Volume 2 · Nº 5 Supl · December 2010
- Osteoporosis. Definition. Importance. Physiopathology and Clinical manifestations [3-7]
- Epidemiology of osteoporotic fractures: vertebral and non-vertebral fractures [8-12]
- Bazedoxifene. First 3rd generation SORM. Safety in endometrium and breast [13-18]
- Efficacy of bazedoxifene, pre-biphosphonate sequential therapy for osteoporosis and the patient profile for bazedoxifene [19-25]
Bazedoxifene is a new drug which belongs to the group of modulators selective for oestrogen receptors (SORMS), a class of drugs which act selectively on oestrogen receptors (ORs). Recently approved in the European Union and in the regulatory review process in the United States for the prevention and treatment of postmenopausal osteoporosis1, bazedoxifene has appeared on the market as a daily oral drug for the treatment of postmenopausal osteoporosis.
The latest clinical data on the modulators selective for oestrogen receptors has served as a base for the re-evaluation of the SORM concept. The SORMs have effects on tissues which contain ORs, such as the breast, bone, uterine and genitourinary tissue, and brain, and on markers for cardiovascular risk. The current evidence indicates that each SORM has a unique range of clinical activity. The differences in the patterns of actions of the SORMs suggest that each clinical variable should be evaluated individually, and that the conclusions around any particular SORM can only be established through appropriate clinical trials.
The action mechanism of the SORMs occurs through the bonding of two types of oestrogen receptors: alpha (OR-α) and beta (OR-β). The SORMs have agonistic and antagonistic properties at the same time, depending on the type of tissue2,3. This is explained, in part, by the availability of different sub-types of ORs in different tissues.
Efficacy of bazedoxifene, pre-biphosphonate sequential therapy for osteoporosis and the patient profile for bazedoxifene
The interest in, and concern about, osteoporosis has resulted in the acquisition of greater knowledge of its epidemiology, achieving advances in diagnostic tools and the discovery of ever more efficacious and safe new drugs. In terms of the drugs, there are currently multiple options, among which are included the biphosphonates and the selective oestrogen receptor modulators (SORMS: raloxifene (RLX) and bazedoxifene (BZA)), the oestrogens calcitonin, parathormone (PTH) and strontium ranelate. With the exception of the oestrogens, the antifractural effects of all these medicines has been demonstrated in women with a densitometric diagnosis of osteoporosis1. All this necessitates an individualised therapeutic indication depending on the benefit-risk profile of each patient.
The SORMs represent a class of drugs with ever more numerous compounds, characterised by acting as agonist/antagonist of oestrogen receptors (OR) in a tissue-specific way2. This pharmacological profile may offer an opportunity to obtain favourable oestrogenic effects, while avoiding any negative effects of them on breasts and endometrium. The SORMS have been shown to have great value in breast cancer. They have also been shown to be efficacious in the prevention and treatment of osteoporosis and in improving lipid metabolism, and there are other possible benefits which are being studied, such as as a treatment for vaginal atrophy3. This versatility of the SORMs is due to the capacity of each of them to produce a different conformational change in the oestrogen receptors α and β, and with this, ultimately, to stimulate or block the activity of the transcription genes for the oestrogens2.
The different SORMs exert a different affinity and competition for the bond to the oestrogenic receptors and determine a different genetic expression. The evidence suggests that each SORM should be studied, and its clinical response evaluated, independently4.
The two SORMs currently most used are tamoxifen, which is used for the prevention and treatment of breast cancer, and raloxifene, indicated for the treatment and prevention of postmenopausal osteoporosis, and for the prevention of breast cancer in the US. Both SORMs have positive effects on the lipids, but are associated with an increased risk of venous thromboembolism and hot flushes. In addition, tamoxifen increases the risk of cancer of the endometrium. On the other hand, none of these SORMs have shown a preventative effect on non-vertebral fractures3,4.
Therefore, of any new SORM it is necessary to ask which has the best efficacy, or the best safety, or both, knowing that the ideal SORM is one which prevents vertebral and non-vertebral osteoporotic fractures, which serves as primary or secondary prevention of breast cancer, and which may have additional benefits regarding cardiovascular risk. This ideal SORM would not increase the risk of either hyperplasmia, or endometrial adenocarcinoma, nor venous thromboembolisms or hot flushes4. Although it is very difficult to find this ideal SORM, the new SORMs are a step forward, based on preclinical selection criteria and data on the clinical response in relation to efficacy and safety.
Up until now, RLX has been the only SORM in the market approved for the treatment of osteoporosis. Now we can also count on bazedoxifene (BZA), a new generation SORM, which has completed its clinical development and has been approved by the European Medicines Agency (EMEA) for the treatment of postmenopausal osteoporosis in women with a high risk of fractures5.
There is no totally satisfactory definition of osteoporosis. In the 50s Fuller Albright defined it as: “too little bone”1, a concept which is incomplete, since it only captures the quantitative, and not the qualitative, aspect of the disease. Subsequently, in 1988 the American National Institute of Health (NIH) published its first definition, in which osteoporosis is referred to as “a condition in which the bone mass diminishes, increasing susceptibility of bones to suffer fractures”2. Nowadays, we accept as the definition of osteoporosis that published by the NIH in the year 2001, updating the earlier definition of 1988, which considered it to be “a disease of the whole skeleton characterised by a low bone mass and an alteration in the bone microarchitecture which causes fragile bone, the consequence of which is an increased risk of fractures.”3.
Although the current definition focuses on what is the fundamental problem in osteoporosis: the existence of greater bone fragility which results in an increase in the risk of suffering fractures, and integrates the loss of quantity (bone mass), with changes in the bone quality, the alterations in microarchitecture, this definition does not have a direct clinical application, because with it we cannot identify patients who suffer from the disease. Thus, in day to day care, the definition of osteoporosis most used is that based the finding of a densitometry with a T-score lower than -2.5, although this definition has the limitation of being based exclusively on quantitative criteria.
Osteoporosis is a common disease, responsible for most of the fractures which occur after the age of 50 years. It is a worldwide health problem of great magnitude which increases with the aging and the lifestyles of the population, especially in Western countries. The main complication is fracture which carries with it a high health and social cost1. In spite of the fact that it is a preventable and treatable disease, to date, policies developed to deal with it so far have not managed to reduce the problem. Osteoporosis is defined as a general disorder of the skeleton characterised by low bone mass and deterioration in the microarchitecture of the bone tissue, which is translated into a diminution of bone resistance which predisposes it to fracture2. Bone resistance is made up of two components – bone density and bone quality. In turn, the concept of quality attempts to integrate all those factors, apart from bone mass, which contribute to bone fragility, and which include among others, the microarchitecture, the degree of bone turnover, the accumulation of lesions or microfractures and degree of mineralisation2,3.
According to the definition, the most significant clinical fact is fragility fracture. The absence of manifestations of osteoporosis without fracture make diagnosis difficult. Without methods of evaluating quality, or its components, the diagnosis is based on the confirmation of low bone mineral density (BMD). Thus, in 1994 the WHO agreed an operative definition based on levels or cut-off points of BMD for white postmenopausal women4. Thus, it was proposed that normal levels for BMD be set at a value higher than a -1 standard deviation (SD) in relation to the average for young adults (T-Score > -1); for osteopenia, values of BMD between -1 and -2.5 SD (T-Score between -1 and -2.5); for osteoporosis, values of BMD lower than -2.5 SD (T-Score lower than -2.5) and established osteoporosis, when, along with these conditions, are associated one or more osteoporotic fractures (Table 1). It has recently been recommended that these same cut-off points be used for osteoporosis in males5.