Estrogens, Estrogen Agonists/Antagonists, and Calcitonin Nelson B
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48 Estrogens, Estrogen Agonists/Antagonists, and Calcitonin Nelson B. Watts Estrogen 408 Calcitonin 409 Estrogen Agonists/Antagonists (Selective Estrogen Receptor Summary 410 Modulators or Serms) 409 Selected Readings 410 Thus, it appears that estrogen has protective effects on ESTROGEN the skeleton only for as long as it is taken. However, women who take estrogen and then stop should be no It is well established that osteoporosis is more common worse off compared with women who have never taken in women than men and fracture risk increases dramati- estrogen at all. cally after menopause. The relationship between estro- Following results of the WHI, estrogen treatment is gen defi ciency and osteoporosis was fi rst suggested in the recommended for relief of menopausal symptoms, but in mid-1900s when Albright showed that treatment with the lowest dose and for the shortest time necessary. Most estrogen reversed the negative calcium balance in post- women are not suffi ciently symptomatic at menopause menopausal women. The positive effects of estrogen on to require estrogen therapy, and most who require estro- peak bone mass and on bone loss have been demon- gen will be able to stop after a few years. However, a strated in both men and women. For years, estrogen was minority will require estrogen long-term. For those considered the treatment of choice for postmenopausal women, estrogen may be suffi cient for prevention and/or women and widely advocated for prevention of bone loss, treatment of osteoporosis. with numerous trials showing prevention of bone loss Several different forms of estrogen are available for in recently menopausal women and increased of bone therapeutic use (e.g., estradiol, conjugated estrogen ester- mineral density (BMD) in women with postmenopausal ifi ed estrogens, etc.) as well as several routes of adminis- osteoporosis. Part of the emphasis on estrogen therapy tration (e.g., oral, transdermal). In addition to different was the assumption of extraskeletal benefi ts (lower rates compounds and routes of administration, the dose can of cardiovascular events and dementia in women who vary as well. After hysterectomy, estrogen can be use chose to take estrogen compared with those who chose “unopposed”; however, for women who still have their not to) and also that the benefi ts would be durable after uterus, “opposing” estrogen with a progestin (of which estrogen was stopped. there are several,e.g., progesterone, medroxyprogesterone The Women ’ s Health Initiative (WHI) confi rmed the acetate) is recommended for protection against endome- value of estrogen administration (with or without a pro- trial hyperplasia and endometrial carcinoma. The spe- gestin) in the treatment of osteoporosis and reduction of cifi c therapy that was shown to reduce fracture risk in risk for hip and other clinical fractures. However, the WHI was orally administered conjugated estrogen, presumed extraskeletal benefi ts were not confi rmed, and 0.625 mg daily (also effective was the combination of the effects on BMD and fracture reduction disappeared 0.625 mg conjugated estrogen plus medroxyprogesterone within a year of discontinuation of estrogen (loss of BMD acetate 5 mg daily; however, there is little or no evidence of approximately 5% in the fi rst year after stopping). that progestins have any effect on bone). It is likely, but Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Eighth Edition. Edited by Clifford J. Rosen. © 2013 American Society for Bone and Mineral Research. Published 2013 by John Wiley & Sons, Inc. 408 Estrogens, Estrogen Agonists/Antagonists, and Calcitonin 409 not proven, that other estrogen preparations, as well as pausal women, although the gains in BMD appear to be lower doses, might have benefi cial effects on mainte- about half of what is observed with estrogen. The risk of nance of BMD and reducing fracture risk. new and worsening vertebral fractures was signifi cantly Estrogens are considered by many to be “antiresorptive reduced, but raloxifene has not been shown to have an agents”; however, they reduce the rates of both bone effect on hip and nonvertebral fractures. Confi rming a resorption and bone formation but reduce resorption reduction in breast cancer noted in the osteoporosis more than formation. study, raloxifene was shown in the Study of Tamoxifen In summary, despite its important role in physiology and Raloxifene (STAR) trial to reduce the risk of breast and pathophysiology, estrogen is not recommended for cancer in postmenopausal women at increased risk of prevention or treatment of postmenopausal osteoporosis, breast cancer and in postmenopausal women with osteo- but should provide protection against bone loss and frac- porosis. Raloxifene does not stimulate the endometrium. tures for women who require estrogen from relief of Although raloxifene has effects on lipids that suggest it menopausal symptoms. might be cardioprotective (decreased triglycerides, total, and LDL cholesterol), no benefi t was shown in the large Raloxifene Use for the Heart (RUTH) trial. The occur- ESTROGEN AGONISTS/ANTAGONISTS rence of stroke was not different between raloxifene and placebo groups; however, there were more fatal strokes (SELECTIVE ESTROGEN RECEPTOR in the raloxifene group. Enthusiasm for the use of raloxi- MODULATORS OR SERMS) fene has been limited because of the lack of evidence for protection against hip and other nonvertebral fractures, Tamoxifen, widely used for treatment and prevention of as well as side effects and safety concerns (increased breast cancer, was thought of as an antiestrogen, based menopausal symptoms, increased risk of venous throm- on the concept that a compound that blocked estrogen boembolic events such a deep vein thrombosis, pulmo- receptors in breast tissue would reduce the risk of recur- nary embolus, and retinal vein thrombosis). The increase rence or spread of breast cancer. Clinical trials of tamoxi- in venous thromboembolic events is similar to estrogen fen in postmenopausal women that were expected to and is highest during the initial months of treatment. show acceleration of bone loss actually showed modest Several estrogen agonists/antagonists have fallen by gains in BMD, as well as decreases in bone turnover the wayside, while a few have made it into Phase 3 trials markers, establishing that this compound blocks the for osteoporosis. Commercialization of arzoxifene was effect of estrogen in some tissues but acts like estrogen abandoned because of lack of protection against hip and in others. other nonvertebral fractures. Lasofoxifene and bazedoxi- Rather than being an antiestrogen, tamoxifen and func- fene are approved in Europe but not in the U.S. Bazedoxi- tionally related compounds are classifi ed as estrogen fene has been studied in combination with estrogen, with agonists/antagonists, also known as selective estrogen the estrogen improving vasomotor symptoms and vulvo- receptor modulators (SERMs) and tissue-selective estro- vaginal atrophy. gens. They bind with estrogen receptors, activating estro- gen pathways in some tissues and blocking them in others. Effects appear to be similar and consistent in some tissues (e.g., antagonists to estrogen in breast tissue CALCITONIN and partial agonists in bone) but compound-specifi c in others (e.g., some stimulate the endometrium, while In humans, calcitonin is a 32-amino acid peptide pro- others are neutral, and still others are antagonists). The duced by specialized C cells in the thyroid. Osteoclasts ideal compound would relieve menopausal symptoms express receptors for calcitonin and respond to calcitonin (including vasomotor symptoms and vaginal dryness), with a rapid decrease in resorptive capacity. Unlike estro- maintain or increase BMD and reduce the risks of frac- gen defi ciency in adults, which has been shown to cause tures at all skeletal sites, as well as reducing the risks of bone loss and increase fracture risk, there is no evidence cardiovascular disease, dementia, genitourinary prob- for an important physiologic effect of calcitonin in adults, lems, and breast, endometrial, and ovarian cancer without and patients with calcitonin defi ciency (i.e., after total increasing the risk of venous thromboembolic events. thyroidectomy) show no changes in skeletal status or This “holy grail” has not yet been attained. Several mineral homeostasis. As a pharmacologic agent, human, promising compounds failed or have been limited because eel, and salmon calcitonin have all been tried, but syn- of safety concerns (tamoxifen increases the risk of endo- thetic salmon calcitonin has been the major product in metrial hyperplasia and carcinoma) or because the skel- clinical use. Given by subcutaneous injection, salmon etal effects were limited to reducing fractures in the calcitonin has been use to treat Paget ’ s disease, hypercal- spine, with no effect on nonvertebral sites. cemia, and osteoporosis but with signifi cant side effects Raloxifene, the fi rst of these agents specifi cally mar- of injection site reactions, fl ushing, and nausea in up to keted for positive bone effects and given orally in a dose 20% of patients. In women with osteoporosis who were of 60 mg daily, was shown to prevent bone loss in recently at least 5 years postmenopausal, nasal spray salmon cal- menopausal women and increase BMD in postmeno- citonin in a dose of 200 IU daily was shown to reduce the 410 Osteoporosis risk of vertebral fracture and was well tolerated; however, 3. Cauley JA , Robbins J , Chen Z , Cummings SR , Jackson lower (100 IU/day) and higher (400 IU/day) doses did not RD , LaCroix AZ , LeBoff M , Lewis CE , McGowan J , show an anti-fracture effect. Changes in BMD and bone Neuner J , Pettinger M , Stefanick ML , Wactawski-Wende turnover markers were minimal. There have been small J , Watts NB , Women ’ s Health Initiative Investigators . trials of salmon calcitonin treatment in men with osteo- 2003 . Effects of estrogen plus progestin on risk of frac- porosis and men and women with glucocorticoid-induced ture and bone mineral density: The Women ’ s Health osteoporosis. Initiative randomized trial . JAMA 290 : 1729 – 1738 .