Research updates
Osteoporosis   p 8
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4. What causes osteoporotic fractures? Link to the Medical Research Council web site
4.2 Determinants of peak bone mass (cont'd)
On page 7, we saw that the main determinants of peak bone mass are:
Let's continue to look at their detail.



Research at the MRC Environmental Epidemiology Unit has shown that physical activity is a stronger determinant of peak bone mass than dietary calcium intake.
The evidence came from a longitudinal study. This is a type of statistical investigation in which data from the same individuals is collected at intervals over a period of time. In this study 153 women born in Bath during 1968 –1969 were traced and studied in 1990. Data on their growth during childhood was obtained from linked birth and school health records; current bone mineral measurements were made by dual energy X-ray absorptiometry. Information about lifestyle, including physical activity, was obtained in interviews using a structured questionnaire. The women were asked how long they walked each day and whether or not they had taken part in school sports. The results showed that physical activity in childhood is a strong determinant of bone mineral density in women.

It is thought that the mechanical stress occurring during exercise leads to an increase in the activity of osteoblasts and that this in turn increases the bone mass.

Is all exercise effective?
Weight-bearing exercise certainly helps to develop strong bones but very intensive exercise can actually be harmful. The damage occurs when a dancer or athlete does not eat enough to provide the high output of energy needed for training and performing. The desire to have a very low body weight may be a factor too. In young women the hormonal balance can be upset with the result that oestrogen levels fall leading to amenorrhea. This is a serious symptom since oestrogen is essential for healthy bone in women (see below). The combination of too much exercise and too little food can cause young women to develop the disease.
Anna Richman
Figure 15. Anna Richman suffered spinal fractures due to osteoporosis. Now, as a doctor, she helps alert young women to the risks of osteoporosis.



A lack of sex hormones (androgens and oestrogens) is associated with low bone density. This is because they are physiologically antagonistic to parathyroid hormone (PTH). PTH is part of the feedback system controlling the calcium balance in the plasma. If the level of calcium falls, PTH release is stimulated to raise blood calcium. One of the ways it does this is by increasing the rate of osteoclastic bone resorption. Sex hormones act in opposition to PTH, preventing the increase.

The eating disorder Anorexia Nervosa can lead to a low bone density. The disorder upsets the hormone balance so that the oestrogen level falls. The lack of oestrogen causes a reduction in bone mass density so that even young women can develop osteoporosis as a result.

Case study - Anna Richman

Anna was 15 when she began suffering from Anorexia Nervosa. Four years later, as she was finally recovering from the eating disorder, Anna's back gave way. At first she was told it was a slipped disk. However, when she got up from the prescribed bed rest, her mother noticed she was no longer as tall as her sisters: she had lost two inches in height due to spinal fractures. She was diagnosed with osteoporosis and prescribed high dose contraceptive pills to boost her oestrogen levels. She takes regular weight–bearing exercise and has a calcium-rich diet, helping to increase her bone density. Anna has now qualified as a doctor and helps the National Osteoporosis Society (NOS) to alert young women to the risks of osteoporosis.

Genes and programming

It is likely that genetic makeup will affect the skeleton and it has been suggested that it will be a determinant of peak bone mass. Studies on twins, comparing the risk that they will develop osteoporosis, suggest that the risks are closer if they are identical (monozygotic) than if they are unidentical (dizygotic). Although this finding supports the idea that genetic makeup has an effect, it is equally consistent with the results of recent research which suggest that intrauterine influences interact with the genome, a phenomenon known as programming.

Investigating genes

The influence of the genes is investigated by identifying candidate genes and then looking for polymorphisms in these genes to see if they affect BMD. The gene for vitamin D receptor (VDR) has been studied. However it is found that allelic variation in the VDR gene can only explain a small proportion of the variation in individual peak BMD. Other candidate genes are the genes for collagen and genes which promote growth by their effect on the endocrine system.

Recent research, by Professor Cooper’s team, has shown that the risk of osteoporosis may be determined by environmental influences during intrauterine and early post-natal life. It is thought that these influences may interact with the genome to affect the function of the endocrine systems that control growth. Fetal programming is a new area of research and is described in section 5 - ‘Current research on programming’.

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Question 7
What do you understand by the terms:

a) candidate gene?

b) polymorphism?