be more effective than saline infusion to achieve calciuresis [226]. Other electrolyte abnormalities should be corrected as well. Hypokalemic alkalosis is frequently seen in severe hypercalcemia [227] and the administration of large amounts of saline potentiates renal potassium and magnesium losses. This is of special importance in patients

VI-C.I. Phosphates Whether given intravenously or by mouth, phosphate mainly acts by inhibiting bone resorption and depositing calcium into bone. The effect of phosphate is independent of any action on the kidney [230], but when given orally it may increase fecal calcium. Phosphate was initially introduced in 1930 for the treatment of hypercalcemia of malignancy [23 l] due to recommendations by Albright et al. [232]. No report of its use was published during the next 30 years. Following the reintroduction by Goldsmith and Ingbar in 1966 [233] there has been considerable controversy over the efficacy and safety of phosphate therapy. The principal concern has been that extraskeletal calcifications will damage vital structures. There have been considerable numbers of publications reporting massive and pathological calcifications of the heart, lungs. spleen, pancreas, blood vessels, and endocrine glands after phosphate therapy [23&236]. Acute renal failure and hypotension have also been reported as major complications [237,238]. At

18

present the use of phosphate, intravenous or orally, should be abandoned because other less hazardous methods are available. VI-C.2. Glucocorticosteroids Glucocorticosteroids decrease intestinal calcium absorption [239] and inhibit bone resorption. Moreover, these steroids may inhibit the local factors [240], which promote bone resorption. Finally, they may have a direct antitumor-effect reducing the bulk of the tumor burden, and thereby decreasing the hypercalcemia. The use of corticosteroids is appropriate in patients with vitamin D intoxication, sarcoidosis and some lymphomas with increased vitamin D activity. They may also be effective in myelomas although the response is variable [241-2431. In the treatment of patients with hypercalcemia of malignancy due to solid tumors the results have generally been disappointing [244,245]. The fact that the potential response to gmcocorticoid therapy may be delayed up to one week or more makes it imperative that more effective means of lowering serum calcium levels are used in symptomatic patients. Since large doses of prednisolone or its equivalent are usually needed to achieve optimal effect, long-term treatment is seldom employed because of the potentially serious complications of Cushing’s syndrome. VI-C.3. Plicamycin Plicamycin (Mitramycin), a cytotoxic antibiotic used for chemotherapy in several tumors, was found to produce hypocalcemia during treatment of patients with embryonal cell carcinoma of the testis [246]. This unwanted side-effect led to its application in the management of malignancy related hypercalcemia [247,248] and hyperparathyroidism caused by parathyroid carcinoma [249]. Plicamycin acts through its potent inhibition of RNA synthesis. In the treatment of hypercalcemia the drug is used in a dose of 25 pg/kg body weight which is about one-tenth of the antitumor dose. The hypocalcemic action, therefore, appears to be a direct effect on bone resorption [250] rather than an effect on tumor [249]. Indirect evidence has shown that the drug acts either by blocking the peripheral action of parathyroid hormone or by rendering the patient resistent to vitamin D [251]. Plicamycin must be infused slowly intravenously, usually over 8-12 h, to minimize nausea. Maximal hypocalcemic action usually takes place after 24 to 48 h and lasts for 1 to 2 weeks [248]. Multiple infusions of Plicamycin may be used in patients whose hypercalcemia is otherwise uncontrollable. This treatment schedule, however, increases the risk of toxic drug reactions. The sideeffects comprise renal, hepatic, and especially bone

marrow affection. However, in a consecutive study 43 patients with hypercalcemia of malignancy treated with plicamycin did not develop toxic reactions more serious than nausea and vomiting [252]. VI-C.4.Calcitonin (CT) On a theoretical basis, the inhibitory effect of CT on bone resorption [72] and blood-bone barrier [55,56] makes it the ideal agent for treating hypercalcemia. The transient calciuric effect also potentiates the rapid hypocalcemic response in patients with an increased tubular reabsorption of calcium [253]. The recommended dose of CT is 4600 IU in half a liter of saline infused over 336 h. Unfortunately, most patients treated with CT show only a limited and transient effect [243]. In vitro this escape phenomenon is prevented by glucocorticoids [77], but most clinical studies have shown a variable response to combined CT and glucocorticoid treatment [243,248,254]. CT treatment can be used also in patients with renal or cardiac failure. It is often associated with nausea and vomiting, but otherwise the treatment is safe with only minimal short-term toxicity. VI-C.5. Bisphosphonates The bisphosphonates (diphosphonates) are analogues of pyrophosphate. They are stable in vivo because no enzyme in the body can hydrolyze these compounds [255]. They have a high affinity for bone, especially hydroxyapatite, in skeletal areas of increased bone turnover, as occurring near metastatic bone lesions. The precise effects of bisphosphonates on bone and bone cells

S-calcium

(mmolll)

+

l

= Etidronate

l

= Placebo

4 = i.v. treatment I = Mean + sem

1 0

1

2

, 3

4

5

6

Day;

Fig. 11. Effect on serum calcium weight given intravenously

levels of ethidronate

7.5 mg/kg

body

with 3 liters of saline per day compared

placebo and saline on in patients vith hypercalcemia of malignancy. (Redrawn from: Hasling, C.. et al., Am J Med. 82 (2A):51, 1987).

to

19

are not known

in detail.

However,

be taken up by osteoclasts tion of these cells. Numerous intravenous bisphosphonates

they are thought

and appear

to inhibit

to

the ac-

clinical trials using oral or in hypercalcemia of malig-

nancy have been published during the last years. These publications have demonstrated that aminohydroxyprolidene diphosphonate (APD) [248,256259], dichloromethylene diphosphonate (Clodronate) [257,26&265] and etidronate (Didronel) [266268] are all effective medications in the treatment of hypercalcemia of malignancy.

APD and Clodronate

are equally

effective in the

treatment of hypercalcemia of malignancy whether used orally or intravenously. However, the generally poor absorption of the bisphosphonates makes much greater doses (IO- to 50-fold) needed, when given orally. In our experience Didronel in a dose of 7.5 mg/kg body weight is effective in controlling hypercalcemia of malignancy in more than 90 percent of the patients when administered with 3 liters of saline and 40 mg of furosemide for five days. In a double blind placebo controlled study we found that I 1 out of 12 patients became normocalcemic when treated in this manner (Fig. 11) [267]. The relative efficacy of the different bisphosphonates may be a matter of the dose administered. The extensive clinical experience with bisphosphonates have shown that they are relatively free of significant toxicity. When patients with normal renal function are well hydrated and the bisphosphonate infusion is given over several hours renal function is not likely to be affected [269,270]. The drugs should, however, probably not be used in patients with renal failure. The administration of APD is often accompanied by a rise in body temperature during the first 2-3 days [248,257,258], but this do not persist and has not required termination of therapy. Oral therapy with APD has been associated with oral ulcers, nausea, esophagitis and diarrhea. In earlier studies Clodronate has been associated with the development of acute leukemia in a few patients. However, it is more likely that this was a chance occurrence than related to the drug. Long-term (more than three months) treatment with Didronel may produce osteomalacia due to the effect of the drug on osteoblast function and mineralization [266]. The demonstrated high efficacy and relative safety of the bisphosphonates make them at present ‘the drug of choice’ in the treatment of hypercalcemia of malignancy. APD is commercially available in the United Kingdom and pending in Belgium, Holland and France. Clodronate is available in the United Kingdom and France, and pending in Belgium, Holland, and Austria. Didronel is available in the United Kingdom, USA, Ireland, Belgium. Holland and France, and pending in Denmark and Italy.

VI-C.6. Prostaglandin Aspirin,

synthetase

indomethacin,

prostaglandin hypercalcemia of carcinomas

inhibitors

and other

drugs

that inhibit

synthesis have been reported to. correct of malignancy in patients with a variety [271-2731, but not in others [274]. The ra-

tionale for their use is, as previously described, that some cases of malignancy-related hypercalcemia are associated with increased prostaglandin synthesis, which is partially responsible for the hypercalcemia. practice, however, prostaglandin synthetase

In clinical inhibitors

are rarely effective in the treatment of hypercalcemia of malignancy. Further studies are needed to define those patients in whom a response to treatment is to be expected and to establish a simple discriminatory biochemical

test for this selection.

VI-C. 7. Miscellaneous Mobilization. Hypercalcemia, hypercalciuria, and renal stones are known complications to immobilization especially in young individuals, but also in elderly patients with enhanced bone turnover. Hence, immobilisation may contribute to the hypercalcemia observed in patients with malignant diseases. The best way to treat these patients are to let them return to the weight bearing position as soon as possible. Diafysis. Both hemodialysis, and peritoneal dialysis have been used in the treatment of hypercalcemia of malignancy in patients with renal failure. The effect is of short duration and is most likely to be necessary in myeloma patients. EDTA. Ethylenediaminetetraacetic acid (EDTA) is effective in reducing the ionized calcium in hypercalcemic patients. The duration of the effect is, however, short lived and the treatment may cause irreversible renal damage. Nevertheless, EDTA is the only therapeutic agent that has an instantaneous effect on serum ionized calcium an it could be used where a patient with severe TABLE

5

Main pathophysiological

mechanisms

in hypercalcemia

Increased intestinal calcium absorption Lymphoma Hodgkin’s

(occasionally) disease (occasionally)

Increased bone resorption osteolytic

bone metastases

myeloma humoral

hypercalcemia

of malignancy

Lymphoma Hodgkin’s

disease

Increased tubular reabsorption of calcium humoral

hypercalcemia

breast cancer

of malignancy

of malignancy

6

34 liters 0.9% saline

intravenous

intravenous

Calcitonin

Gallium

1 liter of

body weight

over 24 h

I liter of saline over

300 mg/day 7.5 mg/kg body weight

intravenous

intravenous

Chlodronate

Ethidronate over 3 h

in 300 ml of saline

saline over 4 h

intravenous

30 mg in 1 liter of

12h

in

25 pg/kg

dextrose

surface in 1 liter of 5%

200 mg/m’ body

saline over 6 h

600 IU in

per day

(or

or more

APD

Bisphosphonates

Mitramycin

intravenous

30 mg prednisone

oral or parenteral

Corticosteroids

nitrate

50 mmol over 68

intravenous

equivalent)

l-3 grams/day

oral

Phosphate

h

40-160 mg over 24 h

over 24 h

intravenous

intravenous

Dosage

of acute hypercalcemia

Furosemide

Sodium chloride

administration

Route of

for the treatment

infusion

of methods

Form of therapy

Evaluation

TABLE

decreased

decreased

decreased

decreased

decreased

increased

variable

decreased

increased

increased

calcium

Urinary

urinary

bone tract

decreased

decreased

decreased

decreased

decreased

calcium

osteolysis

bone resorption

bone resorption

bone resorption

osteocystic

bone resorption

intestinal

bone

of

of local

excretion

decreased

absorption?

resorption;

urinary decreased

increased calcium;

factors

inhibition

bone resorbing

to vitamin

on intestine;

as above

antagonism

binding D effects

of calcium

except for gastrointestinal

the gastrointestinal

binding

in

increased

formation?;

mineralization

bone marrow

renal failure‘!

dysfunctton;

hepatic

defect

toxicity’?

renal insufficiency

bleeding disorders;

hypophosphatemia

or acute steroid

calcification

hypophosphatemia

complications

hypercorticism

as above

extraskeletal

and shock;

resorption;

hypotension,

hyperphosphatemia,

in bone and bone

decreased

volume depletion:

of calcium

hypokalemia;

hypernatremia

hypomagnesemia

soft-tissue:

of

hypokalemia:

sodium overload:

deposition

excretion

of

complications

hypomagnesemia

urinary

with

excretion

Potential

calcium

increased

_ of action

associated

natriuresis

calcium

increased

Mecdnism

congestive

to use

serum phosphorous

are inadequate

as above

as above

nausea

disorders?

or liver failure

renal failure; bleeding

bone marrow

renal failure?

or

and 50% of of malignancy escape phenomenon:

hypercalemia

hyperparathyroidism

delayed effect: not effective in

methods

as above; use only when all other

elevated

and saline

not

heart

high normal

to furosemide

renal insufficiency;

responsive

renal failure with oliguria

failure; renal insufficiency

hypertension:

Limitations

hypercalcemia calcium-EDTA

is about to die from cardiac arrest. The complex is easely removed by dialysis.

Gulliurri nitrate. Gallium-containing have been shown to inhibit bone resorption

compounds [275]. X-ray

crystallography indicates that gallium alters the structure of hydroxyapatite making bone mineral less susceptible to dissolution. In clinical studies [276] gallium nitrate

has

been

shown

to control

hypercalcemia

malignancy in about 75 % of the cases treated. fects of chronic administration are not known.

of

The ef-

percalcemia:

evidence

8 Godsall

9 Stewart tion

hypercalcemia

AF. Insogna

tracts of tumors

drugs

interest in developing a new generation of bisphosphonates for the treatment of hypercalcemia of malignancy. Several compounds are at present under investigation. They seem to be very potent, and should also be effective in patients without bone metastases. I/-C.Y. Compurison of uvailahle treutnwnt modalities The various forms of therapy are shown in Table 6. At present we treat a case of symptomatic hypercalcemia with rehydration and a bisphosphonate given intravenously. If symptoms are severe. the initial serum calcium level is > 3.50 mmol/l or renal function is affected we add intravenous CT to the drug regime on the first day or two to achieve a faster decrease in serum calcium. Loop-diuretics are only given to prevent overhydration in selected patients. Glucocorticosteroids are used in hematological malignancies. sarcoidosis and vitamin D intoxication.

from patients

with humeral

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hyperplasia

carcinomatosis.

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JB. Smelin A. Moss J. Hypercalcemia

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AF. Horst

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clon-

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