Jean Calleja-Agius1 and Mark Brincat1
(1)
Department of Obstetrics and Gynaecology, Mater Dei Hospital, Birkirkara, Malta
Jean Calleja-Agius
Email: jean.calleja-agius@um.edu.mt
Mark Brincat (Corresponding author)
Email: brincatm@maltanet.net
19.1 Introduction
Osteoporosis and related fractures are a significant concern for the global community. As the population continues to age, morbidity and mortality from fractures due to osteoporosis will likely continue to increase. The menopause has been shown repeatedly to have a negative effect on the connective tissue in the bone matrix. Such an effect is prevented and in some cases reversed with oestrogen therapy. Studies show that oestrogen prevents osteoporosis partly by inhibiting bone resorption. Selective oestrogen receptor modulators (SERMs) act through oestrogen receptors and are agonists for bone and antagonists for breast and uterine tissue. A new approach to menopausal therapy is the tissue selective oestrogen complex or the pairing of a selective oestrogen receptor modulator with oestrogens. Novel bone-targeting oestradiol delivery systems have the potential to improve the safety profile of oestradiol in the treatment of osteoporosis.
19.2 Bone
Postmenopausal osteoporosis is a silent systemic progressive disease characterised by a decrease in bone mass per unit volume. This condition compromises the physical strength of the skeleton and increases the susceptibility to fractures on minor trauma. The imbalance between bone formation and bone resorption is known to be responsible for postmenopausal bone loss. Oestrogen deficiency contributes to bone loss by increasing the production of proinflammatory cytokines by bone marrow and bone cells. Clinical and molecular evidence indicates that oestrogen-regulated cytokines exert regulatory effects on bone turnover implicating their role as being the primary mediators of the accelerated bone loss at menopause.
At menopause, bone turnover increases, and may remain high for up to 25 years after the last menstrual period [1]. Bone turnover is controlled by a complex interrelationship of a number of factors, including oestrogen, progesterone, testosterone, Vitamin D, corticosteroids, thyroid hormones and retinoids [2]. Oestrogen alone has a known beneficial effect on reducing bone fractures and limiting bone loss. A number of studies have shown the positive effect of progesterone on bone proliferation and inhibition of bone resorption [3–6]. However, another study showed no difference between progesterone and placebo in terms of any difference in markers of bone resorption [7]. Consequently, large-scale randomised controlled trials are necessary to determine the role of progesterone alone in the prevention or treatment of osteoporosis [8]. Oestrogen and progesterone alone could have distinct yet complimentary roles in maintenance of bone [9–11].
19.3 Intervertebral Discs
Each intervertebral disc is composed of high collagen content and glycosaminoglycans. Intervertebral discs are responsible for 20 % of the spinal column height and allow flexion and extension of the back and also act as “shock absorbers” of the spinal column. This may have an important role on osteoporotic compression fractures [12].
With the ageing process, there is a change in collagen type [13], with a more profound difference with increasing years since menopause [14]. The collagen Types I, III and VI predominate at the expense of collagen Types II, IV and IX. There is also a significant decrease in glycosaminoglycans and elastin in the aged intervertebral disc [15]. The comparison between a normal and an aged intervertebral disc is shown in Fig. 19.1a, b.
Fig. 19.1
(a) Normal intervertebral disc, (b) Aged intervertebral disc
The lumbar intervertebral disc height has been shown to be significantly higher in the premenopausal group (height of three lumbar discs 2.16 ± 0.1 cm) and hormone-treated group (disc height 2.2 ± 0.12 cm), compared to the untreated postmenopausal women (disc height 1.86 ± 0.06 cm) (p < 0.0001)[14]. This has been confirmed by another study on a bigger cohort. The premenopausal women and hormone-treated women had disc heights of 2.01 ± 0.09 cm and 2.15 ± 0.08 cm, respectively, the latter results being significantly higher than the untreated postmenopausal group (height of three lumbar discs 1.82 ± 0.06 cm) and the osteoporotic fracture group (1.58 ± 0.1 cm) (p = <0.0001) [14].
These results may be due to the effect that the menopause has on the connective tissue components of intervertebral discs. This may lead to loss of the shock-absorbing properties of the intervertebral disc and an altered discoid shape, influencing the occurrence of osteoporotic vertebral body fractures [16]. After menopause, intervertebral disc space shows a progressive decrease that almost entirely occurs in the first 5–10 years since menopause, suggesting that the decline in oestrogen level may rapidly change connective tissue metabolism in the intervertebral discs [17].
19.4 Muscle
In menopause, there is a decline in muscle mass and strength ensues when serum oestrogen declines. Oestrogen improves muscle strength. The underlying mechanism involves oestrogen receptors to improve muscle quality rather than quantity [18].
Hormone therapy attenuates exercise-induced skeletal muscle damage in postmenopausal women. Postmenopausal women not using hormonal therapy experience greater muscle damage [19].
19.5 HRT-Where Do We Stand?
In the wake of the WHI trial, many dilemmas have yet to be resolved regarding the use of HRT in postmenopausal women. Several factors may have contributed to the widely different conclusions of the WHI trials in comparison to the observational studies.
WHI included two randomised double-blind, placebo-controlled investigations of unopposed oestrogen (0.625 mg of conjugated equine oestrogen, CEE) alone for women with a prior hysterectomy [20] and of combined oestrogen–progestin (the progestin component consisted of 2.5 mg of medroxyprogesterone acetate, MPA) for women with a uterus [21]. The combined HRT arm of the WHI was stopped in May 2002 after a mean of 5.2 years follow-up, because the test statistic for invasive breast cancer exceeded the stopping boundary and the global index statistic supported risks exceeding benefits [22]. The conclusions from the study at that time were that the risks of coronary heart disease, stroke and pulmonary embolism were significantly increased in the intervention group, the risks of hip fracture and colorectal cancer were reduced and the mortality risk was unchanged [21].
The oestrogen-alone arm of the WHI study was stopped in February 2004, 1 year earlier than planned, due to excess stroke. It was concluded that CEE alone increases the risk of stroke, reduces the risk of hip fractures and does not affect the risk of cardiovascular heart disease in postmenopausal women with prior hysterectomy over an average of 6.8 years. There was a possible reduction of breast cancer risk, but this required further investigation [20].
The potential side effects and risks involved in taking HRT may be reduced by using lower HRT doses; minimising or eliminating systemic progestogens; using non-oral routes in some women; and initiating HRT in symptomatic women near menopause. When HRT is initiated near menopause for symptom control, there may be additional benefits including reduced fracture and cardiovascular risk. These benefits outweigh the risks, which are not significantly raised in women under age 60 years. As long as their therapy and risks are assessed on an individual basis and each patient is aware of the risks, older women with continuing symptoms should not be denied HRT [23].
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