Description of the condition
Postmenopausal osteoporosis is a chronic metabolic disease related to the alternation of hormones, especially estrogen, during the perimenopausal or postmenopausal (or both) period in women. It is characterized by deterioration of bone mineral density (BMD), trabecula (reticular structure that forms the interior bone filled with bone marrow), cortical bone (compact stratum forming the outer shell of most bone), and extension of the medullary cavity (central cavity storing bone marrow). BMD is measured by dual-energy X-ray absorptiometry bone densitometer (DXA). For adult women, osteoporosis is defined as a value of BMD 2.5 standard deviations below the mean of young normal women (T-score ≤ -2.5) according to the World Health Organization (WHO) diagnostic criteria (Kanis 1994). The decreased BMD and microarchitectural changes will lead to fragility fracture, which is caused by mild to moderate force.
Postmenopausal osteoporosis-related fractures predominantly occur in vertebral, upper femur, or distal radius, and the prevalence of fractures positively correlates with menopausal years (Looker 1998; NAMS 2010). As the most serious complication of postmenopausal osteoporosis, fractures affect at least one-third of women aged 50 years and older. Besides, it has been estimated that lifetime risk for osteoporotic fracture is higher in women aged above 50 years than age-matched men (54% versus 5% to 6%) (Grossman 2001; Johnell 2005). Postmenopausal osteoporosis is a universal disease and subsequently results in heavy economic burden (Cummings 2002; Lewiecki 2004). Furthermore, the increase in life expectancy and elderly population may make the plight more serious. Therefore, the prevention and treatment of postmenopausal osteoporosis is urgent for the whole of society. Nonpharmacologic therapies of postmenopausal osteoporosis include optimizing nutrition, lifestyle changes such as doing more exercise, smoking cessation, avoiding excessive caffeine, and reducing alcohol consumption. Pharmacologic therapies include antiresorptive agents such as bisphosphonates, calcitonin, and hormone therapy, and anabolic drugs such as parathyroid hormone. The benefits of vitamin D with calcium for fracture prevention in postmenopausal osteoporosis have been demonstrated by Cochrane systematic reviews (Avenell 2009), and with bisphosphonates including alendronate, etidronate, and risedronate (Wells 2008a; Wells 2008b; Wells 2008c). Although fluoride increases BMD of lumbar spine, it does not have beneficial effects on reducing both vertebral and nonvertebral fractures (Haguenauer 2010).
Description of the intervention
Selective estrogen receptor modulators (SERMs) belong to a class of compounds that lack the steroid structure of estrogen, but have an alternative structure that binds to estrogen receptors (ER) (Riggs 2003). They have both estrogenic and antiestrogenic effects depending on the target tissue or gene. SERMs, which have been used clinically for several decades, are widely prescribed for estrogen-related diseases, such as breast cancer, ovulation induction, and hypogonadotropic hypogonadism (Shelly 2008a). Among pharmacologic therapies for postmenopausal osteoporosis, SERMs belong to antiresorptive agents, which focus on the relationship between estrogen efficiency and bone loss. Unlike hormone therapy, SERMs may avoid some side effects due to its selective effect (estrogenic and antiestrogenic effect) on different organs (Barrett-Connor 2002; Cummings 1999; Lippman 2006). As a large family with structurally various members, these compounds can be mainly classified into triphenylethylenes, benzothiophenes, naphthalenes, indoles, benzopyrans, and flavonoids.
Although triphenylethylenes were not originally designed for treatment of postmenopausal osteoporosis, clinical trials have demonstrated that they exert substantial positive effects on BMD in long-term management except for toremifene (Chi 2012; Moskovic 2012; Santen 2011). In contrast, administration of clomiphene and tamoxifen is limited by side effects such as abnormal vaginal bleeding, hot flashes, abdominal discomfort, headache, nausea, vomiting, or a combination of these. Furthermore, tamoxifen interacts with warfarin, rifampicin (rifampin), cholestyramine, and aromatase inhibitors (Morello 2003).
Raloxifene is the most well-known available benzothiophene and it is considered as second-line treatment for postmenopausal osteoporosis in most clinical guidelines (Hodgson 2003). Based on several clinical trials, especially the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene has a productive effect on bone loss and consequent osteoporosis-related fractures, and may also be beneficial for coronary heart disease (Barrett-Connor 2002; Kanis 2003; Siris 2002). However, its usage is limited by increased risk of venous thromboembolism for the first two years (Grady 2004). Besides, cholestyramine causes a 60% reduction of absorption and enterohepatic circulation of raloxifene, thus, cholestyramine or other anion exchange resins should not be coadministered with raloxifene (Morello 2003).
Like other SERMs, lasofoxifene (the naphthalene class) and available bazedoxifene (the indole class) are well absorbed orally and highly bound to plasma proteins. These two drugs are both approved for the prevention and treatment of postmenopausal osteoporosis.
The clinically available benzopyran ormeloxifene can be used as a weekly oral contraceptive agent. It is also effective in mastalgia and dysfunctional uterine bleeding, and shows antiresorptive activity in bone metabolism in vitro. Unfortunately, reported cases of urinary incontinence and uterovaginal prolapse limited its further development for chronic usage (Singh 2001).
Femarelle is a natural compound derived from soybean. It has been used for the treatment of menopausal symptoms and postmenopausal osteoporosis with no effect on thromboembolism and endometrial thickness (Nachtigall 2011; Yoles 2004).
Most of the above drugs have long serum half-lives (120 to 168 hours) except raloxifene (16 to 87 hours), and their doses ranges from 20 to 60 mg/day except for femarelle (644 mg/day) (Morello 2003; Yoles 2004). When considering SERMs prescription, liver function needs to be taken into account as most of them are metabolized in the liver and eliminated in the bile. Currently, new agents are under development for better efficacy, higher oral bioavailability, and fewer adverse effects/events.
How the intervention might work
Estrogen, a steroid hormone that dramatically fluctuates in the perimenopausal phase and decreases in the postmenopausal phase of women, has essential impact in regulating bone resorption and formation. Through body-widespread ERs, a type of a nuclear hormone receptor that belongs to the family of activated transcription factors (Bord 2001), estrogen can interact with special sequences of deoxyribonucleic acid (DNA) (Kumar 1988). In vitro studies have shown that estrogen could improve proliferation and early osteoblastic differentiation of mesenchymal stem cells (MSCs) (Hong 2011; Okazaki 2002), which have the ability of osteogenic differentiation, and can also act directly on osteoblasts by regulating bone nodule formation and matrix protein/cytokine production (Waters 2001). Different types of ER (α and β) may mediate different functions on different tissues, which forms the theoretical basis of developing SERMs. ER-α may play a more important role in increasing the expression of alkaline phosphatase and osteocalcin on the bone formation compared with ER-β (Bodine 1998). With high affinity for ERs, SERMs can alter receptor conformation, facilitate binding of transcription-related proteins of estrogen target genes, which further leads to tissue-dependent estrogen agonist responses in some target tissues such as bone, or antagonistic effects on uterine endometrium and breast tissue (Bryant 1999; Ke 1995; Lippman 2006). To date, clinically available SERMs have been used in many estrogen-related diseases including postmenopausal osteoporosis (Shelly 2008). For example, raloxifene shows high affinity for ERs on bone without significant binding to other major steroid hormone receptors. This will produce protective effect on the skeleton without stimulating an effect on the uterus and breast. Thus, theoretically, there are fewer concerns about any estrogen-like effect on endometrium or mammary tissue during raloxifene treatment (Bryant 1999).
Why it is important to do this review
Many published randomized controlled trials (RCTs) using SERMs showed beneficial effects on postmenopausal osteoporosis. The evidence supports the efficacy of raloxifene or bazedoxifene for the prevention of osteoporotic fractures. However, the results remain imprecise due to the small number of fracture events (Levis 2012; Murad 2012). In addition, published systematic reviews did not include other SERMs such as lasofoxifene, ormeloxifene, and femarelle. As clinicians do not have a global picture of all SERMs, which may further influence decision making, it is necessary to evaluate the efficacy and safety of all those drugs for the prevention and treatment of postmenopausal osteoporosis.