What is the purpose of the Bone Sub-study?

The Bone Sub study has been designed to examine the effects of anastrozole on Bone Mineral Density (BMD) and the risks of developing osteoporosis and/or fractures among women participating in the IBIS-II prevention part of the study. It will look at the following three areas:

• Changes in bone spine and hip among women receiving anastrozole. These will be compared to the changes in the placebo group.
• The effectiveness and tolerability of risedronate (a bisphosphonate drug which prevents bone loss) in women taking anastrozole.
• How changes in blood levels of biochemical markers involved in the body's process of making bone predict longer-term changes in bone mineral density.

Who can take part in the Bone Sub-study?

Women who have already decided to join the IBIS-II prevention part of the study, will also be invited to join this Bone sub study. Women who already have a serious problem with their bones will not be eligible to join the sub study. These problems include:

• Having any type of metabolic bone disease including: Paget's disease, disorders of calcium or mineral metabolism, renal calculus, certain unstable thyroid conditions. Women with previous conditions that have been corrected are eligible.
• Taking prescribed medication affecting bone metabolism within the past 12 months including oestrogen, any bisphosphonate, parathyroid hormone, calcitonin, oral or systemic steroids (glucocorticoids.)
• Breaking both hips and / or having both hips replaced. This is because reliable bone scans cannot be performed.

Women can take part in the sub-study if they are postmenopausal and aged between 40-70 years with either, a family history of breast cancer or a personal history of non-invasive breast cancer or an atypical benign breast lesion.

What will happen to me if I take part?

Once you decide to participate you will be asked to have a DXA scan. Depending on the results from this scan you will then be allocated to one of the following three groups:

Group I.

Women in this group will have good bone strength but will be recommended to take calcium and vitamin D to ensure this is maintained.

Group II.

Women in this group have some evidence of mild bone loss and it is unclear as to whether they may be at increased risk of further loss should they be taking anastrozole. The women will be randomised to take either risedronate 35mg or a placebo once a week. Therefore this group of women will have to take an extra tablet each week together with the daily tablet they are already taking in the main study.

Group III.

Women in this group have markedly reduced bone strength at the beginning and will only be able to participate in the main study as well as this sub study if they agree to take risedronate treatment. Therefore this group of women will have to take an extra tablet each week together with the daily tablet they are already taking in the main study.
All women will be monitored and given advice on maintaining healthy bones. Supplementation with calcium and vitamin D is recommended for all women in this study. You will be attending follow up checks during your five-year participation in IBIS-II Prevention. In addition to these we will be asking you to have:

• Follow-up DXA scans of the spine and hip at 1 year, 3 years, 5 years and 7 years.
• Height and weight measurements at every DXA scan visit.
• An extra blood sample at 6 months as well as at entry into the study, 12 months and at the final visit.

What do I have to do once I take part in sub-study?

It is important that you take all trial medication regularly and follow the advice given for the main study. In order to maximise the effect of risedronate treatment, tablets should be taken in the morning on an empty stomach with a full glass of water. You should then not eat or lie down for 30 minutes.

There are no dietary restrictions associated with this study. You will still be able to drive, drink and take part in any sport you wish to.

You will be asked to attend for DXA scans and blood tests at specific times so that any changes in your bones can be measured accurately.

What are the drugs that are being tested?

Anastrozole is a drug that is being used to treat breast cancer. It works by blocking the production of oestrogen by interfering with an enzyme called aromatase. Therefore it is called an aromatase inhibitor. In postmenopausal women, oestrogens are produced primarily from the conversion of other hormones through the aromatase enzyme complex in peripheral tissues, e.g. fatty tissue. Anastrozole prevents this happening, thus reducing the amount of oestrogen in the body. This reduction has been shown to produce a beneficial effect in women with breast cancer. It cannot block oestrogen produced by the ovaries, so can only be used in postmenopausal women.

This study will be investigating how anastrozole affects bone and the value of risedronate in managing any bone loss. This drug will be taken by all women in Group III and half the women in Group II.

Bisphosphonates

are non-hormonal drugs that work by slowing down the cells which break down bone tissue (osteoclasts), thus allowing the bone building cells (osteoblasts) to work more effectively. This will result in halting the loss of bone mineral density and repairing the damage already done. There are several different types of bisphosphonates used to treat osteoporosis. The type used in this study requires only one 35mg tablet to be taken each week. It is called Risedronate.

Vitamin D

stimulates the formation of new bone protein and calcium intake.

Calcium

is the mineral that gives the bones strength.

What are the alternatives for preventing Osteoporosis?

There are a number of approaches to dealing with osteoporosis in the general population. These include the use of hormone replacement therapy (HRT), drugs such as tamoxifen and raloxifene which affect oestrogen activity (SERMs), bisphosphonates and calcium and vitamin D supplementation. HRT and SERMs cannot be used here, because they interfere with the action of anastrozole, and HRT increases the risk of breast cancer. Currently we do not know the best way to prevent osteoporosis in women taking anastrozole. It is clear that some women are at greater risk of getting osteoporosis, especially if they have other conditions that affect their bones. We know that a healthy diet and weight bearing exercise helps to maintain good bone strength, but it is not clear how much benefit is obtained from taking calcium and vitamin D supplements. It is also unclear as to how effective bisphosphonate treatment is in the presence of anastrozole. We are also uncertain as to when bisphosphonates should be recommended.

What are the side effects of any treatment received when taking part?

Bisphosphonates are generally well tolerated and no serious side effects are reported. The most common problems experienced are usually associated with the digestive system. These can range from mild stomach pain and nausea to diarrhoea and some inflammation of the gut. These side effects are substantially reduced by taking treatment once a week, as will be the case in this study. In order to minimise the risk of any irritation in the lower end of the oesophagus (gullet), the tablet should be taken with a full glass of water first thing in the morning.

Apart from mild indigestion and constipation, calcium and Vitamin D have no untoward side effects unless taken in excessive doses.

What are the possible disadvantages and risks of taking part?

A DXA scan uses a small dose of X-rays. The total dose received from the five scans in this study is the same as that from a chest X-ray, a holiday flight to North America, or 1 weeks exposure to natural background radiation"

What are the possible benefits of taking part?

If serious bone loss is detected in a woman she will be offered risedronate or other appropriate treatment under the direction of the local bone physician. We know that the sooner osteoporosis is diagnosed and treated then the better the outlook. This is because the bone thinning process can be stopped by medication.

What if new information becomes available?

Any relevant, new, scientifically proven information that becomes available during the running of the study will be made available to all participants. This will be accompanied by appropriate advice.

What happens when the research study stops?

Recruitment to the bone sub study will continue for 4 years or until 1000 women are recruited. All women will be actively participating for five years and a further DXA scan will be taken 2 years later to see if any long-term problems exist. During all this time trial data will be regularly checked by the Independent Data Monitoring Committee and should important new information be discovered, women will be informed and advised appropriately.

What if something goes wrong?

If you become ill you should consult your GP in the usual way, but always remind him / her of your participation in the study. Tell your IBIS local research coordinator of the illness at your next follow-up visit. Please telephone your local study centre at any time if you are worried about any symptoms. The monitoring provided in this sub study will allow treatment to be given early if substantial bone loss is detected.

If you are in Group II and need to know whether you have been taking risedronate or placebo then the code may be broken to supply this information to you and your doctor if necessary.

Compensation for any injury caused by taking part in this study will be in accordance with the guidelines of the Association of the British Pharmaceutical Industry (ABPI). Broadly speaking the ABPI guidelines recommend that 'the sponsor', without legal commitment, should compensate you without you having to prove that it is at fault. This applies in cases where it is likely that such injury, not previously warned about, results from giving either drug or any other procedure carried out in accordance with the protocol for the study. Your right at law to claim compensation for injury where you can prove negligence is not affected.

Will my taking part in this study be kept confidential?

If you consent to take part in the research any of your medical records may be inspected by the organisation sponsoring the research for purposes of analysing the results. These records may also be looked at by an independent auditing body and regulatory authorities to check that the study is being carried out correctly. Representatives from the ethics committee may also wish to review some of the data. Your name, however, will not be disclosed outside the hospital, GP surgery, Cancer Research UK or relevant NHS Registers.

What will happen to the results of the research study?

The study hopes to recruit the total number of volunteers over four years and each woman will take the study medication for 5 years. This means that it will be quite a long time before any results are available. However, an Independent Data Monitoring Committee will scrutinise data every 6 months and should important information come to light they will recommend that we inform all women included in the study.

Who is organising and funding the research?

Cancer Research UK are organising this research study and Queen Mary’s University of London are the sponsors .

All Recruiting Centres will be reimbursed for including women in this study.

Who has reviewed the study?

The study has been approved by the North West MREC (Main Research Ethics Committee) and your local ethics committee (LREC)

Contact for Further Information

If you have any questions about the study either contact your local centre or email the IBIS-II office: ibis@cancer.org.uk