When women reach the menopause they experience a
When women reach the menopause they experience a number of physical complaints such as hot flushes, vaginal dryness and mood changes . Bone loss also becomes manifest at this time , , but women will often not suffer from back pain before a vertebral fracture occurs. Women who have had one fracture have a high chance of suffering another fracture within a year . It has been known for a long time that estrogen treatment can prevent climacteric complaints . It is also known that steroid hormones play an important role in bone homeostasis , , ,  and several studies have shown that estrogens prevent bone loss in early and late postmenopausal women and in younger women with non-functional ovaries resulting from various causes , .
Estriol, estradiol, ethinyl estradiol and estropipate (piperazine oestrone sulfate) are the pure estrogens used for the prevention of postmenopausal osteoporosis. Conjugated equine estrogens (CEE), a preparation consisting of a complex mixture of various estrogenic compounds in conjugated and free form, together with some impurities, are also used. The main routes of administration are oral or via patches. In women with an intact uterus, estrogen treatment requires the co-administration of a progestogen . Unopposed estrogen increases the risk of endometrial pathology, although the combination with a progestogen is known to compromise the breast and the cardiovascular system .
The progestogens used differ with respect to their properties  and can be divided into two main groups: those that are structurally related to progesterone, such as medroxyprogesterone acetate, cyproterone acetate, trimegestone and medrogestone, and those structurally related to testosterone, such as norethisterone (acetate), levonorgestrel, norgestimate and dydrogesterone. Although progestogens may have a positive effect on bone , in other tissues such as the 3-bromo-5-phenyl Salicylic Acid and cardiovascular system, they may diminish the effects of estrogens.
In the last decade, two new agents that also act on bone via the estrogen receptor (ER), i.e. tibolone and the selective estrogen receptor modulator (SERM) raloxifene, have been proven to possess bone-sparing properties , , . Tibolone has a unique mode of action and belongs to a separate class of compounds that can best be classified as selective, tissue estrogenic activity regulators (STEARs). Unlike estrogens, neither needs to be combined with a progestogen because estrogenic activity on the endometrium is counteracted by other properties of the parent compounds , . Moreover, the two compounds have additional positive effects on other tissues. Both show tissue selective effects, although the fact that their profiles are not identical is explained by the difference in other hormonal properties and their different mode of action in various tissues. Tibolone shows a better clinical profile than the other treatments.
Mechanisms of action The focus here is on compounds that act on bone solely via the ER and that have been proven to prevent bone loss. It is well known that estrogens prevent bone loss, but the precise mechanism is still not completely understood. Estrogens may act via ERα and/or ERβ and possess different affinities for these receptors. It has been proposed that ERβ is a type of co-repressor of ERα , although evidence for this is lacking in humans. Estradiol binds equally well to both receptors, as does estrone albeit with a weaker affinity , whilst ethinyl estradiol shows a two-fold higher affinity for ERα . Pure agonists for the ER may all give the same maximal response in the various systems, but the potency may differ. Evidence exists that estrogens induce their own receptor, but when administered at high unphysiological doses, the ER can be down-regulated thus leading to a lower biological response. Both osteoblasts and osteoclasts contain ERs , . Studies with intact ERKO and BERKO mice have shown that both receptors have a role in bone physiology, but it is important to note that endogenous hormone levels undergo drastic changes in intact KO-animals ,  and it remains to be proven whether this is true under physiological circumstances.