3.- Definiciones centrales, normas y procedimientos

The decline in endogenous oestrogen is well documented to affect the turnover and integrity of bone tissue in postmenopausal women. The decline in oestrogen levels leads to increased bone turnover, resulting in a high rate of bone loss and decreased bone mineral density (BMD). This leads to a condition known as osteoporosis, and predisposes sufferers to pathological bone fractures [383-385]_{. Decreased bone mineral}

density measurements and evidence of increased bone resorption, which can be assessed by measurement of the urinary excretion of bone type I collagen degradation products, are indicative of osteoporosis [386]_{. The following evidence exists to support the role of}

Pacifici et al. (1991) [383] _{emphasised that the bone- sparing effect of oestrogen is related}

to an inhibitory effect on bone resorption and importantly, outlined the existence of oestrogen receptors in the osteoclasts and osteoblasts of bone. This is significant because it indicates bone is an oestrogen responsive tissue.

Satoh et al. (1993) [387] _{also demonstrated the importance of oestrogen in the}

maintenance of normal bone structure in their study comparing the BMD of women with hysterectomy and unilateral or bilateral oophorectomy (OVX). In the bilateral OVX group accelerated bone changes were obvious immediately following surgery, and the rapid bone loss continued throughout the follow-up period. In contrast, the unilateral OVX group exhibited no initial signs of accelerated bone loss post surgery, with a slow phase of bone loss during the follow-up period. Therefore bone loss was greater in the bilateral OVX group in which oestrogen had been removed completely.

A prospective study of bone loss in menopausal Australian women was conducted by Guthrie et al. in (1998) [388]_{, demonstrating the influence of menopause on bone loss.}

BMD of the hip and lumbar spine was assessed in 224 women; 74 pre-menopausal, 90 peri-menopausal and 60 post-menopausal. Results showed BMD loss was accelerated during the transition from peri to post-menopause, indicating that menopause and the associated oestrogen deficiency is a catalyst for osteoporosis.

In 1999, Meunier et al. [389] _{again highlighted the important role of oestrogen in}

prevention of osteoporosis. They studied the effect of raloxifene, a selective oestrogen receptor modulator, on the bone density of post-menopausal women. Post-menopausal women were tested because they are at high risk of osteoporosis, with an estimated 23% of post-menopausal women over 50 yrs being affected. Results showed raloxifene

increased bone density and decreased bone turnover, therefore may prove an effective treatment for osteoporosis in post-menopausal women. This conclusion was reiterated by Ringa (2000) [390]_{, who stated that osteoporosis is directly associated with hormonal}

changes at menopause, and that hormone replacement therapy is proven to be effective in the prevention of bone loss.

A study by Picard et al. (2000) [391] _{assessed the bone density of the lumbar spine in 141}

women pre-menopause, and again 10 years later post-menopause. Multiple regression analyses of bone mineral density results and information gained from questionnaires revealed bone density pre-menopause, time without oestrogen, weight and vitamin D intake were the only significant predictors of present bone mass or bone loss. This study emphasises the importance of good bone mass prior to menopause, and the early commencement of oestrogen replacement therapy to minimise bone loss in the years post-menopause, therefore reducing the risk of osteoporosis.

In order to assess the influence of other hormones on bone density, Guthrie et al. (2004)

[392] _{performed a study of 159 Australian born women during the menopause transition.}

They tested the association of a number of hormones with bone loss at the lumbar spine and femoral neck. In addition to oestrogen, free testosterone, sex-hormone binding globulin and dehydroepiandrosterone were also tested. Results showed oestrogen was the only hormone tested to have a significant effect on BMD during the menopause transition.

Zecchin et al. (2004) [393] _{examined the association between osteoporosis and oestrogen}

disease. Their study focussed on the essential role of MMPs play in the remodelling of the bone extracellular matrix after tooth extraction. They compared the healing process in 2 groups of rats; ovariectomised to simulate menopause versus sham operated controls. The OVX animals showed a significant delay in the healing process. This was attributed to a decrease in the gelatinolytic activities and expression of MMPs and collagen types I & III, which was observed in the OVX group. Therefore it can be concluded form this study that the absence of oestrogen contributes to delayed healing by interfering with bone extracellular matrix turnover.

In 2005, Jochems et al. [394] _{studied the link between rheumatoid arthritis (RA) and}

osteoporosis. In postmenopausal RA, osteoporosis is caused both by the deficiency in oestrogen and the inflammation associated with the arthritis. Statistically, the peak incidence of RA in women occurs around the time of menopause, with 50% of sufferers having generalised osteoporosis. In this study, non-arthritic OVX mice were compared to OVX and RA induced mice. At completion of the trial period, the OVX group showed trabecular BMD reduction of 22%, whereas the OVX and RA group showed BMD reduction of 58%. This study proves interesting because it examines the compounding effect inflammation has on osteoporosis. A similar situation may exist in the knee joint, where inflammation associated with osteoarthritis may compound degeneration of ligament tissue.

Akhter et al. (2007) [395] _{examined the effect of menopause on the structure of trabecular}

bone. Their study focussed on the excessive remodelling of bone that results from oestrogen deficiency in postmenopausal women. This results in a deficit of bone which compromises bone structure, and is characteristic of osteoporosis. They showed that measuring the activation frequency of new bone remodelling sites is a more powerful

predictor of bone strength and bone fragility fractures than BMD alone. Their study showed that at the onset of menopause, the remodelling rate of bone increases to twice the rate of that pre-menopause, highlighting the important role oestrogen plays in the regulation of normal bone turnover.

Mas et al. (2007) [396] _{demonstrated that OVX is associated with systemic bone loss in a}

baboon model. Their study showed bone loss following acute oestrogen deficiency takes up to 5 years to plateau, with the maximal deleterious effect on bone density occurring in the first 12 months. Another 2007 study conducted by van Essen et al. [385]

suggested that increased osteocyte apoptosis, as a result of oestrogen deficiency, could play a role in the decreased bone strength and bone mass seen in postmenopausal osteoporosis. Furthermore, a study by Taxel et al. (2008) [397]_{, suggests that oestrogen}

deficiency at menopause causes an increase in osteoclast formation and activation, therefore leading to excessive bone resorption and osteoporosis.