Raloxifene Vs. ERT in Osteoporosis What Do We Know?

Raloxifene Vs. ERT in Osteoporosis What Do We Know?

I. Vered

Institute of Endocrinology, Sheba Medical Center, Tel Hashomer

Sackler Faculty of Medicine, Tel Aviv University, Israel

Almost 6 decades ago, Albright described the clinical features of postmenopausal osteoporosis and its amelioration by estrogen (E). Estrogen replacement therapy (ERT) has become the mainstay of the prevention and treatment of osteoporosis since then, having alleged additional benefits such as the prevention of coronary artery disease and other aging related processes and diseases. These possible added benefits of ERT make it perhaps a more attractive option for the post menopausal, osteoporosis-prone woman than bone specific agents such as bisphosphonates or calcitonin. ERT indeed is prescribed often and yet, the compliance with its use is quite poor due to frequent side effects and the fear of breast cancer promotion. Recently, the introduction of the selective E receptor modulator Raloxifene (R), which may provide E - like benefit with less untoward effects offers a new exciting alternative. The purpose of this presentation is to compare the use of E vs. R for the prevention and treatment of osteoporosis. In addition the role of both compounds in skeletal physiology and their effects on bone mineral density (BMD) and fractures will be explored.

E maintains skeletal integrity by direct and indirect effects on bone. E regulates the production of cytokines and growth factors in bone. Both E & R stimulate TGF beta gene expression by means of the E receptor. The AF-1 domain is critical to E - induced TGF beta activation, while the AF-2 domain is required for the R - induced effect. TGF beta inhibits the differentiation of progenitor cells into mature osteoclasts and reduces the bone resorbing activity. Both E and R promote the apoptosis of osteoclasts. E also prevents the increase in osteocyte apoptosis in ovariectomized animals. Both compounds decrease postmenopausal bone loss by slowing bone turnover with comparable results on bone histomorphometry, calcium balance, and changes in biochemical markers of bone turnover. Similar effects are produced by E and R on bone biomechanical strength.

BMD and the risk of osteoporotic fractures in elderly women are greatly influenced by serum levels of endogenous E. It seems that even extremely low, albeit detectable serum estradiol plays an important role in skeletal health. BMD is maintained or even augmented by ERT, up to a 10% increase, depending on the type of ERT, the duration of treatment and the age at onset of treatment. Yet, elderly women may continue to lose bone despite apparently adequate treatment. E - using participants in the Study of Osteoporotic Fractures lost 1.1 - 4.1 mg/cm2 in total hip BMD (only 33% less than age-adjusted non - E users). R exerts a modest positive effect on BMD, 2 – 3% increase in 2 – 3 years in postmenopausal women over a wide age range. The protective effect of E on BMD is short lived. Bone loss is resumed once ERT is withdrawn. BMD in women who discontinue therapy for 5 years or more is similar to that of women had never used E. No comparable data are available on R as yet.

E may reduce the risk of fractures by other, non-skeletal mechanisms such as improved balance skills and reduced risk for falls. There is little evidence to support this notion: A better postural balance was observed in longterm E - users compared to non users. Data on the neuromuscular effects of R should be available soon from the MORE trial. Other bone sparing effects of E such as renal conservation of calcium, increased production of 1.25(OH)2 Vitamin D and promotion of intestinal calcium absorption have not yet been investigated with R.

The main goal in treating osteoporosis is the prevention of fractures. Despite the long track of E use, for more than 50 years, clear-cut evidence of its efficacy in preventing fractures is still lacking. It is estimated that ERT reduces the risk for hip fracture by 25 – 75%. These estimates are based on observational and case-control studies which are prone to various biases. It seems that the continuing use of ERT is crucial for fracture protection and the protective effect diminishes significantly within 5 years from E withdrawal. Sadly, the impact of ERT on hip fracture risk has not been studied as a primary endpoint in any randomized clinical trial. In one major trial, the HERS, fracture data was collected as a secondary endpoint and no reduction in risk was observed during 4 years of follow-up. In the Study of Osteoporotic Fractures, a substantial number of women who reported on continuous use of ERT since menopause, experienced an osteoporotic fracture during a 9 year follow-up period. The MORE trial, studying the effect of R, focused on vertebral fractures. Hip fractures were reported as a secondary endpoint, and occurred in a very low incidence during the first 3 years of follow-up, precluding any conclusions. The evidence for reduction in spine fractures in osteoporotic women by ERT is again, mainly from observational studies, and is estimated at 50%. One randomized clinical trial (Lufkin et al, 1992) comparing transdermal E to placebo in a small group of 75 postmenopausal women with prevalent spine fractures, reported a significant reduction in fracture rate. When re-analysed more appropriately, looking at the number of patients sustaining new fractures, the statistical significance is lost. R reduced the risk for vertebral fracture in the MORE trial on 7705 osteoporotic women by 50%.

In conclusion: While E has been used for several decades in postmenopausal women its exact value in preventing or treating osteoporosis has not been established properly. There is a large and consistent body of evidence from observational analyses to support the efficacy of E in fracture risk reduction but the magnitude of the effect may be overestimated. The optimal duration, timing and type of ERT have not been established yet. Hopefully, the data expected from ongoing randomized clinical trials will help to clarify the true value of ERT in osteoporosis as well as other health issues. R, the first SERM to be approved for osteoporosis may overcome some of the limitations of ERT. This new medication has been carefully studied in large-scale randomized clinical trials, and seems to have limited side effects. In addition there is a growing body of evidence that R may exhibit beneficial effects on the cardiovascular risk profile and the most exciting data is related to the possible reduction in the incidence of breast cancer.