Rationale for the use of bisphosphonates in bone metastases

Bone, 12, Suppl.

1, Sl3-Sl8

Printed in the USA.

(1991)

8753282/91

All rights reserved.

Rationale for the Use of Bisphosphonates J.A. KANIS, E.V. McCLOSKEY,

Deparfmenr

of’Humat1 Melaholism

Address jiw

correspondence

in Bone Metastases

T. TAUBE, N. O’ROURKE

and Clinical

and reprints:

$3.00 + .OO

Copyright 0 199 I Pergamon Press plc

Biochemistry,

University

ofSht$ield

Medical

School. Shejfield SIO 2RX. UK.

J.A. Kanis, Department of Human Metabolism and Clinical Biochemistry, University of Sheffield Medical

School, Sheffield S IO 2RX, UK

Abstract

in which this is disturbed in skeletal disease. As might be expected, malignancy affecting the skeleton does so in a heterogeneous manner, but accelerated bone resorption is an event common to all patients with osteolytic bone disease, whether this be generalised as often seen in the case of myelomatosis, or focal as commonly seen in metastatic carcinoma. These observations have led to the use of bisphosphonates in these disorders, since the bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption. This paper reviews the pathophysiology of tumour-induced osteolytic bone disease and those properties of the bisphosphonates of relevance to their potential in the treatment of such disorders. Oncologists and haematologists traditionally view holes in bone due to neoplastic osteolysis as a function of tumour activity. Whereas this is undoubtedly true, the holes in bone result from interactions which occur between tumour cells and bone cells normally responsible for the maintenance of skeletal integrity. It is therefore relevant to review briefly the manner in which bone cells maintain skeletal health and the way in which their activity is disturbed in neoplasia, before considering the properties and actions of the bisphosphonates.

Neoplasia affecting the skeleton is an important cause of morbidity, which includes hypercalcaemia, bone pain and fracture. In most instances these events are mediated by an increase in the resorption of bone which decreases bone density and disrupts skeletal architecture, either at focal sites or generally throughout the skeleton. Neoplastic activation of bone resorption is heterogeneous, but there is now good evidence that this is due to the increased activation of osteoclasts, the cells which mediate bone resorption in health. Bisphosphonates are specific inhibitors of osteoclastmediated bone resorption and are capable of inhibiting osteoclastic activation independent of the mechanism of its stimulation. This provides the rationale for the use of bisphosphonates in the hypercalcaemia of malignancy. Despite refinements in the use of endocrine therapy, chemotherapy and radiotherapy these interventions have had relatively little impact on the skeletal morbidity or mortality of common malignancies affecting the skeleton, particularly breast cancer and myelomatosis. In addition, there is good evidence that skeletal disease is progressive in many patients despite the use of chemotherapy and radiotherapy. Since accelerated bone resorption can be inhibited by long-term treatment with bisphosphonates, their use is likely to decrease skeletal complications such as bone pain and fracture. The bisphosphonates, therefore, hold great promise as agents to improve the quality of life of such patients. Key Words: Bisphosphonates - Tumour-induced Bone resorption - Bone turnouts - Osteoclasts.

osteolysis

Bone Remodelling In adults in whom longitudinal growth has ceased, much of the skeletal turnover (>95%) is accounted for by bone remodelling. The remodelling process is made up of a series of discrete events, which are well characterised morphologically, but physiologically ill-understood (Parfitt, 1983). The process is important for the self-repair of skeletal tissue and when remodelling is inhibited experimentally it results in spontaneous fracture (Flora et al., 1980), presumably related to the inability of the skeleton to repair fatigue damage (Frost, 1960). Bone remodelling describes the removal of old fatigued bone and its replacement with new bone. In trabecular (spongy) bone these events occur on the bone surface (Fig. 1). Early in the process, several osteoclasts, working as a team, are attracted to the bone surface where they excavate a resorption cavity. When the resorption cavity has been formed, mononuclear cells smooth off the resorption surface and disappear. These cells

-

Introduction There have been significant advances in our knowledge of the way in which the metabolism of the skeleton is coordinated in health and this has led to an improved understanding of the way

5413

J.A. Kanis et al: Use of bisphosphonates in bone metastases

M 0

0

D

a&v+

PI H

Fig. 1.

Steps in the remodelling

sequence

of

trabecular

bone. Early in

the sequence, osteoclasts are. attracted to a quiescent bone surface (A) and excavate a resorption cavity (B&Z).

Mononuclear

matrix synthesis (F) is followed by calcification bone.

When complete,

surface

(H).

Neoplasia and Bone Remodelling

cells smooth off

the resorption cavity (D), which is a subsequent site for the attraction of osteoblasts which synthesise an osteoid matrix (E).

quantitative relationship between the amount of bone lost during bone resorption and that which is subsequently formed. Thus, in Paget’s disease, where bone remodelling may be augumented by as much as IO-fold, the skeletal balance is usually close to zero, indicating that the high rates of bone resorption are accompanied by equally high rates of bone formation. The reason for this is related to the ‘coupling mechanism’ which determines that osteoblasts are attracted to sites of previous resorption. Although the mechanisms for the coupling process are poorly understood, they are clearly important for the maintenance of skeletal balance as well as the architecture of trabecular bone.

Continuous new

(G) of newly formed

lining cells once more overlie the trabecular

may be responsible for signals that ultimately attract osteoblasts, bone-forming cells, to sites of previous resorption, a phenomenon termed coupling. Osteoblasts within the resorption cavity synthesise an uncalcified osteoid matrix, which undergoes mineralisation several days later. Each resorption cavity is formed in two or three weeks, but it takes much longer, up to 3 months, to infill this with new bone tissue. A similar sequence of events occurs in cortical bone, except that the resorption cavity is a tunnel, usually running through in the long axis of compact osteons. The sequence of events is similar to that in spongy bone in that when part of the tunnel has been fully excavated, this is infilled with newly formed osteoid which then undergoes mineralisation. The metabolic activity of bone is, however, a surface-based event and the surfaces available in trabecular bone tissue are much greater than those at cortical sites. For example, the surface to volume ratio in trabecular bone is IO-fold greater than that of cortical bone. This means that the majority of skeletal activity occurs in trabecular bone and that, when this process is disrupted, lesions appear more floridly and more rapidly at trabecular bone sites than at cortical sites. At any one time approximately IO-15% of the bone surface is being remodelled, the remaining surface being relatively quiescent. When bone remodelling rates are increased, more osteoclast teams assemble to create resorption cavities and this is followed by an increased recruitment of osteoblasts. The accelerated numbers of remodelling units which are initiated is termed an increase in activation frequency. When activation frequency is increased, progressively more and more of the bone surface undergoes active resorption or formation. Indeed, in disorders characterised by high bone turnover (eg. renal osteodystrophy, Paget’s disease etc), the whole of the bone surface may be undergoing formation and resorption, representing a 5 to IO-fold increase in turnover. A consideration of the bone remodelling process is important for an understanding of the relationships between the various aspects of skeletal balance. In health, as well as in a number of metabolic bone disorders, there is a close

In the healthy adult, who is neither gaining nor losing bone, the rate of bone resorption equals the rate of new matrix formation Approximately 5 mmol of calcium is and mineralisation. resorbed from bone daily and this is matched by an equal amount deposited during the mineralisation of bone. Thus, the net flux of calcium from bone to the extracellular fluid attributable to bone remodelling, is close to zero. However, the amount of bone deposited in a resorption cavity does not always equal the volume of bone removed. This leads to skeletal imbalance of calcium without necessarily implying a disorder of coupling. In tumour activation of the skeleton and osteolytic bone disease, there is evidence for both increased resorption and formation. In the case of osteolytic bone disease, formation occurs predominantly at sites of previous resorption so that some aspects of coupling are preserved. However, the number or activity of osteoblasts attracted to resorption surfaces is inadequate, and this leads to skeletal imbalance. If there is imbalance at each remodelling site then any acceleration of bone turnover will in turn accelerate the rate of bone loss (Fig. 2). In most types of osteolytic bone disease due to neoplasia there is evidence for both increased rates of resorption and

BB

Fig. 2.

Schematic

representation

of a trabecular

bone surface to

illustrate the effect of balance and remodelling on bone loss. The top panel shows the infilling of a resorption cavity with an equal volume of new bone.

The centre panel shows less bone deposited at a site of

previous resorption.

If bone turnover is increased without altering this

balance (lower panel), the rate of trabecular bone loss will increase in proportion to the increment in bone turnover.

J.A. Kanis et al: Use of bisphosphonates in

bone metastases

formation, but the amount of bone formed is inadequate to infill the resorption cavity completely. The reasons for depressed osteoblast function are not known, but a potential factor is immobilisation which is common in patients with widespread skeletal disease and has inhibitory effects on bone formation. A second reason may be related to the secondary effects of accelerated osteolysis. Osteolysis discharges bone-derived calcium into the extracellular fluid which in turn suppresses the production of parathyroid hormone (PTH) and the active form of vitamin D, calcitriol. Both these hormones have trophic effects on bone and suppressed serum concentrations are restored to normal when the increased bone resorption due to neoplasia is inhibited (Lawson-Matthew et al., 1989). Thirdly, some of the cytokines which stimulate bone resorption such as IL-I may also inhibit bone formation. The activation of bone resorption by tumour cells is not invariably followed by bone formation at these sites. This uncoupling appears to occur in some solid tumours and in myelomatosis where osteolytic lesions are observed. Thus, there is a progressive wave of bone resorption which is not followed by bone formation and represents the uncoupling of formation from resorption. After the completion of resorption the eroded cavity remains, until a new wave of uncoupled bone resorption begins. Both focal skeletal imbalance and uncoupled bone resorption contribute to osteolytic bone disease, but an additional important component to irreversible skeletal loss is the destruction of bone architecture. For example, if a wave of bone resorption transects a trabecular strut then, because bone formation occurs almost exclusively at sites of previous resorption, the surface on which bone formation might have occurred is destroyed by the remodelling process. Thus, perforated trabecular or cortical structures cannot be restored by the remodelling process, This has obvious implications for skeletal strength since the disruption of the connectivity of bony trabeculae may decrease the resistance of the skeleton to both compressive and bending forces out of proportion to the amount of bone lost. These considerations also have important therapeutic implications when skeletal metabolism is altered by changes in bone remodelling (Fig. 3).

Fig. 3.

Schematic

representation

of trabecular bone showing normal

trabecular architecture and the thinning and discontinuity of trabecular elements.

The disruption

of continuity

weakens the structure out of

proportion to the amount of bone lost. Conversely, the deposition of new bone by influencing

bone remodelling

(right hand panel) may thicken

remnant structures without necessarily restoring trabecular continuity.

s15

Uncoupling of bone formation from bone resorption need not necessarily imply skeletal loss. In tumours associated with osteosclerotic metastases, such as prostatic cancer, new bone may be formed at sites which have not previously undergone bone resorption. Indeed, new bone may be formed from condensations of fibrous tissue within the marrow cavity (Fig. 4). Uncoupled bone formation is common in prostatic cancer, rare in myelomatosis and variable in breast cancer.

Fig. 4. Schematic diagram to show various types of uncoupling of bone formation remodelling bone.

and resorption.

The upper panel (A)

shows a normal

sequence where a resorption cavity is infilled with new

The left hand panels denote uncoupled

new bone formation

occurring, not at sites of previous resorption but on the quiescent bone surface (B) or within the marrow cavity (D). depict uncoupled resorption

The right hand panels

with the creation of resorption cavities

without subsequent bone formation (C), and the transection of a skeletal trabeculum by a wave of resorption (E) which destroys potential bone forming sites.

Despite the heterogeneity of the pathophysiology of skeletal disease, changes in the metabolism of bone are mediated principally by the activation of normal bone cells (O’Grady et al., 1985; Stewart et al., 1982; Percival et al., 1987). In patients with osteolysis, this is associated with the activation of osteoclasts, but it is likely that the mechanisms responsible for osteoclast activation differ between malignancies and also between patients with a single tumour type. Myeloma is the most frequent haematological cause of increased bone resorption, and is due to the activation of osteoclasts by factors which have now become known as osteoclast-activating factors. It is clear that several agents derived from leukocytes are potent bone-resorbing agents, and there is now good evidence that lymphotoxins and the interleukins are responsible for the hypercalcaemia and bone loss which is seen in some patients with myeloma (Mundy, 1989). Less is known about the mechanisms which induce excessive bone resorption in patients with skeletal metastases from solid tumours. Candidates include procathepsin D, prostaglandins and the transforming growth factors (Mundy et 1985b; Brereton et al., 1974). al., 1985a; Mundy,

Sl6

J.A. Kanis et al: Use of bisphosphonates in bone metasla\ej

Hypercalcaemia and increased bone resorption is also observed in some patients with solid tumours who have no evidence of skeletal metastases (humoral hypercalcaemia of malignancy HHM). These patients with HHM appear to secrete factors which induce hypercalcaemia by increasing the renal tubular reabsorption of calcium, as well as by effects on bone (Kanis et al., 1986; Percival et al., 1985). These activities, similar to those of parathyroid hormone, are probably related to the secretion of PTH-related protein by the tumour tissue (Burtis et al.. 1988). Bisphosphonates

The bisphosphonates (also known as diphosphonates). are analogues of pyrophosphate (Fig. 5). Like pyrophosphate. they are absorbed onto bone mineral, a property which is exploited Unlike pyrophosphate. the in skeletal scintigraphy. bisphosphonates are resistant to enzymatic hydrolysis. In tissue culture, they inhibit normal and stimulated bone resorption, and prevent osteolysis due to parathyroid hormone, PTH-related protein, calcitriol. prostaglandins and a variety of cytokines (Fleisch. 1989). The wide spectrum of inhibitory activity suggests that the bisphosphonates act at a distal step in the cellular events which effect bone resorption, and are thus suitable agents for the management of accelerated osteoclast activity, irrespective of the cause. The precise mechanism of action of bisphosphonatea on bone cells is uncertain (Fig. 6). It is certain that the bisphosphonate structure itself allows the targetting to skeletal sites, and additional structural modifications affect their potency and range of activity. For example. the amino bisphosphonates are particularly potent inhibitors of bone resorption, and their potency varies according to the length of the side chain (Shinoda et al., 1983). Some bisphosphonates also inhibit bone mineralisation. The relative potency of bisphosphonates to inhibit mineralisation and resorption differs between compounds. Of those tested in man, etidronate has the most marked effects on mineralisation. This makes etidronate less suitable for long-term use to inhibit bone resorption. compared with either clodronate or pamidronate.

OH I

OH

ONa

OH

m&i

I

I

I

I

o=p-c-P=0

o=p-o-p=0 I OH lnorganlc

I

I

I

I

OH

OH

Ct.

OH

pyrophosphale

I -hydroxyethyllde”e~1

I

Cl

I

Schema showing the inductmn of osteoclast formation

and

Osteoclasts (OC) are formed by the fusion of osteoclast

precursor cells (OCP) which are then altracted and attach to the bone wrfacc and secrete acid and lysosomal enlymes.

The bisphosphonate\

decrease the recruitment of osteoclast precursors (A).

They may also

inhibit their attachment 10 bone (B) and decrease their activity on hone clthcr directly (C) or due 10 adsorption of bisphosphonatc onto bone (D).

Hypercalcaemia of malignancy is nearly always associated with osteolytic metastases (Table I). However. several other factors are important, both for the induction and maintenance of hypercalcaemia. For example, increased renal tubular reabsorption of calcium is found in about one-third of patients with breast cancer and skeletal metastases (Percival et al., 1985). probably due to the secretion of PTH-related protein, and this contributes to hypercalcaemia independently of any effect on bone. In some patients with HHM. increased renal tubular reabsorption of calcium may be the principal cause of hypercalcaemia (Table II). In addition, hypercalcaemia may be maintained by the secondary effects of the hypercalcaemic state. These effects include nephrogenic diabetes insipidus resulting in polyuria, sodium depletion and a secondary increase in renal tubular reabsorption of calcium. Intravascular volume depletion may impair renal function, as may hypercalcaemia through inducing structural renal damage. All these factors decrease the ability of patients to withstand a hypercalcaemic challenge. These variable mechanisms for the induction and maintenance of hypercalcaemia are important to consider when

Pamdronatr

Clodronate ONa

1 -dlphospho”afe

Fig. 6.

aclivation.

ONa

I

ONn

I

ON

I

OIV,,

Table I.

I

cancer.

Note

that hypercalcaemia

is most frequentI>

associated with osteolyric metastases.

o=p-C-P=0

o=p-c-p=0

Serum calcium and the nature of skeletal metaStases m breast

I

I

I

I

I

I

OH

Cl

OH

OH

ICH

OH

Fig. 5. Structure of pyrophosphonate and of the rhrcc bisphosphonateh which are available for treatment in malignant disorders.

Metastasec

n

% hypercalcaemic

% hypocalcaemlc

Osteoblastic Mixed

25

0

12

IS

13

0

Orleolytic

31

76

0

Unknown

22

IX

5

J.A. Kanis et al: Use of bisphosphonates in

bone metastases

Sl7

Table 11. Mechanisms for the maintenance of hypercalcaemia in patients

Use in accelerated

osteolvsis

with malignant disease. Values shown are the proportion (%) of the increment

in serum calcium

attributable

to these

mechanisms. Myelomatosis

Solid tumours

HHM

with metastases Number of patients

10

13

4

3.14

3.34

3.56

Total serum calcium (mmol/l) Increment in serum calcium (%) due to increased bone resorption

51

36

28

impaired GFR

29

23

I

20

41

65

- increased renal tubular reabsorption of calcium

evaluating the activity of bisphosphonates in hypercalcaemia. For example, most hypercalcaemic patients are volume depleted, and the administration of saline alone will improve hypercalcaemia (Hosking et al., 1981). The apparent efficacy of agents given with saline or other concomitant medications may be incorrectly attributed to the trial agents. For example, the use of saline and corticosteroids is well established in the management of hypercalcaemia resulting from solid tumours. It is clear, however, that the principal effect of this regimen is due to saline; and corticosteroids, contrary to popular belief, have little, if any, additional effect (Percival et al., 1984). In assessing the effects of the bisphosphonates, these problems must be overcome, either by the use of controlled trials, or by pretreatment of hypercalcaemic patients with intravascular volume expansion until a new steady state for serum calcium has occurred. Under these conditions and in the absence of concomittant therapy, further changes in serum calcium can be attributed to the bisphosphonates. A large clinical experience (reviewed by Bonjour; this volume) indicates that the bisphosphonates are capable of lowering hypercalcaemia due to malignancy, and that the major mechanism is the inhibition of bone resorption. The ultimate effect of bisphosphonates on serum calcium depends critically upon the factors responsible for its maintenance. In the case of breast cancer with skeletal metastases, normocalcaemia is usually attained. In contrast, in HHM, serum calcium is rarely normalised since the bisphosphonates do not decrease renal tubular calcium reabsorption. Thus, the failure to restore serum calcium to normal in some patients with hypercalcaemia should not be taken on this account alone as evidence that bone resorption has not been effectively inhibited. Despite wide differences in potency between the various bisphosphonates, the therapeutic end result appears to be similar. The action of the bisphosphonates to inhibit tumour-mediated bone resorption appears to last throughout the treatment period, both in myelomatosis and in solid tumours associated with skeletal metastases. Thus, the bisphosphonates may be used not only to treat hypercalcaemia, but also to prevent its recurrence.

Bone pain, pathological fracture and hypercalcaemia account for significant morbidity and some of the mortality associated with neoplasia. Focal and generalised skeletal disease often responds to chemotherapy and local radiotherapy. It is clear, however, that in many patients, skeletal disease is slowly progressive, despite the induction of otherwise satisfactory responses or stable remission. Several studies have now shown that bisphosphonates are capable of inhibiting bone resorption in normocalcaemic patients over prolonged periods, either with continuous treatment or with intermittent intravenous administration (Van Holten et al., 1988; Elomaa et al., 1983; 198.5; 1987; Jung, 1982; Siris et al., 1983; Paterson, this volume; Delmas, this volume). A potential concern with the long-term use of bisphosphonates, is that although they may inhibit bone loss, the decrease in bone turnover and remodelling may increase skeletal fragility. In the case of clodronate, histomorphometric measurements from bone have shown that long-term treatment is associated with a reduction in osteoclast numbers at the site of metastatic breast cancer, but with no adverse effects, either on bone formation or on mineralisation (Elomaa et al., 1987). Because etidronate impairs the mineralisation of bone, the long-term use of this agent in the control of skeletal metastases is likely to be problematic and its use is only recommended for I month as an adjunct for the maintenance of normocalcaemia after its intravenous use. At present the most suitable bisphosphonates available for longterm use are clodronate and pamidronate. Whereas pamidronate is more potent, clodronate is available in an oral formulation which lends itself to long-term administration. It is likely that these bisphosphonates and other new bisphosphonates currently being tested are capable of profoundly affecting skeletal metabolism in neoplasia. Large double-blind studies are now in progress to examine the long-term effects of bisphosphonates in breast cancer and in myeloma. The available evidence suggests that such trials are likely to show a major effect for the bisphosphonates in altering the natural history of the expression of skeletal disease in neoplasia.

We are grateful to the Medical Research Council and to Rhone-Poulenc Rorer Central Research for programme support of our work. Our own work in myeloma and in breast cancer has been supported by the Leukaemia Research Fund, the Yorkshire Cancer Research Campaign and the Breast Cancer Research Trust.

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