Bone Metastases

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Introduction

Metastasis is a fundamental problem in clinical oncology. Once established in the skeleton or elsewhere, the malignancy is systemic and can no longer be cured by surgery alone. This is the reason that tumors are regarded as systemic from the moment osseous or other metastases are detected. Some even consider all malig- nant tumors as systemic from the moment they are established and certainly as soon as they have attained a clinically detectable size.

Skeletal metastases can remain dormant and symptomless for many years. But when they begin to spread, metastases cause a drastic reduction of the patient’s quality of life due to complications such as pain, immobility, fractures, spinal cord compression, hypercalcemia and hematopoietic insufficiency. The situa- tion is made even worse by the fear, depression and hopelessness which inevi- tably accompany the physical condition. Prevention of metastatic spread is as yet unattainable simply because it has already occurred in many patients before the tumor itself is diagnosed. Studies have shown that over 10% of patients with breast cancer have metastases which have been dormant for over 10 years. Cases of recurrence of metastatic spread after more than 20 or more years have also been reported. What intrinsic and/or extrinsic factors enable malignant cells to survive in a state of “hibernation” or dormancy, and what events/circumstances trigger their subsequent awakening and renewed growth are as yet completely unknown.

Frequency

The lungs, liver and bone marrow act as filters for disseminated circulating malig-

nant cells and are the most frequent sites for hematogenic spread. And of these, the

bone/bone marrow environment offers ideal conditions for establishment of metas-

tases. However, the frequency of metastatic involvement of the skeleton at autopsy

varies from 25% to 85% probably due to differences in the method and thorough-

ness of search (Table 25.1). Skeletal metastases are found at autopsy in 70–85% of

patients with tumors of the breast, prostate and lung, but fewer than half of these

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200 Chapter 25 Bone Metastases

Table 25.1 Incidence of bone metastases in autopsy studies

Primary Tumor Site Incidence (%) Range (%)

Breast 73 47–85

Prostate 68 33–85

Bronchus 45 33–60

Thyroid 42 28–60

Kidney 35 33–40

Gastrointestinal tract 8 5–13

Fig. 25.1 Vascular system in the bone marrow

had been recognised clinically during the patients’ lifetime. The overall impres-

sion from previous studies is that up to 90% of all patients who die of malignant

tumors had skeletal metastases. Certain tumors exhibit osteotropism, that is, a par-

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ticular affinity to metastasise to the bones. These include tumors of the breast, prostate, lung, kidney and thyroid, and they are responsible for over 80% of all metastases in bone.

Regional Distribution within the Skeleton

Metastases “home” to bones which house red hematopoietic marrow. Several fac- tors are responsible for this proclivity: the extensive vascular system (Fig. 25.1), the thin vascular walls, often without a basal membrane, and the slow blood flow through the sinusoids. These are ideal conditions for intra-vascular tumor cells to migrate into the surrounding tissues and to implant, i.e. establish themselves (seed and soil hypothesis).

The retrograde venous plexus of the spine (Batson’s plexus) also contributes to metastatic spread in the vertebrae and pelvis. First described in 1827 by G.

Breschet, this valveless extensive plexus anastomoses with epidural, thoracic and abdominal veins (Fig. 25.2). Malignant metastatic cells are frequently found in the endosteal sinuses in iliac crest biopsies from patients with mammary or with prostatic carcinomas and from here they invade the surrounding stroma. It is also thought that the vertebral venous plexuses and the sinusoids in the bone marrow present tumor cells with ideal conditions for prolonged “hibernation/dormancy”

until the opportunity for growth arises even many years later as mentioned above.

Development of Skeletal Metastases

Tumor cells circulate in the blood stream in the early stages of development of the primary tumor. The following steps are distinguished in development of skeletal meta- stases: (Fig. 25.3):

▶ Circulating tumor cells occupy niches in the sinusoids and invade the stroma.

Alternatively they die or remain dormant and unrecognised in small colonies only to become active after years or earlier in aggressive cases.

▶ Activated tumor cells use proteinases to penetrate the thin vessel walls and the adjoining connective tissue. They must protect themselves from immune at- tacks and, if they survive, they attach themselves to the interstitium of the ad- jacent tissues.

▶ The cells of the endosteal sinusoids lie on the bone, are easily penetrated by the tumor cells which gives them access to the osseous surface to which they attach themselves; and so skeletal micrometastases are initiated Fig. 25.4a.

▶ Once established, the tumor cells secrete cytokines which stimulate neo-an-

giogenesis and stroma, at which point a micrometastasic nodule is established

(Fig. 25.4b) and can be detected by MRI even when only 3 mm in size.

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▶ The micrometastases then expand in the bone marrow and secrete cytokines that produce typical osteolytic/osteosclerotic lesions now demonstrable by bone scan and X-ray.

Osseous Reactions

As outlined above, an osseous reaction with markedly increased remodelling par- ticularly resorption occurs in 93% of patients with skeletal metastases, and bone

Fig. 25.2 Retrograde spread of tumor cells via the venous complex (Batson’s) in the vertebral column. This is a common route for metastases to the axial skeleton. The tumor cells invade the bone marrow by way of the endosteal sinuses, which are the terminal vessels of the venous system in the bone marrow

Fig. 25.3 Six stages in establishment of bone metastases

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turnover markers are used for diagnosis, prognosis and as predictors of skeletal complications in many solid tumors. The type of osseous reactions to the metasta- ses depends on the primary tumor. Usually osteoclastic resorption is accompanied by osteoblastic formation. Metastases of breast cancer exhibit this reaction, while the metastases of prostatic carcinomas evoke an almost exclusively osteoblastic re- action. Five different histologic patterns can be distinguished in bone biopsies, their frequency depends on the primary tumor (Table 25.2).

Table 25.2 Bone reactions in various primary tumors (% of the cases with metastatic bone disease)

Breast Prostate Bronchus

Normal 5 0 28

Porosis/Osteolysis 20 7 18

Mixed form 41 38 27

Trabecular sclerosis 22 0 26

Woven bone 12 55 0

Fig. 25.4a,b Initial stages in the process of establishment of metastases in the bone marrow.

a Dissemination of tumor cells in the marrow and incipient adhesion to the surface of the bone.

bDevelopment of a micrometastasis with induction of stroma

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Two mechanisms are involved in the development of neoplastic osteolytic lesions:

▶ The most frequent is osteoclastic resorption stimulated by cytokines produced by the neighboring tumor cells. When the tumor cells are diffusely scattered in the bone marrow, the result may be a generalised osteoporosis.

▶ Occasionally, but only when the metastases are particularly aggressive, there is a direct expansive destruction of bone by lytic enzymes secreted by the tumor cells themselves.

Bisphosphonates

Targets for their Actions

The main steps in the establishment of bone metastases are all vulnerable to the effects of bisphosphonates:

▶ Adhesion

▶ Invasion

▶ Induction of stroma

▶ Growth: multiplication of metastatic cells

▶ Skeletal destruction

All these steps are inhibited by bisphosphonates which can therefore obstruct the establishment of metastases at many points in the process (Fig. 25.5):

Fig. 25.5 Cascade of reactions in the development of skeletal metastases and the inhibitory effect of bisphosphonates (BIS), BM = bone marrow

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▶ Blockage of adhesion molecules: Incubation of mammary and prostatic tumor cells with bisphosphonates in the incubation medium prevents their adhesion to mineralised and non-mineralised matrices as well as their passage through vessel walls and extracellular matrix. Even low doses of ibandronate and zole- dronate produced these effects, which can be further increased by addition of taxoids. The inhibition of tumor cell adhesion was probably brought about by modulation of adhesion molecules such as cadherin, laminin and integrins.

This may be one of the mechanisms by which bisphosphonates inhibit tumor cell invasion of the extra-cellular matrix.

▶ Inhibition of proteinases: Bisphosphonates inhibit the secretion and activation of numerous matrix metalloproteinases such as MMP2 and MMP9, thereby also inhibiting tumor cell mobility and vascular permeability. This inhibition can be abolished by adding zinc 50 µM to the medium.

▶ Inhibition of growth factors: There are many growth factors in bone (TGFβ, BMPs, FGFs, PDGFs, and IGFs) which are released during osteoclastic resorp- tion and stimulate the proliferation of tumor cells. Moreover, tumor cells them- selves produce PTHrP, which in turn stimulates osteoclasts, thus closing the vicious circle, in particular the interactions between PTHrP and TGFβ.

▶ Inhibition of prostaglandins: Bisphosphonates also inhibit secretion of prosta- glandins and cytokines by osteoblasts, bone marrow stromal cells, monocytes and macrophages.

▶ Inhibition of neo-angiogenesis: Induction of blood vessels is essential for de- velopment and survival of metastases. In vitro, ibandronate and zoledronate inhibit proliferation of human endothelial cells obtained from umbilical cord veins (anti-angiogenesis). Therefore, inhibition of blood vessels in and around metastases in vivo is likely, and this is similar to the action of thalidomide, which is now used in patients with refractory myeloma and with myelodysplas- tic syndromes.

In summary, metastatic cancer cells possess the capacity to modulate the bone and bone marrow microenvironment by inter-actions with the marrow and the bone cells. Bisphosphonates can effectively and specifically disrupt this cycle and thereby inhibit bone metastases.

Anti-proliferative Effect

Bisphosphonates are able to induce apoptosis of both tumor cells and osteoclasts

by activating caspase-3 and caspase-3 like proteases. Moreover, the aminobisphos-

phonates also stimulate Bcl 2, as well as preventing activation of RAS whereby

intra-cellular signalling is interrupted and apoptosis is triggered. Clearly there is

a highly complicated interplay between bisphosphonates, osteoclasts, various ele-

ments of the bone marrow and the tumor cells themselves. Bisphosphonates also

induce a significant decrease in telomerase expression in tumor cells, which in turn

inhibits their multiplication.

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Moreover, there appears to be a relationship between skeletal retention, rate of resorption, degree of bone turnover and timing of therapy with bisphospho- nates in patients with breast cancer. This is important with respect to metastases in bone, as well as, needless to say, in many other conditions.

In summary, there is no longer any doubt about the inhibitory effect of bisphos- phonates on skeletal metastases. Whether or not bisphosphonates are able to inhibit primary tumors and visceral metastases currently being tested in large-scale clinical trials.

Figure 25.6 summarises the actions of the bisphosphonates on the various cas- cades of metastatic development. According to the data presently available there

Fig. 25.6 Ten actions of bisphosphonates (BIS) on metastases in bone

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