A review of the EMAS clinical guide: Selective oestrogen receptor modulators for postmenopausal osteoporosis
In Europe, osteoporotic fractures account for more Disability Adjusted Life Years (DALYs) lost than common cancers with the exception of lung cancer. The economic burden is considerable and it has been estimated that the direct cost of osteoporotic fractures in Europe is about EURO 36 billion.
Osteoporosis is defined by the World Health Organisation (WHO) as a bone mineral density that is 2.5 standard deviations or more below the mean peak bone mass (average of young, healthy adults) as measured by DEXA.
Various therapies such as bisphosphonates, strontium ranelate and more recently enomsumab are available. However concerns have been raised regarding safety such as oesophageal cancer, osteonecrosis of the jaw (ONJ) and subtrochanteric fractures with bisphosphonates and venous thromboembolism with strontium ranelate.
Santiago Palacios from Madrid, Spain and colleagues recently produced a clinical guide on the evidence for the clinical use of selective oestrogen modulators (SERMs) in the management of osteoporosis in postmenopausal women.1
In the guide the authors explained that SERMs are chemically diverse compounds that lack the steroid structure of oestrogens, but interact with oestrogen receptors (ERS) as agonists or antagonists depending on the target tissue. The agonist and antagonist properties of SERMs derive from differentially expressed ERS, ligand-dependent receptor conformational changes, interactions with various co-activators and co-repressors expressed and recruited in different tissues, and subsequent changes in gene transcription. Differential gene regulation with different SERMs ultimately contributes to the different cell- and-tissue-speciﬁc activities of SERMs. The early SERMs such as tamoxifen, toremiﬁne and raloxifene, were originally developed for the prevention and treatment of breast cancer and were subsequently found to conserve bone mass. Two new SERMs, bazedoxifene and lasofoxifene, are now licensed in Europe. Bazedoxifene (BZA) is a third-generation SERM, developed for the prevention and treatment of postmenopausal osteoporosis.
In a pivotal phase III clinical study to evaluate the effectiveness and safety of BZA in preventing fractures in postmenopausal women with osteoporosis (55–85 years of age). Participants received daily treatment of BZA 20mg(n = 1,886) or 40mg (n = 1872), Raloxifene (RLX) 60mg (n = 1849) or placebo (n = 1.885), as well as a daily supplement of 1200 mg calcium and 400–800 IU of vitamin D. Among 6,847 subjects in the intent-to-treat population, the incidence of new vertebral fractures was signiﬁcantly lower (p < 0.05) with bazedoxifene 20 mg (2.3%), bazedoxifene 40 mg (2.5%), and raloxifene 60 mg (2.3%) compared with placebo (4.1%), with relative risk reductions of 42%, 37%, and 42%, respectively. The treatment effect was similar among subjects with or without prevalent vertebral fracture (p = 0.89 for treatment by baseline fracture status interaction). The incidence of non-vertebral fractures with bazedoxifene or raloxifene was not signiﬁcantly different from placebo. In a post hoc analysis of a subgroup of women at higher fracture risk (femoral neck T-score ≤ −3.0 and/or ≥1 moderate or severe vertebral fracture or multiple mild vertebral fractures; n = 1772), bazedoxifene20mg showed a 50% and 44% reduction in non vertebral fracture risk relative to placebo (p = 0.02) and raloxifene 60mg (p = 0.05),respectively. The 2-year extension included a total of 4,216 women providing 5 year data . The raloxifene arm was discontinued after 3 years; subjects receiving bazedoxifene 40mg were transitioned to bazedoxifene 20mg after 4 years. Five-year ﬁndings were reported for bazedoxifene 20 and 40/20mg cohorts and placebo. At 5 years, the incidence of new vertebral fractures in the intent-to-treat population was signiﬁcantly lower with bazedoxifene 20mg (4.5%)and 40/20 mg (3.9%) versus placebo (6.8%; p < 0.05), with relative risk reductions of 35% and 40%, respectively. Non-vertebral fracture incidence was similar among groups. In a subgroup of higher-risk women (n = 1324; femoral neck T-score ≤ −3.0 and/or≥1 moderate or severe or ≥2 mild vertebral fracture[s]), bazedoxifene 20mg reduced non-vertebral fracture risk versus placebo (37%; p = 0.06); combined data for bazedoxifene 20 and 40/20mg reached statistical signiﬁcance (34% reduction; p < 0.05). After 7-years continuing beneﬁt on vertebral fracture risk was still found.
The number of reported cardiac disorders and cerebrovascular events was equally low among all treatment groups up to 7 years. While the general occurrence of pulmonary embolism and retinal vein thrombosis was increased in the treatment groups compared to placebo, this was not statistically signiﬁcant. However the risk of deep vein thrombosis was significantly increased after 3 years (RR 8 (CI, 1.01–64.25)). The SPC* for bazedoxifene also mentions a “description of selected adverse reactions: In the osteoporosis treatment trial in 7,492 evaluable subjects (mean age=66 years), the bazedoxifene-treated women had an increased risk of venous thromboembolism (deep vein thrombosis, pulmonary embolism and retinal vein thrombosis).”
After 3, 5 and 7 years, there were no differences in breast cancer incidence between the different groups. The authors concluded that BZA has demonstrated a favourable endometrial proﬁle over 5 years of therapy.
Lasofoxifene** is a naphthalene derivative, third-generation SERMs with better oral bioavailability than other compounds, and, was developed for osteoporosis prevention and treatment in post-menopausal women.
The pivotal Lasofoxifene (PEARL) trial randomized 8,556 women aged 59–80 with a BMD T score of −2.5 or less at the femoral neck or spine, to receive a daily dose of lasofoxifene (0.25mg or 0.5 mg) or placebo for 5 years. Lasofoxifene at a dose of 0.5mg/day, as compared with placebo, was associated with reduced risks of vertebral fracture (13.1 cases vs. 22.4 cases per 1,000 person-years; hazard ratio, 0.58; 95% conﬁdence interval [CI], 0.47–0.70), nonvertebral fracture (18.7 vs. 24.5 cases per 1,000 person-years; hazard ratio, 0.76; 95% CI, 0.64–0.91). Lasofoxifene administration was associated with signiﬁcant reductions in ER-positive breast cancer (0.3 vs. 1.7 cases per 1,000 person-years; hazard ratio, 0.19; 95% CI, 0.07–0.56), coronary heart disease events (5.1 vs. 7.5 cases per 1,000 person-years; hazard ratio, 0.68; 95% CI, 0.50–0.93), and stroke (2.5 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.64; 95% CI, 0.41–0.99). Lasofoxifene at a dose of 0.25mg/day, as compared with placebo, was associated with reduced risks of vertebral fracture (16.0 vs. 22.4 cases per 1,000 person-years; hazard ratio, 0.69; 95% CI, 0.57–0.83) and stroke (2.4 vs. 3.9 cases per 1,000 person-years; hazard ratio,0.61; 95% CI, 0.39–0.96).
Both the lower and higher doses, as compared with placebo, were associated with an increase in venous thromboembolic events (3.8 and 2.9 cases vs. 1.4 cases per 1000 person-years; hazard ratios, 2.67 [95% CI, 1.55–4.58] and 2.06 [95% CI, 1.17–3.60], respectively), but there was no evidence of an increase in the incidence of pulmonary embolism.
In the conclusion the authors pointed out that the EMA approved an indication for BZA in the treatment of osteoporosis in postmenopausal women at increased risk of fracture. These new SERMs points to a greater anti-fracture potential than raloxifene with positive breast, endometrium, coronary heart disease and stroke safety proﬁles over seven years. Currently BZA is available in Spain, Switzerland, Italy, Ireland and Japan and it is anticipated will be launched soon in other countries. Lasofoxifene was approved in Europe in 2009 for the treatment of osteoporosis in postmenopausal women at increased risk of fracture. FDA (Food and Drug administration) approval has not been granted. Safety ﬁndings noted by the FDA included increased incidence of uterine diagnostic procedures, increased incidence of VTE, and a small, but signiﬁcant increase in all-cause mortality with the 0.25mg, but not the 0.5mg, dose. The decision, of when to begin and what type of treatment to use, should be based on the need to reduce fracture risk. All treatments including SERMS should include recommendations for a healthy life style and adequate calcium and vitamin D intake. Additional beneﬁts of different agents (i.e. climacteric symptom improvement with oestrogens, breast cancer prevention for SERMs) must be considered when selecting the most suitable anti-osteoporosis drug. Furthermore what agent is used (oestrogen, SERM, bisphosphonates) may vary over a woman’s life time.
This review is a summary of the paper published by Santiago Palacios and colleagues.
Reference: Palacios S, et al. EMAS clinical guide: Selective oestrogen receptor modulators for postmenopausal osteoporosis. Maturitas (2011), doi:10.1016/j.maturitas.2011.11.01
*SPC for Bazedoxifene from www.Medicines.ie on 19 April 2012
**Lasofoxifene – please note that this product is not yet approved for use in Ireland