Osteoporosis After Breast Cancer

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Breast Cancer and Bone HealthOptimum care of osteoporosis and bone metastasesin people affected by breast cancer

August 2005 Printed using an educational grant from Novartis


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Foreword

RCN President Sylvia Denton OBE FRCNAs President of the Royal College of Nursing, I am delighted to endorse this importantresource for nurses caring for women with, or at risk of, osteoporosis and bone metastases .It provides information and signposts other sources of information which will enable nursesto offer practical advice and support to patients.

As a practising cancer nurse with many years experience, I am delighted that we are helpingso many people to live longer despite a cancer diagnosis. There is a price to pay for everythinghowever, and one of the risks for women who are being helped by treatment for cancer todayis that they can be at increased risk of osteoporosis .

I have seen for myself the pain and the reduction in quality of life which can result fromosteoporosis and bone metastases . We owe it to our patients to do everything in our power to minimise the risks and overcome the problems they present. I congratulate the RCN BreastCare Nursing Society for teaming up with Novartis to produce this comprehensive guide.It will help nurses working in breast care improve their knowledge and understanding of theimportant issues in bone health for their patients.

Nurses working in other specialties, whether in hospital or the community, will also be ableto use this guide to update themselves on treatment and care for people with bone metastases .

Patients deserve to be cared for by people who are well informed and understand the clinicalevidence that underpins their practice. Increasingly, the patients of today want to be partnersin their care and treatment. Nurses are ideally placed to help patients access information,understand it and make meaningful choices. For that, we need to be informed and educated ourselves.

As a recent survey shows, breast care nurses like many other nurses have increasinglyheavy workloads and patient caseloads, leading to concern about the amount of time they haveto spend with their patients. Time is precious; time spent listening to patients, offering themsupport and helping them make choices about their care and treatment is very precious indeed.

Nurses are the backbone of the health care workforce and we have a crucial role to playin working to achieve high standards of care. Health care today is more sophisticated,time-consuming and intense. All registered nurses are required to keep up to date as part of maintaining their NMC registration. Yet we are granted less time than other colleagues in themultidisciplinary team for our continuing professional development. The RCN continues tocampaign for nurses to get time and support from employers and colleagues to keep up to date.

This education tool will help busy nurses everywhere update their knowledge. I know thatmany patients will benefit.

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This publication contains information, advice and guidance to help members of the RCN. It is intended for use withinthe UK but readers are advised that practices may vary in each country and outside the UK.

The information in this booklet has been compiled from professional sources, but its accuracy is not guaranteed. Whilstevery effort has been made to ensure the RCN provides accurate and expert information and guidance, it is impossibleto predict all the circumstances in which it may be used. Accordingly, the RCN shall not be liable to any person or entitywith respect to any loss or damage caused or alleged to be caused directly or indirectly by what is contained in or leftout of this publication.

Published by the Royal College of Nursing, 20 Cavendish Square, London, W1G 0RN.

2005 Royal College of Nursing. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any formor by any means electronic, mechanical, photocopying, recording or otherwise, without prior permission of the Publishers or a licence permitting restricted copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1T 4LP. This publication may not be lent, resold, hired out or otherwise disposed of by ways of trade in any form of binding or cover other than that in which it is published, without the prior consent of the Publishers.

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Acknowledgement to Emma Pennery, Nurse Consultant, for writing and editing this document.


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8. Interventions for osteoporosis and bone metastases 21

8.1 Lifestyle (diet and exercise) for treatment of osteoporosis

8.2 Selective Oestrogen Receptor Modulators (SERMS) for treatmentof osteoporosis

8.3 Calcitonin for treatment of osteoporosis

8.4 Phytoestrogens for treatment of osteoporosis

8.5 Parathyroid hormone for treatment of osteoporosis

8.6 Hormone Replacement Therapy (HRT) for treatment of osteoporosis

8.7 Bisphosphonates for treatment of osteoporosis and bone metastases

8.8 Radiotherapy for treatment of bone metastases

8.9 Chemotherapy for treatment of bone metastases

8.10Endocrine therapy for treatment of bone metastases

8.11 Orthopaedic surgery for treatment of osteoporosis andbone metastases

8.12Vertebroplasty for treatment of osteoporosis and bone metastases

9. Assessing response to interventions 33

10. Complications of osteoporosis and bone metastases 34

10.1 Hypercalcaemia

10.2Pain

10.3 Pathological fracture

10.4Spinal cord compression10.5 Bone marrow suppression

11. The way forward? 37

12. Useful addresses and contacts 39

13. References and bibliography 40

Contents page

i. About this resource 6

ii. The implications for nurses 7

a) Optimising psychological support

b) Information provision

c) Acquisition of knowledge

d) Multidisciplinary team working

1. Introduction 9

2. Anatomy of bones 9

3. Aetiology and physiology: osteoporosis 11

4. The impact of menopause on bone health and osteoporosis 12

5. What effects do breast cancer treatments have on inducing menopause? 12

5.1 Chemotherapy

5.2 Endocrine therapy

6. Aetiology and physiology: bone metastases 16

7. Investigating bone health 17

7.1 Bone density scans: used in the detection of osteoporosis

7.1.1 Definition of osteoporosis

7.2 Quantitative ultrasound: used in the detection of osteoporosis

7.3 Blood test for serum calcium levels

7.4 Isotope bone scans: used in the detection of bone metastases

7.5 Plain x-rays

7.6 Blood tumour markers: used in the detection of bone metastases

7.7 Computerised tomography (CT) and magnetic resonance imaging (MRI) used in the detection of bone metastases

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ii. The implications for nurses

The implications for nurses highlighted by thisresource are detailed below and throughoutthe document, denoted by this symbol:

Note: Nurse input in provision of emotional support and adequate, meaningfulinformation for people with breast cancer are recommended in English, Welsh and Scottish national guidelines, including:

National Institute of Clinical Excellence guidance on Improving Outcomes inBreast Cancer (NICE 2002).

National Institute of Clinical Excellence guidance on Supportive and palliative careguidance for adults with cancer (NICE 2004a).

Scottish Intercollegiate Guidelines Network Guideline 29 Breast Cancer in Women(SIGN 2002).

a) Optimising psychological supporthelping individuals to cope with the prognostic implications of advanced disease(bone metastases ) or an incurable chronic condition ( osteoporosis ).

helping to reducing fear and uncertainty about the future and assist with planning.

facilitating formal psychological support and support group as required.

demonstrating empathy and respect towards the patient.

providing time and space to talk to the patient in a private setting.

appropriately involving relatives and friends (including advising on talking to children).

responding to the emotional needs of the patients taking into account their social,cultural and ethnic variations.

if metastatic disease remains confined to the bones, patients can live for years and therefore require continuing skilled, needs-led supportive care.

b) Information provision (written and verbal)assisting with decision making.

contributing to informed consent for treatments and investigations.

assessing risk and risk factors.

ensuring the patient has an understanding of risk.

teaching interventions, health education and promotion.

explaining about clinical trials.

introducing peer support if required, including input from national organisations. 7

i. About this resource

Developments in interventions for the management of people with breast cancer inrecent years have had implications for maintaining optimum bone health and thisdocument was conceived with this in mind. The Royal College of Nursing Breast Care

Nursing Society was keen to develop an education tool that would appeal to clinicalnurse specialists with a wide variety of experience and knowledge in breast care.

Nurses with specialised oncology backgrounds may have gaps in their knowledgerelating to causes, diagnosis and treatment of osteoporosis , whilst nurses with moregeneral medical or surgical backgrounds, may require an update on interventions for bone metastases . Hence this document aims to provide a comprehensive guide for allnurses working in breast care and to promote their knowledge and understanding aboutthe significance of issues r elating to bone health and breast cancer.

It is hoped that improvements in knowledge and appreciation of the implicationsfor nurses will result in improved quality of care for people at risk of or living withosteoporosis or bone metastases after a diagnosis of breast cancer. You may choose toread the entire document or to dip in to it whenever you need more information about

specific clinical areas relating to patients in your care. Full references, including websites and a bibliography are listed at the end to direct you to further reading if youwould like greater depth or to read any of the cited research studies in full.

Key learning points for users of this resource are:i) to be able to describe the causes of, investigations and interventions

for osteoporosis and bone metastases , in the context of people with breast cancer.

ii) to understand the crucial role of nurses in promoting optimum care in thisimportant area of practice.

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1. Introduction

Breast cancer is inextricably linked to two aspects of bone health, osteoporosis and bone metastases .

OsteoporosisThe majority of women with breast cancer are near to or past the age of naturalmenopause at the time of their diagnosis and increased use of chemotherapy has resulted in more young women experiencing a premature, treatment-induced menopause. Anearly menopause (reduced levels of circulating oestrogen) has implications for bonehealth in later life because it may increase the individual risk of developing osteoporosis .

Bone metastasesThe bone is the most common site in which people develop distant metastases froma primary breast cancer and represents approximately 2540% of all first metastases(Gralow 2002). Indeed over 70% of people with advanced breast cancer have skeletalinvolvement at some time and bones may remain the only sites of secondary disease for approximately a fifth of patients.

2. Anatomy of bones

Bone is living tissue and is therefore constantly changing. It is comprised of a hard and sturdy outer shell called cortical bone and a softer, spongy inner layer called trabecular bone. This inner layer has a latticework structure, made up of struts of boneand contains bone marrow [see below].

Resting

( Resorption

Formation

ReversalNormal bone remodelling 1Resorption Stimulated bone-lining cells(osteoblast precursors) release factors that bindto osteoclast receptors, leading to osteoclastdifferentiation and activity. Osteoclasts removebone mineral and matrix, creating an erosion cavity.Reversal Mononuclear cells prepare bone surfacefor new osteoblasts to begin building bone.Formation Successive waves of osteoblastssynthesise an organic matrix to replace resorbedbone and fill the cavity with new bone.Resting Bone surface is covered with flattenedlining cells. A prolonged resting period followswith little cellular activity until a new remodelling cycle begins.1. Mundy GR. Bisphosphonates as cancer drugs.Hosp Pract. 1999; 34: 8 1-94 .

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c) Acquisition of knowledgenurses need to have knowledge about risks to bone health arising from treatment for

breast cancer and potential presentation of bone metastases.

the National Institute of Clinical Excellence has produced an updated document on breastcancer service guidance (NICE 2002). It reiterates that long-term follow-up has not beenshown to offer any clinical benefit to women and thus check ups should continue for onlytwo to 3 years (except if clinical trial protocols require longer). However it also states that all

patients should have indefinite access to the breast care nurse specialist, who should providetelephone support and arrange appointments at the breast clinic if there seems to be cause for concern. Patients are also advised to report to the breast care nurse if they have any problemsor symptoms that could be linked to their cancer or treatment and should be given specificinformation about what sorts of things they should report to the breast care nurse specialist.This necessitates nurses to have a sound knowledge of:

pathological variables and their prognostic significance(to interpret the relevance of the patients medical history).

the sites of metastatic breast cancer and the symptoms they may produce(to assess the relevance of those symptoms being reported).

indications for referral to the medical team.

local referral mechanisms.

relevant national guidelines(such as National Institute of Clinical Excellence, Clinical Outcomes Group).

accountability with regard to documentation.

professional and legal implications of accountability.

nurses also need knowledge of the increased risk of osteoporosis after an ea rly,treatment-induced menopause, strategies for assessment and management and theimplications of popular dietary changes following a diagnosis of breast cancer (suchas omitting dairy products).

integral to possession of up to date knowledge, is an awareness of clinical trials and researchfindings. Research studies are presented throughout the document in orange boxes.

d) Multi disciplinary team working liaison with team members.

referring on to relevant professionals, specifically remembering those from outsidethe breast unit team (including orthopaedic surgeons and nurses, physiotherapists,occupational therapists, pain control teams, palliative care teams, complementarytherapists, psychological support teams).

A review of women with breast cancer and bone metastases showed that clinicalreview by an orthopaedic surgeon was requested on less than 50% of occasions

when it would have been clinically appropriate (ODonoghue et al 1997).

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Bone growth and metabolism are regulated by cell activity on its surface:

Osteoblasts are responsible for synthesis and mineralisation.

Osteoclasts are responsible for bone destruction.

Both of these work together naturally in a process called coupling.

A diagrammatic representation of bone metabolism

The three main factors modulating bone resorption a re parathyroid hormone, vitamin Dand calcitonin. In children, the osteoblasts work faster to ensure the skeleton increasesin size, strength and density and approximately 95% of all adult bone is laid downduring adolescence. This increase in bone density continues throughout younger life,reaching maximum strength (peak bone mass) during the mid 20s. At around the ageof 35 years bone loss begins as part of the natural ageing process.

IMPLICATIONS FOR NURSES:

Information provision and possession of knowledgeenable clear explanations of bone metabolism to patients in whom

bone health may be compromised.

This balance of

old bone destruction[resorption]and bone formationis called remodellingand is a normal

part of healthyskeletal activity

Osteoclasts are attracted to sites of the bone affected by injury, disease or

fatigue. They then remove the damaged

area by eroding a cavity

Osteoblasts synthesise new boneto replace what has been lost and

eventually refill the cavity

3. Aetiology and physiology: osteoporosis

The literal definition of osteoporosis is porous bones. It can occur when an eroded area (or cavity) within the bone fails to attract bone synthesising osteoblasts, thereforethere is no longer pairing with osteoclasts (refer red to as uncoupling). As osteoclastscontinue to outperform osteoblasts, more bone is destroyed than laid down.

Progressive and persistent erosion can produce holes in the bone because the strutsforming the inner trabecular, latticework matrix become thinner and begin to break.Increasing numbers of holes emerging in the bone results in it becoming porous or

perforated hence the name. The result is thinning bones that have reduced strengthand are at greater risk of fracture, even when no trauma has occurred.

Trabecular bone, whilst representing only about 20% of the skeletal mass, makes up80% of bone turnover, whilst cortical bone makes up most of skeletal mass but onlycontributes about 20% to bone turnover. This explains why osteoporosis , the resultof abnormal bone turnover, is seen primarily in trabecular bone (Fleisch 1995).

Of relevance to people with breast cancer, women are more at risk of developingosteoporosis than men because they generally have smaller, less dense bones and

because of the effects of going through the menopause. In the United Kingdomosteoporosis affects 1 in 3 women and 1 in 12 men over the age of 50 years and thereare an estimated 3 million people cur rently living with the condition. Overall, hipfractures account for 20% of all orthopaedic hospital bed occupancy in the UK and osteoporosis results in over 200,000 fractures each year (including 60,000 hip fractures)at an annual cost to the National Health Service of over 940 million (Royal Collegeof Physicians Working Party Report 2001).


Information provision and possession of knowledgeenable clear explanations of osteoporosis to patients who are affected

and identification of those who may be at risk.

Risk factors for the development of osteoporosis include: An early menopause, before the age of 45 years.

Cessation of menstruation for 6 months or more due to excessive exercisingor weight loss.

Low body weight.

Smoking.

Long term use of cor ticosteroid medication.

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Women over 40 years are more susceptible because they already have a depleting number of follicles and are nearer the natural age of onset of the menopause (Goodwin et al 1999). Loss of menstruation may happen a few months after treatment is completed.Conversely, function may take a few months (even up to 2 years) to return after treatment.It is difficult to predict an individuals exact chances of becoming menopausal after treatment because the few studies investigating this have relied on small numbers and have included various drug regimens. However a review of ovarian function in

premenopausal women treated with adjuvant chemotherapy for breast cancer, concurs thatthe risk of ovarian damage is related directly to the age of the woman. That is, womenover 40 years have a consistently higher chance of premature menopause compared tothose under 40 years of age. In this review, the average rate of premature menopause was40% in women under 40 years and 76% in those aged 40 and over (Bines et al 1996).

Type of drug regimen usedThe category of drug most likely to induce ovarian failure is the alkylating agents, for example, cyclophosphamide. Other drugs reported to affect fertility include vinblastineand cisplatin. Drugs considered less toxic include some of the antimetabolites suchas doxorubicin, 5-Fluorouracil and methotrexate. Estimates of risk are not alwaysavailable because some drugs have not been well studied or are too new to a ssess their true effects (for example the taxanes). Greater cumulative doses and longer duration(total number of cycles/doses received) of therapy are associated with gr eater incidenceof amenorrhoea even in younger women.

5.2 Endocrine therapyGoserelin (Zoladex) is a highly potent Luteinising Hormone Releasing Hormone (LHRH)agonist (synthetic copy). It causes suppression of oestrogen stimulation from the ovaries

by down-regulating LHRH cell surface receptor activity in the pituitary gland, whichin turn reduces the levels of follicle stimulating hormone (FSH) and luteinising hormone(LH). It is therefore only used in premenopausal women. It can be given to younger women who do not require chemotherapy treatment, or who have chemotherapy but inwhom it does not induce an early menopause. As its purpose is to cause a menopause bychemical means, its effects are therefore reversible. However, women are still susceptibleto osteoporosis risk whilst on it and will have reduced levels of circulating oestrogenduring the time of administration, which can be as long as 2 years.

Shapiro et al (2001) conducted a prospective study to evaluate the effects of chemotherapy-induced ovarian failure on bone loss and markers of skeletalturnover in young women with breast cancer receiving adjuvant chemotherapy.The results demonstrated that chemotherapy-induced ovarian failure causes rapid and significant bone loss in the spine and femur, detectable within 6 months of starting the treatment and that this decline continues up to twelve months later. Nosignificant bone mineral density decreases were found in the women who did notexperience early menopause as a result of the cancer treatment. Thus the effects of chemotherapy on bone health may be more rapid than with a naturally occurringmenopause where oestrogen levels commonly take years to decline.

4. The impact of menopause on bone healthand osteoporosis

The menopause is defined as ovarian failure accompanied by oestrogen deficiencyresulting in permanent cessation of menstruation and loss of reproductive function(Utian 1999). The menopause occurs naturally in women between the ages of 45 and 55 years, the average age in the United Kingdom being 51 years. An early menopauseis usually defined as occurring before 45 years of age and can happen for several reasons,including damage resulting from undergoing chemotherapy treatment for cancer [see below]. Coinciding with amenorrhoea, women also lose their ability to produceviable ova (eggs).

The stopping of menstruation occurs as the ovaries stop producing the female hormone,oestrogen. However oestrogen is essential to bone health, so a decreased supply resultsin a lowering of bone density. There is evidence to suggest that the extent of bone lossis worse for the first few years after the menopause but that this slows down over time.Clearly a lower bone density, and therefore more fragile bones, increases the risk of fracture and the commonest sites at which this occurs are the hip, wrist and spine.

5. What effects do breast cancer treatments haveon inducing menopause?

5.1 ChemotherapyChemotherapy works by interfering with cell division, thus as well as causing damageto cancer cells, it also affects nor mal cells. Chemotherapy can stop the follicles within awomans ovaries growing and maturing, which in tur n reduces the amount of the femalehormone, oestrogen, in the body, leading to complete absence of eggs (ova) or smaller numbers of eggs overall. If this dysfunction occurs, the periods may become irregular or may eventually stop (amenorrhoea), causing temporary or per manent infertility.

Even when periods recover after completion of the cancer treatment, the menopausemay occur at a younger age than usual. The likelihood of developing temporary(reversible) or permanent infertility after having chemotherapy for breast cancer depends on two main factors:

AgeAge is the most important determinant of ovarian failure. Generally younger womenare much less likely to become infertile after chemotherapy. The younger the person,the more able they are to tolerate cumulative doses of chemotherapy before developingamenorrhoea and the greater the likelihood of resuming menses after treatment stops.

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All of the above reiterates that strategies to prevent accelerated bone lossin peri/post-menopausal women with breast cancer are imperative (Ganz andGreendale 2001). The situation is compounded by the reduced mortality ratesfrom breast cancer. In recent years, age-standardised 5 year relative survival hasimproved from 62% in the early 1980s to nearly 80% in the late 1990s (CancerResearch UK 2004, National Office of Statistics 2005).Whilst this is excellentfor those affected, it also means a greater potential for impaired bone healthas women live longer with the after effects of treatments and lifestyle changes.


Information provisionand possession of knowledge enable clear explanations of howthe menopause impacts onosteoporosis risk and how treatments for breast cancer

can induce the onset of menopause.Optimising psychological supportis integral to helping individuals cope with a

treatment- induced menopause (including altered body image and physical and emotionalsymptoms) and with an increased risk of developingosteoporosis in the future.

Multi disciplinary team working ensures the input of all relevant health professionals tooptimise care interventions for people with treatment-induced menopause and/orosteoporosis.

In the IES 031 trial 4742 women were randomised to 5 years of tamoxifen(n=2380) versus 23 years of tamoxifen followed by exemestane (n=2362). After a median follow-up of 30.6 months, 449 first events (local or metastaticrecurrence, contralateral breast cancer, or death) were reported, 183 in theexemestane group and 266 in the tamoxifen-only group. This represented a 32%reduction in risk and corresponds to an absolute benefit in terms of disease-freesurvival of 4.7 percent at 3 years after randomisation. Overall survival was notsignificantly different in the two groups, with 93 deaths occurring in theexemestane group and 106 in the tamoxifen group. Contralateral breast cancer occurred in 20 patients in the tamoxifen group and 9 in the exemestane group.The researchers concluded that switching to exemestane after two to 3 years of tamoxifen therapy significantly improved disease-free survival as compared withthe standard 5 years of tamoxifen treatment (Coombes et al 2004).

In the MA-17 trial 5186 women were randomised to 5 years of tamoxifenfollowed by letrozole or a placebo. At the f irst interim analysis, there were 207local or metastatic recurrences of breast cancer or new primary cancers in thecontralateral breast, 75 in the letrozole group and 132 in the placebo group. Thisrepresented a 43% reduction in likelihood of disease relapse and a 46% reductionin contralateral breast cancers at a median follow-up of 28 months. New diagnosesof osteoporosis were made in 8% of the women in the letrozole group (n=209) and 6% of the women in the placebo group (n=155); the rates of fracture were similar.

After the interim analysis, the independent safety monitoring committeerecommended early termination of the trial and prompt communication of theresults to the participants, concluding that as compared with placebo, letrozoletherapy after the completion of standard tamoxifen treatment significantlyimproves disease-free survival (Goss et al 2003).

Of note, studies are underway to determine if goserelin given alongside chemotherapycan mediate ovarian damage associated with adjuvant chemotherapy by decreasingthe growth stimulation of rapidly growing germ cells. The extent and success of thistechnique to protect against premature ovarian failure and thus preserve fer tilityis unknown and requires demonstrating through randomised clinical trials.

Tamoxifen is a competitive inhibitor of oestrogen, blocking its action in cells by binding to the receptors first and then inhibiting any further oestrogen binding at thatsite. Given for 5 years, tamoxifen does not induce a menopause but as an antagonist(acting in opposition) to oestrogen it can cause side effects that mimic oestrogendeprivation, such as hot flushes and menstrual irregularities. However, tamoxifen is alsoan agonist of oestrogen, enabling it to mimic the beneficial effects of oestrogen in someareas of the body. Thus it is considered to have a protective, rather than harmful, effecton the bones and as such its use does not represent a significant concern whenconsidering osteoporosis risk in women being treated for breast cancer.

Aromatase inhibitors are a newer group of endocrine therapies and include drugs suchas anastrazole (Arimidex), letrozole (Femara) and exemestane (Aromasin). They are onlyused in postmenopausal women and they work by inhibiting the conversion of androgento oestrogen in fat cells, the main source of oestrogen production postmenopausally,when the ovaries have ceased to function. Thus they do not induce a menopause butdo serve to reduce the already depleted quantity of circulating oestrogen even further.This means that they do not retain the same degree of protective benefits that tamoxifencan offer on the bone (ATAC Trialists Group 2003, 2004). This becomes increasinglyrelevant as aromatase inhibitors may begin to replace tamoxifen as the preferred initialtreatment for postmenopausal women with hormone-receptor-positive primary breastcancer. This is as a result of research trials which are now demonstrating the superiorityof anastrazole over tamoxifen in terms of significantly prolonging disease-free survivaland time to recurrence and significantly reducing the incidence of distant metastases and contralateral breast cancers (ATAC TrialistsGroup 2004).

Recent trials have also explored the use of aromatase inhibitors taken after tamoxifen,sometimes termed the extended adjuvantsetting. Extended use of both letrozole and exemestane have resulted in significant improvements in disease-free survival whencompared with placebo, and further analysis also demonstrates improved overallsurvival in women with lymph node positive disease taking letrozole (see summaries

of trials opposite). The trend seen in such trials to date is that the benefits areincreased the longer the aromatase inhibitor is taken for. This has potential implicationsfor osteoporosis risk years after discharge from follow-up care and the long-termeffects of extended adjuvant therapy on bone health are yet to be evaluated. However,encouragingly, subsequent analyses of the ATAC trial (adjuvant, rather than extended adjuvant use) demonstrate that the risk of fractures, whilst significantly higher for women on anastrazole compared to tamoxifen, did remain constant, that is no timerelated increase in risk was observed (Sainsbury 2003, ATAC TrialistsGroup 2004). Inaddition, studies are underway that aim to explore the use of adjuvant bisphosphonatessimultaneously with aromatase inhibitors to mitigate against bone loss (see section 8.7),therefore this might prove a useful approach in the future.

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Bone represents the most common site of metastatic breast disease a nd accounts for approximately 2540% of all first metastases (Gralow 2002). This may be due in partto the highly vascular supply of bone marrow. Over 70% of people affected byadvanced breast cancer have skeletal involvement at some time. The distribution of bone metastases favours the spine, ribs, pelvis and appendicular skeleton, and is muchless common in the smaller bones of the forearms, hands and feet. Patients can achievegood responses to treatment for bone metastases , with most surviving for more than2 years and approximately 25% still alive after 5 years. Of note, it is estimated that thecost of metastatic bone disease is high. Indeed problems relating to bone metastasesaccount for over a third of all nights occupied in hospital in advanced breast cancer care (Richards et al 1993).

7. Investigating bone health

7.1 Bone density scans:used in the detection of osteoporosis

Some decline of bone mass is normal with advancing age. Bone mineral density is ameasured calculation of the true mass of bone and this usually correlates with bonestrength and the ability to weight-bear without sustaining damage. Measurement of

bone mineral density enables a prediction of risk based on the amount of decline and thus directs possible medical interventions to alleviate this risk.

Bone mineral density is measured with dual energy x-ray absorptiometry(or DEXA) scans:

Easy to perform.

Low radiation exposure (less than one tenth the dosage of a chest x-ray).

Large machine producing two x-ray beams at high and low energy.

Takes around 10 to 20 minutes.


Information provision and possession of knowledge enable clear explanationsto patients of what bone metastases are and how breast cancer spreads.

Optimising psychological support is integral to helping individuals cope withboth the threat and the reality of a diagnosis of bone metastases and incurable

disease with an uncertain prognosis.

Multi disciplinary team working ensures the input of all relevant healthprofessionals to optimise care interventions for people with bone metastases.

6. Aetiology and physiology: bone metastases

Bone metastases occur when some cells break away from the primary breast cancer and settle in the bone to form a secondary cancer. This can affect only one area of the boneor several areas at any one time. Having reached the bones the tumour cells causedamage by deregulating the balance between bone resorption and new bone formation.

Either the numbers of osteoclasts are increased because the tumour cells secrete factorsthat overstimulate (activate) them to resorb bone and therefore gradually destroy it.

Or, osteoblasts , the cells that balance resorption and fill cavities, are decreased innumber or rendered dysfunctional.

Malignant cells secrete substances such as parathyroid hormone related protein(PTHrP) which lead to an increase in bone resorption. This in turn results in the releaseof breakdown products such as transforming growth factor beta (TGF) which stimulatesthe further growth of malignant cells thus per petuating the destructive cycle and enhancing localised tumour growth (Rosen et al 2001).

Recently improved understanding of these biochemical processes has prompted investigations into whether skeletal events in patients with malignant bone disease maycorrelate with levels of serum and urine markers of bone turnover, thus facilitatingearlier detection or screening for such events.

Prolongation of this imbalance between osteoclasts and osteoblasts leads to osteolysis(dissolving, separating bone), loss of skeletal calcium, hence increased serum and urinarycalcium, and eventually hypercalcaemia. Most of the skeletal morbidity associated with bonemetastases is due to this osteolytic activity in which trabecular bone is destroyed by

progressive waves of bone resorption combined with the absence of any new bone formation.The outer cortical bone would only be a ffected much later in the process, but its involvementalso has profound adverse affects on bone structure (Coleman and Rubens 1992).

Bone

Lung

Liver

Brain

Lymph nodes

Spreadof metastaticbreast cancer -common sitesof metastases

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18 19

Involves lying on a couch with a large mechanical arm passing over the body, no useof tunnels or injections.

Bone density is calculated on the difference between the amount of x-rays passingthrough the bone for each of the two beams. Usually this measurement is taken at thehip and the spine. As osteoporosis involves the whole body, measurements at one or two sites can be predictive of elsewhere. Results of bone scans are based upon the bonemineral density compared to that in the average young healthy population (T score) or,less commonly, an aged matched population (Z score). To obtain a result, the difference

between the average reference range and the individual being measured is calculated.

Measurements of bone mineral density at different sites of the skeleton, or at the samesite but with different methods in the same individual, do not correlate well, so auniversal T score would be inappropriate if readings varied according to the site and method of measurement. Therefore a gold standard for the site and method of

measurement is the hipbone mineral density, as measured by DEXA scans.

7.1.1 Definitions of bone mineral density using the T score(World Health Organisation 1994)

Normal: a bone mineral density measurement that is not more than 1 standard deviation below the mean of the average young adult population. People with thisresult are within a normal range.

> advise on lifestyle.

Low bone mass: a bone mineral density measurement that is between 1 and 2.5 standard deviations below the mean of the average young adult population.People with this result have a 23 fold increased risk of fracture and may betermed as having osteopenia but would not fulfil the criteria for a diagnosisof osteoporosis .

> advise on lifestyle and consider supplement depending on dietary intakeof calcium and vitamin D.

Osteoporosis : a bone mineral density measurement that is more than 2.5standard deviations below the mean of the average young adult population.

Interpretation of bone mineral density results is subjective because normalvalues are based only on Caucasian data and natural difference can occur

between different ethnic populations. Severe osteoporosis would also be a bonemineral density measurement that is more than 2.5 standard deviations belownormal, but in addition, the individual will have suffered at least one fracture.

> advise on lifestyle and ensure adequate intake of calcium and vitamin D,consider pharmacological treatment.

Diagrammatic illustration of bone mineral density definitions of osteoporosis

Bone density scans are less accurate in the elderly population because degenerativechanges such as osteoarthritis in the spine can make bone appear denser. In this casethe measurement may be also taken from the forear m or heel.

It is suggested that bone mineral density is measured at around the time of the onsetof menopause for those at risk of osteoporosis , and then again 1824 months later to help assess the actual rate of bone loss over this time frame (Abernethy 2002). Of note, guidelines giving categories of women who should be referred for bone densitymeasurement include women with an early menopause (natural or treatment-induced)and those with prolonged amenorrhoea (Lee 2000). Clearly this has implications for women who sustain temporary or permanent ovarian failure as a result of havingchemotherapy for breast cancer.

7.2 Quantitative ultrasound:used in the detection of osteoporosis

The use of ultrasound to evaluate bone mineral density is being investigated. Theultrasound beam is directed at the area being analysed (the heel area is most commonlyused) and the scattering and absorption of the waves enables an evaluation of the bonedensity. An advantage is that no radiation source is used and the equipment is cheaper and more manageable to install and use, however the results are not curre ntly as precise

as with DEXA scans and this remains a relatively new technique still undergoingresearch to demonstrate its efficacy.

7.3 Blood test for serum calcium levelsThis may supplement information during the management of osteoporosis or bonemetastases but would not be used for diagnosis on its own as patients may retainnormal measurements in the presence of either condition.

Normal adult range 2.33.3 (optimum 2.6) mmol/l.

1 SD

Normal

Low bone mass

2.5 SD No fracture osteoporosis

Fracture severe osteoporosis

Bone mineral density

Peak bone mass


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7.7 Computerised tomography (CT) and magnetic resonanceimaging (MRI) used in the detection of bone metastases

It is unusual to produce findings of bone metastases on the CT scan if the preceding bone scan is negative, thus CT scans are not used in diagnosis. MRI scans can be used to confirm the presence of bone metastases if the bone scan and plain x-rays areequivocal or negative in the presence of a high level of clinical suspicion. Patients

presenting with bone metastases are commonly re-staged to ensure a full clinicalassessment of the existence of any other sites of metastatic disease before treatmentis commenced. Thus CT scans may be used (in addition to a chest x-ray and liver ultrasound scan) after the diagnosis of bone metastases for the examination of thelungs, liver and brain.

8. Interventions for osteoporosisand bone metastases

8.1 Lifestyle:The following advice on osteoporosis and diet and exercise should be made accessibleto all women undergoing treatment for breast cancer.

Osteoporosis and dieta calcium-rich diet will not cure osteoporosis but will help to maintain bone mass

because strong and healthy bones require a diet rich in calcium, this is the mostimportant mineral in bones and contributes to their strength and rigidity.

optimum calcium intake is best a chieved with a balanced diet however supplementsare recommended for those with restricted or excluded intake of dairy products.The recommended dose of supplement ranges between 8001500mg daily, and it is commonly taken in conjunction with Vitamin D.

IMPLICATIONS FOR NURSES:Information provision and possession of knowledge enable clear

explanations to patients of investigations used to detect osteoporosisand/or bone metastases.

Optimising psychological support is integral to helping individualscope with having these investigations and with the anxiety

that they may demonstrate presence of new disease.

7.4 Isotope bone scans:used in the detection of bone metastases

Isotope bone scans involve an injection of a small amount of a radioactive substance[usually technetium-labelled diphosphonate] into a vein and then a wait of 23 hoursto allow this to circulate around the skeleton before the scan is performed.

Abnormal bone absorbs more radioactivity than normal bone resulting in the radioactive substance being taken up preferentially at sites of increased osteoblast activity, thusdemonstrating corresponding hot spots[see picture opposite].Therefore bones scans demonstrate a potential change inresponse to the presence of bone metastases , not the metastasesthemselves. This means they may also detect other skeletaldisease (such as traumatic or inflammatory) not re lated tobone metastases and can therefore result in false negatives.

If a bone scan produces equivocal results it may be repeated in 23 months to look for changes that might indicate disease

progression. Alternatively any ambiguous findings may be confirmed with the use of plain x-rays and/or magneticresonance imaging (MRI).

Use of bone scans is no longer recommended for routine asymptomatic surveillancein the outpatient follow-up setting because of its proven lack of efficacy in the absenceof symptoms (National Institute of Clinical Excellence [NICE] 2002).

7.5 Plain x-raysPlain x-rays can be used to help confirm the nature and extent of bone destructionand support any information obtained from isotope bone scans. However around 40%destruction of bone is necessary before the lesion is revealed on plain x-ray so theyare not recommended in isolation for the purposes of diagnosing bone metastases .Plain x-rays are less commonly used in the investigation of osteoporosis but may

be used when a fracture is suspected.

7.6 Blood tumour markers:used in the detection of bone metastases

Blood tumour markers may be of use for supplementary diagnostic purposes,specifically in the presence of equivocal imaging investigations (Molina and Gion1998). However they are not sensitive enough to be diagnostic tools in their own right.For example only approximately 30% of patients will have elevation of the breastcancer antigen CA15-3 in the presence of bone metastases , thus whilst increased levelsmay be confirmatory, their absence does not mean metastases are not present (BritishAssociation of Surgical Oncology 1999).

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Osteoporosis and exerciseregular weight-bearing exercise is good to help maintain bone strength and has beenshown to be beneficial for bones, whereas immobility is associated with more rapid

bone loss.

brisk walking is ideal (and also facilitates exposure to sunlight and thus vitamin D)or swimming if one has had fractures.

other bone building exercises include running, skipping and aerobics.

recommend participation in weight bearing exercise at least three times a week for atleast 20 minutes each time.

recommend avoiding sports where further injury or falls could occur.

those with a history of fractures or at high risk (such as with bone metastases )should avoid high-impact exercise and those that involve curving the spine forward.

(sources: Woolf and St John Dixon 1998, Hope et al 1999, Lee 2000, Royal Collegeof Physicians Working Party Report 2001, Abernethy 2002).

8.2 Selective Oestrogen Receptor Modulators (SERMS)for treatment of osteoporosis

SERMS are drugs that bind to and ac tivate oestrogen receptors thus enabling greater oestrogenic activity.

Raloxifene hydrochloride (Evista) is currently the only SERM licensed for the prevention and treatment of osteoporosis in postmenopausal women:

60mg orally daily.

inhibits bone resorption.

not suitable for those with a history of or at high risk of DVT or with hepaticimpairment.

evidence suggests it reduces the risk of vertebral but not hip fracture(Neer et al 2001) and helps to prevent bone mineral density loss (Ettinger et al 1999).

8.3 Calcitonin for treatment of osteoporosisThis is a natural anti-osteoclast agent that inhibits continued bone resorption.Only intra-muscular injections of calcitonin are licensed for use in postmenopausalosteoporosis (although nasal preparations are being investigated); 11 IU daily isrecommended in conjunction with calcium 600mg and vitamin D 400 IU. Studies havedemonstrated some reduction in fracture rates but the benefits are less than thoseachieved with bisphosphonates so its usage in this setting has declined.

milk and dairy products (such as butter and cheese) are good sources of dietarycalcium. This is relevant because women with breast cancer may choose to restrictor exclude dairy products from their diet because of their alleged contributionto increasing the risk of breast cancer recurrence.

Recommended daily allowance (RDA) is 700mg of calcium a day for adult women but those already diagnosed with osteoporosis may be advised to have more(nearer 1200mg a day).

Examples of foods containing calcium that may help individuals to achieverecommended daily allowance include:

Vitamin D (800 IU daily) has been shown to decrease risk of fracture when used by institutionalised elderly over long periods (18 months to 3 years) (Chapuy et al 1992). Its use is particularly relevant to this group because they may not mobiliseoutside and thus miss out on activity and sunlight exposure. Calcitriol is a vitamin Dderivative licensed for treatment of postmenopausal osteoporosis.

avoid excessive amounts of caffeine, including fizzy drinks as these can disrupt thenormal calcium balance in the body.

avoid smoking as this can increase the risk of fra cture.

Food Quantity Mg of calcium

Milk (semi skimmed) 1 third of a pint 231

Cheese (cheddar) 100g 720

Yogurt 100g 150

Sardines (in oil) 100g 550

Milk chocolate 100g 220

Almonds 100g 240

Sesame seeds 100g 670

(source: Food Standards Agency 2004)

An on-line survey of 200 women carried out jointly by Breast Cancer Care and the National Osteoporosis Society (2003) reported that exclusion of dietary dairy

products was the single most common dietary change reported by women with breast cancer. Yet fewer than 5% had received any advice about the effects of thisor healthy eating from health care professionals.

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The Committee on Safety of Medicines in the UK advised in December 2003 thatHRT should not be used for the prevention of osteoporosis in women over 50 yearsof age and at an increased risk of fracture. This is despite evidence from randomised controlled trials showing a reduction in the incidence of fracture with HRT usage,thus authors writing on behalf of the British Menopause Society state that preventionand treatment of postmenopausal osteoporosis is an established indication for the

prescribing of HRT (Stevenson and Rees 2003).

8.7 Bisphosphonates for treatment of osteoporosisand bone metastases

Bisphosphonates is a collective name for a group of drugs that are chemical analogues(synthetic copies) of pyrophosphate, a natural constituent of the bone matrix thatinhibits bone resorption (by reducing the number and activity of osteoclasts) and whichalso has a role in bone mineralisation.

Broadly, there are two types of bisphosphonates, nitrogen containing and non-nitrogencontaining. Bisphosphonates work by efficiently attaching to the bone surfa ce,inhibiting the action of osteoclasts and thus substantially slowing down the processof bone resorption and breakdown.

Bisphosphonates disrupt the cycle of abnormal bone remodelling that occursas a result of osteoporosis or bone metastases.

An American Study, the Womens Health Initiative (WHI). WHI is a large,multicentre randomised trial evaluating the effects of HRT on the cardiovascular system, the breast, bones and other organs. Women were randomised to receiveeither combined HRT (if their uterus was intact), oestrogen alone (womenwithout a uterus) or placebo. The study began in 1991 but e nded prematurelywith the termination of the oestrogen-progestogen arm in 2002 and the oestrogen-only arm in March 2004. The preliminary results demonstrated beneficial effectson the bones as a whole and specifically a 34% reduction in the risk of hipfracture and a 34% reduction in the risk of spinal fracture.

Oestrogen-only arm: no effect of HRT was seen on coronary hear t disease(neutral), nor on breast cancer risk, a reduction in hip fractures was observed as well as a small increase in the risk of stroke. (Therefore risk-benefit analysisfavours HRT as a treatment for menopausal symptoms).

Oestrogen-progestogen arm: In the combined arm, users had 8 more strokes per 10, 000 women than those taking a placebo; there was a 26% increase in the risk of breast cancer (30 to 38 cases per 10,000) and a 26% increase in the risk of coronary heart disease. (Of note there are differences between UK and USA

populations, with UK HRT users being on average younger and less overweight,resulting in a lower absolute risk of stroke in UK studies).

8.4 Phytoestrogens for treatment of osteoporosisPhytoestrogens are naturally derived plant oestrogens. The largest single family of

phytoestrogens is the flavonoids. These have a similar structure to hormones such asoestrogen and therefore compete for oestrogen receptors. Within this group lie the subfamily of isoflavones, which are the most extensively studied group overall. Isoflavonesare thought to be able to exert an anti-oestrogenic effect by competitive inhibition, thatis they prevent oestrogen binding to re ceptors by binding to them themselves. There aretwo types of oestrogen receptors in the body and isoflavones preferentially are attracted to ER- which predominate in brain, bones and heart, but show little activity againstER- present in breast and uterine tissues. Thus it has been suggested that higher intakes of isoflavones may help to prevent bone loss in postmenopausal women bycontinuing to activate ER- when natural body oestrogen levels are depleted in thesewomen (Tham et al 1998). However of note, studies to date have demonstrated conflicting reports of efficacy, so further research is needed.

8.5 Parathyroid hormone for treatment of osteoporosisTeriparatide (Forsteo) is a recombinant human parathyroid hormone that stimulatesnew formation of bone. It may also increase resistance to fracture (NICE 2004). Itwas licensed for the treatment of postmenopausal women with established osteoporosisin June 2003. It is given as a daily subcutaneous injection (recommended dose is20 micrograms) and can be self administered by the patient after appropriate training.

It is currently restricted to a maximum of 18 months use and the manufacturersrecommend supplementary calcium and vitamin D if dietary intake is insufficient.Side effects include nausea, headaches and discomfort at the injection site. Substantialdecreases in vertebral and non-vertebral fractures and back pain and increased bonemass have been demonstrated (Neer et al 2001) although more research is needed to compare efficacy and tolerability with bisphosphonates.

8.6 Hormone Replacement Therapy (HRT) for treatmentof osteoporosis

Previous studies have indicated that use of HRT lowers the risk of osteoporosis byreplacing oestrogen that is lost as a result of the menopause, but only with currentusage and it may require between 5 and 10 years duration of use to be e ffective (Felsonet al 1993). However more recent research has resulted in doubts on the eff icacy and application of HRT for the prevention and treatment of osteoporosis .

Waltman et al (2003) tested an intervention for preventing osteoporosis in postmenopausal breast cancer survivors. Twenty-one women who had completed treatment for breast cancer were prescribed an intervention of home based strengthand weight training exercises, 510mg of alendronate daily, 1500mg of calciumdaily, 400 IU of Vitamin D daily and bone health education. The outcomes revealed compliance with the interventions (95% for the drugs and 85% for the exercises);and over 12 months improvements were noted in muscle strength, hip extension and

bone mineral density of the spine and hip. Three participants who had measurable bone loss at baseline had normal bone mineral density after 12 months.

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reduce the need for orthopaedic surgery (when given for longer than 12 months duration).

reduce serum calcium levels (that in turn re duces bone pain) by reducing boneresorption, therefore facilitating a gain of skeletal calcium and a reduction in serumand urinary calcium.

Bisphosphonates are licensed for the prevention of skeletal related events in patientswith metastatic bone disease to control bone pain, reduce the risk of fractures and toassist in the cor rection of hypercalcaemia. They are usually started at the diagnosis of symptomatic bone metastases . However, some clinicians support their commencementeven in the absence of symptoms because of their potential to significantly delay thetime to first skeletal related event (SRE) and thus to result in cost savings as well (Rosset al 2003). Currently bisphosphonates are continued indefinitely until no further benefitis being obtained (Hillner et al 2000), although the optimum duration is unknown. Onsetof skeletal events or progression is not an indication to stop treatment. Their role in

prevention of bone metastases in primary breast cancer is under investigation.Bisphosphonates are licensed in the treatment of osteoporosis to preserve and improve

bone mineral density and to prevent further decline or fractures and in the preventionof osteoporosis in people deemed to be at high risk, for example women experiencingan early menopause. However their application in prevention remains inconsistent.For further information see the National Institute for Health and Clinical Excellenceguidelines on bisphosphonates, selective oestrogen receptor modulators and para thyroid hormone in the prevention and treatment of primary osteoporosis (due in September 2005) and secondary osteoporosis (appraisal No 87, published in January 2005).

Side effects of bisphosphonatesSide effects described vary according to the individual drugs, however common sideeffects can occur with oral or intravenous administration and with the latter are usuallyin direct response to the infusion and last for around 4872 hours afterwards beforeresolving. These include gastritis; nausea; diarrhoea; muscle or joint pain; flu-likesymptoms such as fever or chills; skin reactions and headaches.

Rare side effects can occur later as a reaction to the drugs and include pain and/or inflammation at injection site; generalised pain; renal toxicity; tiredness; nausea and vomiting; muscle cramps; dizziness and insomnia.

The potential for gastrointestinal intolerance has been a limitation of the long-termuse of oral bisphosphonates and therefore studies are exploring the use of intermittentadministration as an alternative to continuous to alleviate this problem. Intravenouszoledronic acid is considered the most potent bisphosphonate and has been shown to besuperior to pamidronate in the treatment of cancer related hypercalcaemia (Major et al 2001) and significantly reduces the risk of developing skeletal complications compared to

pamidronate in women with breast cancer (Rosen et al 2003). It is suited to long intervals between doses because of its high potency (Reid et al 2002). Studies have demonstrated that an infusion of zoledronic acid given at either 6 monthly or yearly intervals achieveseffects on bone turnover and bone mineral density as good as those achieved with dailyoral dosing. As well as inhibiting osteoclast activity, zoledronic acid induces osteocla stapoptosis (programmed cell death) and blocks osteoclastic resorption.

Diagram of pathogenesis of cancer metastasis

Their specific mechanism results in a high therapeutic potential because the drugs aredelivered to the site of action and a low potential for systemic toxicity at other sites.Lost bone cannot be replaced but bisphosphonate treatment can strengthen the existing

bone and its effects can result in rapid control even after a single dose and are longlasting. Newer agents such as teriparatide (recently licensed in the UK) work by boostingosteoblast activity rather than inhibiting osteoclasts, hence the focus is to increase bonesynthesis, rather than decrease bone loss and this approach may be more pertinentin the preventative setting.

Of note, bisphosphonates have no effect on the development of the tumour itself withbone metastases . They do not inhibit tumour g rowth but may induce an inhibition of osseous invasion.

Hence bisphosphonates are used in the management of osteoporosis andbone metastases to:

preserve and improve bone mineral density and thus help prevent or reduce further bone loss and pathological fracture in the future.

inhibit osteolysis (dissolving, separating bone).

significantly prolong the time to f irst skeletal-related event (SRE) [including pathological fractures, spinal instability, intractable bone pain and abnormal serumcalcium levels].

significantly reduce the risk of developing SREs and complications in breast cancer patients for up to 2 years.

reduce the need for radiotherapy.

Adherence

Transformation

Primary tumour

Angiogenesis Motility and invasion

Capillaries, venulesand lymphatics

Embolism and circulation

Multicell aggregates(lymphocyte and platelets)

Metastases

Response tomicroenvironment

Extravasation into organparenchyma

Tumour cell proliferationand angiogenesis

Metastasis of metastases Arrest in capillary beds

Transport

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3 bisphosphonates currently licensed for preventing and treating osteoporosisAlendronate sodium (Fosamax) 510mg orally daily, or 70mg once weekly, takenwith water on an empty stomach, licensed for the prevention and treatment of

postmenopausal osteoporosis ; evidence suggest improved bone mineral densityand reduction in clinical fractures sustained (Cummings et al 1998, Pols et al 1999).

Etidronate disodium (Didronel) 400mg on an empty stomach orally daily for 14 daysevery 90 days, used in conjunction with calcium supplements, 500mg taken orallydaily for the next 76 days, repeat this cycle for 35 years; licensed for the preventionand treatment of osteoporosis in postmenopausal women; evidence suggests areduction in vertebral fracture rate and hip fracture rate in those with established osteoporosis (van Staa et al 1998); 3 days slow infusion in hypercalcaemia.

Risedronate (Actonel) licensed for the prevention and treatment of osteoporosis in postmenopausal women, 5mg orally daily, taken with water on an empty stomach, inconjunction with calcium supplements, evidence suggests improved bone mineral densityand reduction in clinical fractures sustained (Harris et al 1999, Reginster et al 2000).

[Boniva (ibandronate sodium) is the first injectable bisphosphonate available for osteoporosis . Not yet available in the UK, it has been submitted to the American Food and Drug Administration (FDA) for approval for the treatment of postmenopausal osteoporosis .It will also be available as a once monthly oral preparation. The intravenous injectionis given every two months and takes just 30 seconds. This method of administrationaddresses the possible difficulties with oral bisphosphonates of having to fast beforeintake and gastrointestinal side effects].

Bone et al (2004) have confirmed that the therapeutic effect of alendronate in thetreatment of postmenopausal osteoporosis is sustained in the long term.

The multinational study, led by researchers in the United States, began in 1991and first reported 3 years later, but follow-up was extended to eight and then10 years. 247 women were randomised to three groups that received alendronate5mg daily, alendronate 10mg daily, or alendronate 20mg daily for 2 years, then5mg daily for 3 years, then a placebo. All participants also received 500mg of calcium a day. The higher dose of alendronate 10mg daily produced the largestmean increases in bone mineral density as compared with baseline values.However the group who discontinued alendronate and took a placebo after 5 yearssustained a loss of this beneficial effect. In these women, bone mineral densitysignificantly decreased at the hip, neck and forearm.

Recent concerns have been raised about the safety of long-term use of alendronate.By slowing bone turnover, alendronate allows secondary mineralisation to progressand increasing tissue mineral content overall. Too highly mineralised bone becomes

brittle and less tough and could therefore be more susceptible to fractures. Theresearchers in this study concluded that the therapeutic effects of alendronate aresustained in the long term and the drug is well tolerated over these longer timeframes. They noted that the fewest fractures and the least height loss occurred among the women who had received the most alendronate overall.

There are no absolute contraindications to the use of bisphosphonates, but oraladministration should be used with caution in those patients with pre existinggastrointestinal disorders and in particular ulcers. Their use is not advisable during

pregnancy and lactation as they may be damaging to the foetus and can be excreted in milk.

Examples of bisphosphonatesMost oral preparations should be taken with water and on an empty stomach, usuallya minimum of 30 minutes before any food intake to ensure optimum absorption.Regular renal monitoring should be undertaken in all patients receiving intravenous

bisphosphonate therapy because of the potential for renal dysfunction. Examplesof bisphosphonates currently licensed for treatment of bone metastases are:

1st generationSodium clodronate (Bonefos) 1600mg orally daily, contraindicated in pregnancy and in those with kidney problems; infusion in hypercalcaemia.

2nd generationDisodium pamidronate (Aredia) 90mg given intravenously every 3 to 4 weeks,infusion takes 24 hours.

3rd generationIbandronic acid (Bondronate) 6mg given intravenously monthly, infusion takesapproximately one hour, also available orally (after an overnight fast), 50mg daily,found to offer patients up to 2 years effective pain relief whilst not associated withincreases in renal toxicity.

Zoledronic acid (Zometa) 4mg given intravenously every 3 to 4 weeks, infusiontakes 1530 minutes, taken with an oral vitamin D and calcium supplement.

P

P

OH

OHOH

OH

OH

OH

OH

OHOH

OH

HO

HO

OH

OH

O

OHO

N

etidronate

Classes of bisphosphonates 1,2

pamidronate zoledronic acid

1. Thurlimann B. Bisphosphonates in Clinical Oncology: Focus on Pamidronat. 1999.2. Fleisch H, Endocr Rev. 1998.

HOHO

HO

OH OH

OHOH

OH

OH

O

O

P

P

CH3

H2N

H2N

CH3

CH3

O

OP

P

CI

CIOHOH

OH

OHOH

OH

OH

OH

OH

HOHO

HO

OH

O

OP

PSCI

O

OP

P

O

O

N P

PO

O

P

P

N

N

O

O

P

P

clodronate tiludronatealendronate ibandronate

risedronate

OH

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Current dilemmas with bisphosphonates used in prevention (prophylaxis)of osteoporosis and bone metastases

what is the optimum method of administration of bisphosphonates, oral and continuous versus intravenously and intermittent?

what are the effects of long term use of prophylactic bisphosphonates over many years?

when should women with treatment-induced early menopause start prophylactic bisphosphonates?

when is bone mineral density low enough to warrant commencement of prophylactic bisphosphonates?

how long should use of prophylactic bisphosphonates last?

can the substantial costs of prophylactic bisphosphonates be justified?

All patients with confirmed bone metastases should undergo full staging to confirmor exclude the presence of metastatic disease in other sites of the body because diseaseelsewhere will influence the choice and order of oncological treatments given.

8.8 Radiotherapy in the treatment of bone metastasesRadiotherapy is very effective in the management of localised bone pain caused bybone metastases in approximately 80% of patients and up to 50% of these will achievecomplete bone pain relief (Coleman 1997). Usually 2 to 5 fra ctions of external beamradiotherapy is given as a single dose or over a few days to focal large or painfulmetastases and benefits are usually seen within a couple of weeks. However disease

progression can occur and one cannot re-treat the same area on multiple occasions.Radiotherapy is also ineffective for structural strengthening.

8.9 Chemotherapy in the treatment of bone metastasesChemotherapy is less commonly used if bone is the only site of systemic disease, asit is more effective on visceral metastases. However, if used it is important to consider drugs regimens that are less myelo-suppressive.

8.10 Endocrine therapy in the treatment of bone metastasesThere is evidence that aromatase inhibitors, specifically letrozole (Femara), havesuperior efficacy than tamoxifen in those patients who have advanced disease(Mourisden 2003) and so these are commonly used in postmenopausal women withnewly diagnosed bone metastases . Patients might also be re-challenged with tamoxifenif sufficient time has elapsed since its last use. As additional aromatase inhibitors suchas exemestane (Aromasin) become available, as well as newer generation drugs such asfulvestrant (Faslodex), clinicians have a greater ability to tailor treatment to the needsof the individual affected.

Preventative / adjuvant use of bisphosphonatesProspective randomised trials demonstrate that bisphosphonates mitigate bone loss inwomen who develop chemotherapy-induced ovarian failure, by effectively pre-treatingthe surface of the bone, thus inhibiting adherence of breast cancer metastatic cells tothe bone matrix, inhibiting release of growth factors and enhancing osteoclast ac tivityand tumour cell apoptosis. Therefore long term administration may alter the expressionof tumour activity on bone cells and trials are aimed at exploring their use in theadjuvant setting for preventing or delaying bone metastases as well as helping to

prevent osteoporosis .

Randomised trials, largely on oral clodronate, as this method of administration is moresuited to the preventative setting, have so far produced somewhat conflicting results asdemonstrated below.

Two large trials are currently in progress. The AZURE Trial is a randomised c ontrolled trial for patients with stage II and III breast cancer. It aims to compare people whotake adjuvant zoledronic acid (Zometa) in addition to chemotherapy and/or hormonetherapy with those who have no adjuvant bisphosphonates. Outcome measurementsinclude the time to development of bone metastases , overall survival and the number of skeletal related events (SREs) prior to and following the development of bonemetastases . The National Surgical Adjuvant Breast and Bowel Project (NSABP) B34is evaluating oral clodronate for 3 years versus placebo in 2200 patients with stage Ior II breast cancer.

However until results are available from these and other trials the optimal agent, dose,schedule and duration of treatment for enhancement of bone health and thus preventionof osteoporosis and bone metastases remains unknown (Gralow 2002).

1) At 5 years follow-up, after 2 years use of oral clodronate (n=302), a reductionin the incidence of bone metastases , as well as a trend towards a reduction invisceral metastases and improved overall survival was seen (Diel et al 1998).

2) At 5 years follow-up of women with operable, node positive breast cancer,after 3 years use of ora l clodronate 1600mg (n=299), equal numbers of bone metastases were detected in those taking clodronate versus a placebo.A greater incidence of non-skeletal metastases and a worse overall survivalwere associated with the clodronate group (Saarto et al 2001, Saarto et al 1997).

3) During 2 years use of oral clodronate (n=1079) given to patients with primary,operable breast cancer, a significantly lower occurrence of bone metastases wasseen during the period of administration of clodronate when compared with

placebo, although at 5 years this was no longer significant. However overallsurvival also improved with clodronate usage (Powles et al 2002).

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Fulvestrant (Faslodex) is an oestrogen receptor down regulator, it binds to oestrogenreceptors and degrades them. It is c urrently used in advanced breast cancer, commonlysecond line after anastrazole. It is given as an injection and has similar side effectsto anastrazole but has no detrimental effect on bones as down regulating oestrogenreceptors does not have any effect on levels of circulating oestrogen.

8.11 Orthopaedic surgery in the treatmentof bone metastases and osteoporosis

Referral to an or thopaedic surgeon is always indicated when plain x-rays show erosionof a weight-bearing bone (British Association of Surgical Oncology 1999) (see alsosection 10.3 and 10.4 on fractures and spinal cord compression).

8.12 Vertebroplasty for treatment of osteoporosisand bone metastasesPercutaneous vertebroplasty is approved by the National Institute of ClinicalExcellence (NICE 2003) for the purpose of providing pain relief for:

people with severe painful osteoporosis with loss of height and /or compressionfractures of the vertebral body.

people with painful vertebral body tumours ( metastases or myeloma).

Indications are severe, persistent back pain due to vertebral collapse, after use of conventional treatments such as radiotherapy and bisphosphonates have failed to alleviate it sufficiently.

An image-guided, minimally invasive, non-surgical technique procedure thatinvolves injecting bone cement to form a type of internal plaster cast and sostrengthens the bone.

Advantages include immediate and sustained pain relief (McGraw et al 2002)in 5897% (NICE 2003), improved mobility, improved self reported qualityof life [approximately 80% of patients will derive at least some benefit],reduction in medication usage and an avoided necessity for surgery and pinning.

Of note, the evidence base for this procedure mainly derives from case series, to date therehave been no completed randomised controlled trials reported although there are somein progress (of 41 studies reviewed by NICE, none were randomised controlled trials).

Procedure:imagery used to target and plan site for injection(commonly MRI, also isotope bone scans).

performed by an interventional radiologist.

patient has to lie face down on the table.

needle is placed into selected vertebra, guided by high quality imaging.

sedation or a general anaesthetic are used prior to injection of cement.

37mls of cement injected.

procedure takes between 45 and 90 minutes.

up to 3 vertebrae can be treated in one session, but further areas can be treated in later sessions.

bed rest for 3 hours afterwards to allow cement to begin hardening.

overnight stay in hospital usually recommended but not essential.

early mobilisation, then home next day.

cost per procedure averages around 600.

Complications:

cement leakage into disc space, soft tissues or spinal c anal. This is rare (


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35

The merit of ongoing measurement of response with repeated investigations isdebatable. Serial bone scans in metastatic bone disease are sometimes performed butthe optimum frequency is unknown and results can be affected by other fa ctors such astumour flare after commencing systemic therapy. Plain x-rays repeated at six monthlyintervals may help support information pertaining to bone metastases . Tumour markersand blood chemistries such as serum calcium, alkaline phosphatase can also be

performed but will fluctuate as a normal response to treatment as well as other factors.Serial DEXA scans can help determine progression of bone loss in people withestablished osteoporosis but the optimum frequency of repeat scans has not beendetermined (see section 12 (b)).

10. Complications of osteoporosisand bone metastases

10.1 Hypercalcaemia breast and lung cancer are the two most common sources of tumour induced hypercalcaemia.

mechanisms inducing hypercalcaemia:

1) increased bone destruction by tumour cells results in release of calcium fromthe skeleton.

2) increased tubular reabsorption of ca lcium in the kidney caused by systemicfactors produced by the tumour cells such as parathyroid hormone-related peptide(PTHrP), which interacts with both kidney and bone.

normal serum calcium levels are maintained by close interactions between the threecalcium target organs; bone, intestine and kidney and by hormone controlled negative and regulatory feedback systems.

hypercalcaemia occurs rapidly as a result of calcium being released in to the blood stream, due to tumour induced increased osteoclast activity or enhanced renalretention of calcium [the kidneys play a recognised role in hypercalcaemia

by increased tubular reabsorption of calcium].

calcium levels are commonly induced by increased resorption but then maintained by other factors such as depleted volumes of bone cells.

MILD: Serum calcium less than 3.0mmol/l.

MODERATE: Serum calcium 3.04.0mmol/l.

SEVERE: Serum calcium greater than 4.0mmol/l urgent.

it affects approximately 1520% of those with bone metastases and is thought toindicate advanced disease even without the presence of advanced bone metastases.

34

symptoms include nausea, constipation, tiredness, irritability, thirst, fatigue, poor appetite, confusion, drowsiness.

the aims of treatment are to cor rect the condition by inhibiting osteoclast boneresorption and enhancing urinary excretion of calcium and to provide symptom relief.

interventions include IV rehydration with 46 litres of saline infusions daily(to replace reduced circulating volume); Calcitonin (to inhibit osteoclast boneresorption and renal tubular calcium resor ption); and bisphosphonates (commonly asa single day infusion) that have been shown to achieve a reduction in serum calciumlevels (Body 2000, Ralston etal 1997, Pecherstorfer et al 1996).

hypercalcaemia can recur, but 90% will respond to bisphosphonates and achievenormal urinary calcium excretion or reduce bone resorption sufficiently tocompensate for the renal effect.

10.2 Painin both osteoporosis and bone metastases pain is common, indeed bone metastasesare widely cited as the singular most common cause of cancer pain and it is likely to

be the presenting symptom in the majority.

metastatic bone pain is characteristically dull, non mechanical and persistent and can be accompanied by swelling and tenderness in affected areas, it is often reported to be worse at night or after mobility.

accurate assessment is crucial to optimum management.

commonly used analgesics include opiate analgesia, non-steroidal anti-inflammatorydrugs and selective cyclo-oxygenase-2 [COX-2] inhibitors (recent concerns thatCOX-2 inhibitor drugs may increase the risk of a stroke or heart attack among

patients with a history of cardiovascular or vascular disease have led to increased caution in prescribing these drugs).

nerve blocks are occasionally used.

non pharmacological alternatives include acupuncture and transcutaneous electricalnerve stimulation (TENS).

bisphosphonates will also help to alleviate bone pain (Strang 1996, Purohit et al 1994, Thurlimann et al 1994). Pain relief usually occurs within days of being treated with bisphosphonates and is dose-dependent.

(see also sections 8.7, 8.8 and 8.12 on bisphosphonates, radiotherapy and vertebroplasty respectively).

10.3 Pathological fracturethis is usually a later manifestation of bone metastases but can occur at any time withosteoporosis , when the risk of fracture correlates with the degree of cortical destruction.

the commonest sites are the wrist, spine and hip.


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10.5 Bone marrow suppressionOn rare occasions, and usually if left untreated, bone metastases can cause a decreasein blood cell production because these are for med in the bone marrow, which can

be damaged in the presence of bone metastases . The multiplication of cancer cellsin the bone marrow eventually overcrowds and thus suppresses the normal productionof blood cells. This may cause a significant decrease in red blood cells, platelets, and white blood cells causing anaemia, abnormal bleeding, and neutropenia, respectively.Each of these would be treated as they occur, whilst interventions aimed at haltingthe progression of the bone metastases are simultaneously implemented.

11. The way forward?

Organisations such as The National Osteoporosis Society and Breast Cancer Carehave recognised that there is currently no consensus on advice that should be givento women with breast cancer at risk of, or needing management for problems relatingto bone health. Consequently they have released a policy briefing document (2003)outlining their proposals involving a joint campaign, with the purpose of highlightingthe potential of increased risk of osteoporosis in some women treated for breast cancer and initiating research and practice guidelines that will safeguard bone health in womenwith breast cancer in the future. It is important that existing Royal College guidelineson detection, possible prevention and management of osteoporosis and bone metastasesfor women with breast cancer are updated and that omissions and ambiguities(such as recommendations about bone density measurements in those with an earlytreatment-induced menopause) are clarified.


Information provision and possession of knowledge enable promptrecognition of potential complications of osteoporosis or bone metastases ,as well as clear explanations to patients in whom such complications occur.

Optimising psychological support is integral to helping individualscope with these complications and with the resultant effects, such as fear,

hospitalisation and physical and psychosocial impact.

Multi disciplinary team working ensures the input of all relevant healthprofessionals for optimum management of complications and their effects.

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pathological fractures are more likely with lytic lesions, rather than sclerotic and more common in proximal long bones.

patients are considered at increased risk of fracture if:

more than 50% of the cor tex is destroyed in a weight-bearing bone .

lytic lesions are present.

pain is prevalent (often worsens when a fracture is imminent).

cortical destruction is noted.

surgical fixation is usually recommended for large lesions (prophylactic, beforea fracture occurs) or with advanced bone destruction. Access to an orthopaedicconsultation is essential as is consideration of prophylactic fixation because thisis sometimes easier to achieve before the bone has actually fractured.

generally certain bones, such as long bones are more amenable to surgical fixation,whilst others, such as ribs, are not.

fixation may involve metal pins, plates and/or bone cement as well as prosthesis.

radiotherapy is also used to reinforce bone strengthening and relieve pain.

physiotherapy is important for provision of walking aids and help with weight bearing exercise.

10.4 Spinal cord compressionIn all cancers the spinal column is the most frequent site of bony metastases (Gersztenand Welch 2000) and breast cancer is the commonest primary cancer resulting in spinalcord compression secondary to metastases.

Spinal cord compression is vertebral collapse as a result of their destruction by diseaseand results in pressure being applied to the spinal cord and nerves.

considered a medical emergency requiring prompt intervention.

assessed with magnetic resonance imaging scans (MRI) (highly sensitive) and plain

x-rays .symptoms include back pain, motor weakness, tingling sensations, sensory loss(numbness) and autonomic dysfunction (incontinence).

treated with radiotherapy and in rare circumstances surgical decompression(laminectomy or tumour resection).

the cervical spine is more sensitive to radiotherapy than the thoracic or lumbar spine.

studies are exploring the use of less invasive ways to accomplish decompressionsuch as endoscopic entr y (Gerszten and Welch 2000).

steroids may be used to decrease oedema.

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(d) Advances in the way breast cancer is treated, for example the potential forincreasing use of adjuvant and extended adjuvant aromatase inhibitors,will have an impact on the nature and duration of therapy and hence on risk to bone health for people with breast cancer.

clarity about role responsibility with regards to ensuring advice about bone healthis responsive to the changing clinical approaches.

clarity about role responsibility with regards to long-term information provisionafter routine follow-up has ceased (including who will initiate prescribing extended adjuvant aromatase inhibitors 5 years later).

(e) Bone density measurements may not remain the only or optimal methodof detection of osteoporosis and alternatives/additions to bisphosphonatesmay become available in the future.

Biochemical markers of bone turnover detectable in a urine test are currently being investigated.

New agents such as strontium ranelate (Protelos) are currently being appraised by NICE with regards to their use in the treatment of postmenopausal osteoporoticfractures. Recently licensed in the United Kingdom, this is an oral agent that reducesthe activity of osteoclasts without reducing bone formation.

therefore a dedicated organisation needs to be responsible for updatingrecommendations according to new evidence.

resource implications of widespread and possibly long term use will need to be considered.

12. Useful addresses and contacts

National Osteoporosis SocietyTel: 01761 471771www.nos.org.uk

Breast Cancer CareTel: freephone 0808 800 6000www.breastcancercare.org.uk

The Menopause Amarant TrustTel: 01293 413000www.amarantmenopausetrust.org.uk

Macmillan Cancer Relief Tel: freephone 0808 808 0000 / 2020www.macmillan.org.uk

CancerBacupTel: freephone 0808 800 1234www.cancerbacup.org.uk

Tenovus (predominantly in Wales)Tel: 0808 808 1010www.tenovus.com

Maggies Centreswww.maggies.ed.ac.uk (predominantly in Scotland)

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Several important issues remain outstanding:(a) Should bone density scans be offered to all women with breast cancer who

experience an early, treatment-induced menopause to assess their bonehealth and screenfor those who might require intervention?

it might be appropriate to measure bone density in all women prior to startingchemotherapy treatment and/or to include scans as part of the follow-up surveillanceof women who have had chemotherapy and/or have experienced a treatment-induced menopause.

however there are resource implications in terms of sufficient numbers of localmachines, and personnel to operate the machines and inter pret the scan results.

(b) If bone density scans are offered to women, how often should these take place?

The frequency of performing bone density scans is controversial. It has beensuggested that regularly repeated DEXA scans are not helpful because changesin bone density are slow to occur, and because there is no sound correlation betweentreatment-induced increases in bone density and decreases in future fractures.For example, alendronate has been shown to decrease fracture risk by up to 50%

but only to increase bone density by a few percent (Black et al 1996).

changes over time may not assist clinical decision making because research doesnot demonstrate that changing medication in the event of decline in bone densitywill halt further decline. Fluctuations occur normally and are to be expected withtreatments, resulting in the potential for ambiguity with future measurements.

(c) It is indisputable that women need better awareness, information and healthpromotion. For example the implications for bo

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Osteoporosis After Breast Cancer