Raloxifene is a rare example of a molecule that got a «second life». Conceived as a remedy against breast cancer, it initially did not live up to expectations, was shelved, and later returned as the first selective estrogen receptor modulator for treating osteoporosis. The editorial team traced this path.
Prehistory: The Search for Antiestrogens
In the mid-20th century, pharmacologists were actively searching for substances capable of blocking the action of estrogens. One of the first goals was contraception, and later — the treatment of hormone-dependent tumors. Thus appeared compounds of the triphenylethylene series, to which clomiphene and tamoxifen belong.
Tamoxifen, developed at the British company ICI, was also initially studied as a contraceptive, but eventually became the standard treatment for estrogen-receptor-positive breast cancer. Its success spurred other pharmaceutical companies to search for their own antiestrogens with a better safety profile.
At the same time, data were accumulating that tamoxifen behaves ambiguously: in the mammary gland it blocks estrogen, while in the endometrium and bones it partly imitates its action. This paradox did not yet have a theoretical explanation, but it was precisely this that later formed the basis of the concept of selective estrogen receptor modulators (SERMs).
In such a scientific context, work began in the laboratories of Eli Lilly on a new class of compounds based on benzothiophene, to which the future raloxifene belongs. Chemically it differs from tamoxifen, although it acts on the same receptors.
Keoxifene: A Failed Start
In the early 1980s, the molecule known by the working name LY156758, and later as keoxifene, was studied as a potential agent for treating breast cancer. The preclinical data looked promising: the substance effectively blocked the estrogenic stimulation of tissues.
However, in clinical trials in women with advanced breast cancer who had previously received tamoxifen, keoxifene did not show significant antitumor activity. An additional problem was low oral bioavailability due to intensive first-pass metabolism through the liver and intestine.
As a result, its development as an oncology drug was suspended. For the pharmaceutical industry this is a typical story: most molecules that reach clinical trials never obtain registration. But in the case of raloxifene, the «archival» period turned out to be temporary.
An important lesson of this stage was that the effect of an antiestrogen strongly depends on the clinical context. A drug that does not help against an already developed resistant tumor may have a completely different significance for prevention or for other tissues.
The Discovery of «Selectivity» and the Turn Toward Bones
Key was an experimental line related to bone tissue. Researchers, in particular Jordan and colleagues, showed in animal models that tamoxifen and keoxifene preserve bone density after ovary removal, that is, act on bone like estrogens. At the same time, in breast tumor models these same substances worked as antiestrogens.
Thus an idea formed: it is possible to create a drug that protects bones like hormone replacement therapy, but does not stimulate the mammary gland and, ideally, the endometrium. The term «selective estrogen receptor modulator» took hold precisely in the 1990s, when the molecular mechanisms began to be understood: different ligands change the conformation of the receptor differently, and cells of different tissues «read» this signal differently.
Eli Lilly returned to the molecule, now under the name raloxifene, with a new goal — the prevention and treatment of postmenopausal osteoporosis. This was a bold step: it was necessary to prove effectiveness on real endpoints, that is, on fractures, and not just on densitometry.
In parallel, researchers monitored the mammary gland. If the SERM concept is correct, in women receiving raloxifene for bones the frequency of estrogen-receptor-positive breast cancer should decrease. This very hypothesis later received confirmation.
Major Studies and Registrations
In 1997, the FDA approved raloxifene (trade name Evista) for the prevention of osteoporosis in postmenopausal women, and later for its treatment as well. Central was the MORE study (Multiple Outcomes of Raloxifene Evaluation) involving over 7 thousand women with osteoporosis. Ettinger and colleagues (1999) reported a reduction in the risk of new vertebral fractures, whereas for non-vertebral fractures, in particular the hip, no significant effect was found.
| Study | Question | Main result |
|---|---|---|
| MORE (1999) | Fractures in osteoporosis | Fewer vertebral fractures; no proven effect for the hip |
| MORE, cancer analysis (1999) | Breast cancer | Reduction in the frequency of invasive ER-positive cancer |
| CORE (2004) | Continuation of observation | Preservation of the effect regarding breast cancer |
| RUTH (2006) | Heart and vessels | No effect on coronary events; more VTE and fatal strokes |
| STAR (2006) | Comparison with tamoxifen | Similar prevention of invasive cancer, fewer thromboses and uterine cancers |
A secondary analysis of MORE (Cummings et al., 1999) showed a substantial reduction in the frequency of invasive breast cancer, primarily estrogen-receptor-positive. The subsequent CORE study confirmed this effect during long-term observation. For a molecule that once «failed» in oncology, this was an unexpected turn.
The RUTH study (Barrett-Connor et al., 2006) was meant to determine whether raloxifene protects the heart. The answer turned out to be negative: coronary events did not decrease, while an increased risk of venous thromboembolism and fatal stroke was confirmed. In parallel, the STAR study (Vogel et al., 2006) compared raloxifene with tamoxifen for cancer prevention.
In 2007, the FDA expanded the indications: reduction of the risk of invasive breast cancer in postmenopausal women with osteoporosis or at high risk of cancer. Thus keoxifene the failure returned to oncology after a quarter of a century, but now as a preventive agent.
Significance for Science and Sport
The history of raloxifene became a textbook case for pharmacology. It proved that one and the same receptor can trigger different programs in different tissues depending on the ligand. This opened the way to other SERMs: bazedoxifene, lasofoxifene, ospemifene, each of which has its own tissue profile.
It also showed the value of revisiting «failed» molecules. Today such a strategy is called drug repurposing and is considered one of the rational paths of drug development.
- For medicine:an alternative to hormone therapy for bones without stimulating the endometrium.
- For oncology:prevention of ER-positive breast cancer with a different safety profile than tamoxifen.
- For sport:the appearance of yet another antiestrogen that ended up on the WADA Prohibited List.
In the sporting environment, raloxifene appeared as an agent that supposedly helps with gynecomastia. Some clinical data in pediatrics regarding pubertal gynecomastia do indeed exist, but in the context of doping, raloxifene, together with other antiestrogens, belongs to class S4 of the WADA Prohibited List and is banned at all times.
It is important that none of the effects for which raloxifene became popular in bodybuilding was the goal of its development. Everything known about its safety was obtained in postmenopausal women, and the extrapolation of these data to young men is incorrect.
Editorial Conclusions
Raloxifene made the journey from a failed oncology candidate to the first SERM registered for osteoporosis, and later for the prevention of breast cancer as well.
Its history is linked with the formation of the very concept of tissue-selective action on estrogen receptors, which today underlies a whole class of drugs.
Large randomized studies gave a clear picture of both the benefits (vertebrae, prevention of ER-positive cancer) and the risks (thromboses, fatal strokes), which should be taken into account in any discussion of the drug.
We also recommend reading our materials on the medical indications of raloxifene in women, on its effect on the liver, and on the tests monitored during therapy.
References
- Jordan VC. SERMs: meeting the promise of multifunctional medicines. J Natl Cancer Inst. 2007;99(5):350–356.
- Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA. 1999;282(7):637–645.
- Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. JAMA. 1999;281(23):2189–2197.
- Martino S, Cauley JA, Barrett-Connor E, et al. Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst. 2004;96(23):1751–1761.
- Barrett-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355(2):125–137.
- Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP STAR P-2 trial. JAMA. 2006;295(23):2727–2741.
- U.S. Food and Drug Administration. EVISTA (raloxifene hydrochloride) tablets: prescribing information. Eli Lilly and Company.
Andriy Melnyk
A strength-sports coach and author of programs for beginner and intermediate levels. Writes about training planning.
