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Estrogen is essential for building healthy bones, but estrogen replacement therapy carries the risk of serious side effects. Selective estrogen receptor modulators (SERMs) offer the benefits of estrogen for bone health but reduce the risk of side effects.

When women reach menopause, estrogen levels plummet. Changes in estrogen result in a number of obvious symptoms: Hot flashes, mood swings, and dryness. The effects of estrogen on bone health are not as obvious at first, but the consequences of osteoporosis can pose an equally life-changing event (and not in a good way) for about half of women.

What estrogen does for bones

The female sex hormone estrogen activates a class of bone cells known as osteoblasts. These are the cells that build bone by "gluing" crystals of calcium compounds to strands of collagen. Osteoblasts create the matrix of bone. 

Healthy bones are always remodeling themselves to respond to changes in the load of the body on the skeleton. Osteoclasts are another kind of bone cell that "recycle" old bone to make room for new. They don't need estrogen to be activated. They continue to break down bone as if it were going to be replaced. But when estrogen levels are low, the osteoblasts are not activated to finish the process.

Lower estrogen levels aren't the only reason some women develop osteoporosis, a chronic condition of brittle bones. But estrogen replacement therapy reliably restores the rebuilding process in women's bone.

How effective is estrogen replacement therapy?

There is enough confidence in estrogen replacement therapy for bone health that the FDA in the USA and the health agencies of most other countries approve it as a method of preventing osteoporosis. Estrogen replacement therapy(also known as ERT) is particularly helpful in preventing the dreaded broken hip. A study involving 3,964 women found that women who didn't get estrogen replacement therapy were more likely to experience hip fractures. Bone mineral density (BMD), on average, decreased 0.8 percent a year in women who did not get estrogen. Bone mineral density increased 0.8 percent a year in women who did.

Estrogen patches (transdermal estrogen replacement therapy) have proven highly effective in women whose metabolic problem is high turnover. (In high turnover conditions, the bone-recycling osteoclasts get out of sync with and work faster than the bone-restoring osteoblasts,) In another study, two years of estrogen replacement therapy increased bone mineral density by an average of 2.8 percent in women who did not have high bone turnover rates and by an average of 6.6 percent in women who did.

There is no doubt that estrogen replacement therapy works as a preventative measure and as a treatment for osteoporosis. So why don't more doctors prescribe it? The downside of estrogen replacement therapy is that it has been associated with increased risk of breast and uterine cancers, blood clots, stroke, and mental decline. Some of the cancer risk can be ameliorated by adding progestin to the estrogen treatment, but nowadays doctors limit the time a woman receives estrogen replacement therapy even when the doctor believes that it is the single most useful treatment to prevent or control the disease.

From estrogen replacement to selective estrogen receptor modulators

Modern medications for women facing risk of osteoporosis after menopause don't add estrogen to circulation. Instead, they change the way tissues respond to the estrogen that is already found in her body selectively, increasing sensitivity in tissues that would benefit from estrogen while leaving estrogen response in other tissues unchanged. Or at least that is the goal of selective estrogen receptor modulators, also known as SERMs.

The most-often prescribed SERM is raloxifene, marketed as Evista in the US and as Optruma and other brand names outside the US. Raloxifene is a "designer" estrogen that is intended to treat osteoporosis by making bone more sensitive to estrogen and by making the uterus less sensitive to estrogen, so that risk of uterine cancer is not increased. This designer estrogen is not quite as effective as the real thing, but when cancer risk is taken into consideration, "real" estrogen causes more harm to than good, so "designer" estrogen is considered superior to estrogen replacement therapy or therapy with estrogen + progestin. Raloxifene also results in fewer fractures than treatment with bisphosphonates (for example, Fosamax or Boniva) alone.

Raloxifene not the only SERM

Raloxifene is not a wonder drug. Women who take it are just as at risk for deep vein thrombosis (DVT) as women who take estrogen. It reduces the risk of spinal fractures, but it doesn't seem to reduce the risk of hip fractures. But Evista (raloxifene) is not the only SERM. Here is an abbreviated list:

  • Tamoxifen (marketed as Nolvadex and Soltamox) was the first SERM, designed for treating estrogen receptor positive breast cancer. It strengthens bone mineral density in women that use it, but it's not certain that it prevents fractures.
  • Lasofoxifene (marketed as Fablyn) was approved in Lithuania and Portugal to treat both osteoporosis and vaginal atrophy. A clinical trial found that it prevented both fractures of the spine and fractures in the hip. It increases bone mineral density better than Evista. It also carries an increased risk of deep vein thrombosis like Evista, however.

Doctors sometimes prescribe other SERMs for off-label use in women who have osteoporosis and other issues related to menopause. These medications include anordrin (+mifepristone (Zi Yun)), bazedoxifene (+conjugated estrogens (Duavee)), broparestrol (Acnestrol), clomifene (Clomid), cyclofenil (Sexovid), , ormeloxifene (Centron, Novex, Novex-DS, Sevista), ospemifene (Osphena; deaminohydroxytoremifene), and toremifene (Fareston; 4-chlorotamoxifen). In these situations, you have to trust your doctor to know what is best for your unique combination of symptoms.

  • Barrett-Connor EL. The risks and benefits of long-term estrogen replacement therapy. Public Health Rep. 1989 Sep-Oct. 104 Suppl:62-5. Review. PMID: 2517703.
  • Beck TJ, Stone KL, Oreskovic TL, Hochberg MC, Nevitt MC, Genant HK, Cummings SR. Effects of current and discontinued estrogen replacement therapy on hip structural geometry: the study of osteoporotic fractures. J Bone Miner Res. 2001 Nov.16(11):2103-10. PMID: 11697807.
  • Gonnelli S, Cepollaro C, Pondrelli C, Martini S, Monaco R, Gennari C. The usefulness of bone turnover in predicting the response to transdermal estrogen therapy in postmenopausal osteoporosis. J Bone Miner Res. 1997 Apr. 12(4):624-31. PMID: 9101374.
  • Photo courtesy of SteadyHealth

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