Rev Osteoporos Metab Miner. 2012; 4 (1) suplemento: 23-7
2 Universidad de Alcalá – Servicio de Ginecología y Obstetricia – Hospital Universitario de Guadalajara
La Osteoporosis is a disease which does not have a totally satisfactory definition1. Since the 50s, when Fuller Albright defined it as “too little bone”2, an incomplete concept, since it only recognises the quantitative, and not the qualitative aspect of the disease, it has been succeeded by other definitions, such as that of the American National Institute of Health (NIH) which in 1988 referred to osteoporosis as “a condition in which bone mass is reduced, increasing the bone’s susceptibility to suffer fractures”2,3, or that agreed by the Hong Kong Consensus in 19934. In spite of it not being totally satisfactory, nowadays we accept the definition published by the NIH in the year 2001, an update of the 1988 version, which considers osteoporosis to be “a disease of the whole skeleton characterised by low bone mass and an alteration in bone microarchitecture which causes bone fragility, with a consequent increase in the risk of fractures”5.
Even though the current definition addresses the fundamental problem of osteoporosis (the existence of a 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 quality of bone (microstructural changes), this definition of osteoporosis does not have a direct clinical application, because with it we cannot use it to identify those patients who suffer from the disease. Thus in day to day care, the definition of osteoporosis most used is that derived from a densitometric finding of a T-score lower than -2.5, although this has the limitation of being based exclusively on quantitative criteria6.
Clinical situations in which the use of bazedoxifene is indicated
Taking into account the premise that bazedoxifene is indicated for treatment of postmenopausal women with osteoporosis, we are able to profile more specifically those women in whom the drug could have a more precise indication.
a. The patient with densitometric osteoporosis
Given that osteoporosis does not have symptoms in itself, and that the clinical signs are produced as a consequence of its complications, fractures1,7, it is necessary to identify and treat the disease before the fractures appear. At the moment we only have available densitometry, which only evaluates the quantitative, and not the qualitative components of bone. According to the World Health Organisation (WHO) densitometric osteoporosis exists when the patient has a value of T lower than -2.5 in any anatomical location where the measurement is taken 6,8,9.
There is a clear relationship between a decrease in bone mineral density and an increased risk of fracture, in such a way that it is accepted globally that for each reduction in the typical deviation the risk of fracture doubles10. Therefore, in a woman in whom a diagnosis of osteoporosis has been established by densitometry, it is possible to initiate treatment with bazedoxifene.
b.The patient with a high risk of fracture according to the FRAX® tool
In recent years the FRAX® tool, which it is possible to access free on the internet, has been published under the auspices of the WHO. From a series of clinical data, which include various risk factors, the absolute risk in both men and women of suffering a fragility fracture in the next ten years is established11,12.
As with any new tool, it has its advantages and limitations13. One of the advantages is that it allows the estimation of the risk of fracture without densitometry, but on the other hand, it has not been clearly established what the cut off point for the risk of fracture is, at which starting patient treatment is cost-beneficial. In the United Kingdom a calculation has been made with British female patients and with the cost of generic alendronate, that has established a level of 20% for the risk of any fracture, or 3% for the risk of a hip fracture as sufficient for the initiation of treatment11. This has not been demonstrated in Spain, or in many other countries, but as has happened with so many other things, these cut off points, due to inertia or convenience, have ended up being accepted in the whole scientific community.
A study carried out by Kanis et al.12 observed that, compared with the placebo, bazedoxifene produced a global decrease of 39% in the risk of incident morphometric vertebral fractures, without statistically significant differences being observed in the incidence of all fractures. However, when a subgroup which had a risk at 10 years equal to or higher than 16% according to FRAX® (which corresponded to the 80% percentile of the population of the study) was studied specifically, a reduction in the risk of all fractures was observed. In this study it was demonstrated that the beneficial effect of bazedoxifene is higher the greater risk of fracture the patient has. So, for example, in women who are in percentile 41, which is equivalent to a risk of 6.9% at 10 years for all fractures, bazedoxifene only reduces the risk of morphometric vertebral fractures, while in those women who were in percentile 90, a reduction in vertebral and in all fractures was observed. Applying the same FRAX® tool, it was found that bazedoxifene was cost-effective in the treatment of postmenopausal osteoporosis, with the archetypal woman obtaining the greatest benefit being 70 years of age, with a densitometric value for osteoporosis (T<-2.5) and an earlier fracture14. This study, and two others in which the authors of FRAX® have participated, confirmed that the use of bazedoxifene for the treatment of postmenopausal osteoporosis had an acceptable cost-benefit profile, which improved when FRAX® was used.
Therefore, it is possible to consider as candidate patients to receive treatment with bazedoxifene those whose risk of fracture at 10 years is higher than 16% for any fracture and 3% for a hip fracture, independently of whether the patient has a fracture or not.
c. The patient with vertebral fracture
The vertebral fracture is the most prevalent osteoporotic fracture. In an epidemiological study carried out in Europe, in which various Spanish centres participated, it was established that 20% of women over 50 years of age had at least one vertebral fractur15. However, these frequently go unnoticed, firstly because patients are often asymptomatic, and secondly, because for their precise diagnosis it is necessary to carry out a lateral spinal X-ray and apply some criteria for vertebral deformity16, which, although simple to apply, are often not well known17.
It is very important to treat those patients who already have an established vertebral fracture, since without treatment a new fracture will occur in 20% of them18,19. Therefore, any woman who has a vertebral fracture due to fragility, and in whom the possibility that it has been caused by significant trauma has been discounted, is a candidate to receive treatment with bazedoxifene.
Various studies have shown that the administration of bazedoxifene, combined with a supplement of calcium and vitamin D produces a reduction in the risk of vertebral fractures20-22. In the analysis of the follow up at five years of a subgroup of the reference study, made up of 1,324 women with a high risk of fracture (T-score ≤-3 in the femoral neck and/or the presence of one or more moderate or severe vertebral fractures, or &Ge;2 moderate vertebral fractures at the start of the study), bazedoxifene showed a reduction in the incidence of non-vertebral fractures of 37% compared with a placebo at a dose of 20 mg (HR, 0.63; CI 95%, 0.38-1.03; P=0.06), and 42% at 4 years of follow up (HR, 0.58; CI 95%, 0.35-0.98; P=0.04)22.
d. The patient with a high risk of fracture, estimated by other methods
Although we may suspect that a patient has a high risk of fracture, in clinical practice is it difficult to establish unequivocally a criterion or a threshold for which a patient has an increased risk of fracture. In the FRAX®12,14,23,24 and Qfracture®25 scales the risk factors most commonly related to fragility fractures are included, although it is generally accepted that the greater the number of risk factors the greater the probability of fracture. It is also recognised that the existence of an earlier fracture is the most important factor which in itself classifies a patient as having a high risk of a new fracture26.
Mode of administration of bazedoxifene
Bazedoxifene has shown good gastrointestinal tolerability in the clinical trials which have been carried out, being able to be administered at any time of day, with or without food. This allows patients flexibility in its administration, adapting it to their activities and timetables, although it should be recommended that it be taken daily at the same time so that the patient does not forget to take it. In the case in which a dose is missed, this should be administered as soon as possible, in order to continue with the normal timetable, thus avoiding double or extra doses27.
This ease of administration facilitates therapeutic compliance with bazedoxifene, which has been demonstrated in the different clinical trials in which the abandonment rates are similar to those of the placebo23.
As with the other drugs used for the treatment of osteoporosis, bazedoxifene should be associated with calcium and vitamin D supplements since its efficacy in this association has been demonstrated in clinical trials12,20-23. The drug may be taken at the same time as the supplement, there being no interference in its absorption.
In general, bazedoxifene is a well-tolerated drug. The adverse effects most frequently observed in the clinical trials were breathlessness and muscle spasms, especially cramps in the legs. Less frequent but more serious are thromboembolic episodes20.
Other adverse effects report are dry mouth, allergic reactions, increase in triglycerides, peripheral oedema and drowsiness, and an increase in transaminases, although the frequency was similar to that produced with the placebo20,22,27.
To whom should bazedoxifene not be prescribed?
Bazedoxifene is only indicated for the treatment of postmenopausal women. It has no indication for use in premenopausal patients. Other contraindications are27:
– Personal history of venous thromboembolism or of an increased risk of having this pathology.
– Allergy to bazedoxifene or some of its excipients.
– Its safety in women with endometrial or breast cancer has not been sufficiently studied. There are no data regarding its use concomitant with other treatments used in breast cancer. Its use for the prevention of breast cancer is not recommended.
– Its safety in patients with severe renal and hepatic insufficiency has not been established.
– In those women with moderate of intense vasomotor symptoms it should be born in mind that bazedoxifene does not act on these symptoms, which means that they should be treated, in addition, with other specific associated drugs (for example, estrogens).
The patient with high risk of breast cancer
In the clinical studies of bazedoxifene it has not been associated with an increase in tension or pain in the breast, benign or malignant pathology, their presence being similar to that with the administration of a placebo28. These results are maintained after treatment in the long term over 7 years34.
A study with digital mammography in women treated for 2 years with bazedoxifene has indicated that the treatment does not affect mammary density and therefore, does not modify the diagnostic interpretation of the mammography29.
In breast cancer cell lines, bazedoxifene shows a differentiated pattern of genetic expression with respect to raloxifene and lasofoxifene in more powerfully antagonising the stimulator effect of the estrogens30.
In the phase III studies the presence of breast cancer was similar for bazedoxifene, raloxifene and placebo, and the incidence of breast cancer turned out to be low and not powerful enough to properly evaluate this aspect31,32.
Bazedoxifene and the reproductive tract
Treatment with bazedoxifene over 5 years is not associated with changes in endometrial thickness, the frequency of abnormal uterine bleeding, an increase in benign endometrial pathologies such as polyps endometrial hyperplasia or malignant pathology. Nor did it interfere with cervicovaginal cytology results27,29,33. In an extension of the reference study to 7 years, the group treated with bazedoxifene showed an endometrial thickness similar to that with the placebo and lower incidence of endometrial carcinoma than in the placebo group (p<0.05), although the number of cases was very low in both groups34.
In recently postmenopausal women at risk of osteoporosis, treatment with bazedoxifene over two years has shown no differences in relation to the placebo in the measurement of ovarian volume, the number or size of ovarian cysts or in the presence of malign ovarian pathology35.
Preclinical and clinical studies suggest a different and favourable uterine profile for bazedoxifene compared with other SERMs. The marked antagonist effect on the endometrium has permitted the development of the association of bazedoxifene with the estrogens, since it neutralises more powerfully than raloxifene the proliferative effect induced by the estrogens in the endometrium36, which suggest a different endometrial profile for this SERM.
Women with associated pathology
Cardiovascular pathology is the principle cause of dysfunction in postmenopausal women. Hence the effect of an intervention on surrogate markers of cardiovascular disease is seen to have great importance.
In the lipid profile, bazedoxifene has shown a significant reduction in blood cholesterol (-3.75%), cholesterol bonded to low density lipoproteins (-3.6%) and an increase in cholesterol bonded to high density proteins (5.10%), in comparison with the placebo. The effect on the triglycerides was similar to that of the placebo. This favourable effect on the lipid profile is independent of age and has been shown both in the prevention study28 (average age 57.6 years) and in the study with women with osteoporosis (average 65.9 years)27. For this reason, a woman with hypercholesterolemia may be a candidate for treatment20, with the expectation of an additional beneficial effect of an improvement in their lipid profile.
Arterial hypertension is another important surrogate marker for cardiovascular risk. Treatment over 5 years with bazedoxifene has been shown to be similar to the placebo in its effect on blood pressure. Thus, women with hypertension could use bazedoxifene since, in addition, it does not interact with anti-hypertension drugs. Nor has there been reported to be any influence on the glycemic profile in the follow up at 5 years of treatment with bazedoxifene. Women on anticoagulant treatment, and once they have be evaluated for its indication, could be treated with bazedoxifene since there is no medicinal interaction with anticoagulant drugs like warfarin.
A new approach to the treatment of osteoporosis. Sequential therapy
One of the problems which we currently find in the treatment of osteoporosis is knowing how long should be maintained.
It should be born in mind that treatment for osteoporosis does not “cure” the disease, rather it reduces the risk of the appearance of fractures. Most of the reference studies designed to demonstrate the effectiveness of drugs in achieving this last 3–5 years. Up until now the available data has been observational, usually with a very low number of patients participating in the study, which does not maintain the methodological rigor observed during the randomised clinical trial. Therefore, in order to be reasonably safe and legally protected, we are authorised to maintain the treatment for the patients for the same time as the clinical trial lasts.
However, what do we usually do with the patients when they complete the 3-5 years? We consider whether to continue with the treatment or to cancel it, this in a patient affected by osteoporosis in whom there remains a high risk of fragility fracture and in whom, by being 3-5 years older, this risk is even higher. Up until now we have adopted individualised positions, with the agreement of the patient, and in many cases the treatment has been maintained for periods longer than those of the clinical trial, due, on the one hand, to the generally good tolerance of the drug, and on the other, the absence of reported of secondary effects or significant complications. This has been the case until relatively recently when there have started to be reports of the presence of atypical diaphyseal femoral fractures in patients in whom the treatment, usually with biphosphonates, had been sustained for a long period37. The risk of fracture per 100 patients per year in these patients has been established by some authors at 1.46 (CI 95%: 1.11-1.88)38, and by others at values as high as 37.4 (CI 95%: 12.9-119, p<0.001)39. The duration of treatment with biphosphonates appears to be a significant factor in the appearance of these atypical fractures, since when these drugs, especially alendronate, are maintained over 2 years 2 cases for every 100,000 patients treated per year are observed, while when the treatment is prolonged for 8 years, the risk increases to 78 cases per 100,000 patients treated per year37.
In the light of this we need to rethink what to do in the longer term with those patients affected by osteoporosis, especially when we are going to indicate a treatment for the first time, since, with the current data, it does not seem very advisable to maintain a treatment with powerful antiresorptive drugs beyond 5 years, and besides, we already know that the indication for the anabolic drugs, PTH 1-34 and 1-84, is that they can only be maintained for 2 years. There are no data with respect to this, but in these circumstances, in a patient with postmenopausal osteoporosis, we could consider the possibility of beginning the first years of treatment with an antiresorptive drug such as bazedoxifene which is not as powerful as the biphosphonates or denosumab, in order, some years later, to continue with one of these more powerful drugs, precisely when the patient has the greater risk of fracture by being older. We do not have studies available which support this suggestion, which should be taken only as a personal opinion of the authors.
In conclusion, bazedoxifene is a selective estrogen receptor modulator whose prolonged use, for at least 5 years, produces a reduction in the appearance of new vertebral fractures and a decrease in the risk of non-vertebral fractures in those women at high risk, considered to be those who had a BMD in the femoral neck with a T-score lower than -3.0, and/or 1 severe vertebral fracture or two moderate vertebral fractures.
It is a drug with a significant long term safety profile, and has the additional advantage of not increasing the risk of breast cancer and of reducing the risk of endometrial cancer. Therefore, it is a drug which we should consider as the first choice for the treatment of osteoporosis.
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