OSTEOPOROSIS New Data Enhance Our Understanding of the Effects of Some Contraceptives and Key Serms on the Skeletal Health of Users

UPDATE

OSTEOPOROSIS New data enhance our understanding of the effects of some contraceptives and key SERMs on the skeletal health of users

›› Steven R. Goldstein, MD Dr. Goldstein is Professor of Obstetrics and Gynecology at New York University School of Medicine and Director of Gynecologic Ultrasound and Co-Director of Bone Densitometry at NYU Medical Center in New York City. He serves on the OBG Management Board of Editors.

Th e author reports that he serves on the advisory boards of Amgen, Boehringer Ingelheim, Depomed, Eli Lilly, and Novo Nordisk. He is a speaker for the Alliance for Bone Health, Eli Lilly, and Warner Chilcott.

Some hormonal contraceptives

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Berenson AB, Rahman M, Breitkopf CR, Bi LX. Eff ects of colleagues reported a 7.8% increase in BMD depot medroxyprogesterone acetateCopyright and 20-microgramFor personalover 5 years amonguse womenonly 19 to 22 years oral contraceptives on bone mineral density. Obstet old who did not use OCs, compared with no IN THIS Gynecol. 2008;112:788–799. ARTICLE change in BMD among women who used OCs American College of Obstetricians and Gynecologists. containing 20 μg of ethinyl estradiol.2 How does denosumab ACOG Committee Opinion. No. 415. September 2008. compare with Depot medroxyprogesterone acetate and bone eff ects. DMPA, BMD, and the FDA Obstet Gynecol. 2008;112:727–730. alendronate? Th e deleterious eff ect of DMPA on BMD page 26 is particularly relevant in perimenopausal woman’s contraceptive choice may women, who have already begun to experi- A aff ect her bone mineral density ence the age-related decline in BMD that Another SERM (BMD)—particularly if she chooses depot starts around the age of 30. Th e eff ect is also bites the dust medroxyprogesterone acetate (DMPA) or troubling in adolescents, who normally ex- page 27 a very-low-dose oral contraceptive (OC) as perience a large accretion of bone during her method. the teen and early adult years. TSEC, a novel In the case of DMPA, studies have shown In 2004, the US Food and Drug Admin- compound, enters that its use for 2 years signifi cantly impairs istration (FDA) added a boxed warning to development BMD at the hip and spine, regardless of the DMPA labeling advising women to limit their patient’s age, although BMD usually re- use of the drug to 2 years. Since that time, page 27 bounds after discontinuation of the drug.1 other studies have found that BMD increas- In the case of very-low-dose OCs, there es to a greater degree among past users of is evidence that young women who use a pill DMPA than among never users—suggesting that contains only 20 μg of ethinyl estradiol that DMPA-related bone loss is reversible. have a lower increase in BMD than do women the same age who do not use hormonal con- ACOG: DMPA can be used traception. (OCs that contain a higher dos- longer than 2 years in some age of ethinyl estradiol have not been shown In September 2008, the American College to hamper BMD.) A study by Polatti and of Obstetricians and Gynecologists (ACOG)

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FIGURE DMPA-related bone loss is largely reversible

Hip Spine

Normal Loss of bone density

Depot medroxyprogesterone acetate (DMPA) is associated with a loss of bone mineral density at the hip and spine. Once the drug is discontinued, however, bone density appears to recover at least partially at both sites.

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released a committee opinion acknowledg- loss. Th e committee pointed out, however, ing the association between DMPA and BMD that “current evidence suggests that partial or full recovery of BMD occurs at the spine ACOG: Given the and at least partial recovery occurs at the hip efﬁ cacy of DMPA, WHAT THIS EVIDENCE MEANS after discontinuation of DMPA” (FIGURE). the drug may be a FOR PRACTICE Th e ACOG opinion also noted that, good option in some “given the effi cacy of DMPA, particularly for Use of very-low-dose oral contraception populations, populations such as adolescents, for whom (20 μg ethinyl estradiol) may lead to contraceptive adherence can be challenging, despite its effects a small amount of bone loss or failure or for those who feel they could not com- on bone density of bone accretion. Use of depot ply with a daily contraceptive method or a medroxyprogesterone acetate (DMPA) method that must be used with each act of is associated with a greater degree of intercourse, the possible adverse eff ects of bone loss, but this loss is largely reversible at the spine. Use of a 20-μg DMPA must be balanced against the signifi - oral contraceptive (OC) after discon- cant personal and public health impact of tinuation of DMPA may slow bone unintended pregnancy.” recovery. Th e committee recommended that, de- As ACOG has indicated, concerns spite concerns about bone loss, practitioners about skeletal health should not inﬂ uence should not hesitate to prescribe DMPA. Nor the decision to initiate or continue DMPA. should they limit its use to 2 consecutive Likewise, such concerns should not lead years or perform BMD monitoring solely to restrictions on the use of OCs in teens in response to DMPA use. “Any observed or adult women. However, clinicians may short-term loss in BMD associated with wish to take bone effects into consider- DMPA use may be recovered and is unlikely ation when choosing the estrogen dos- age of OCs for women younger than 30 to place a woman at risk of fracture during who have yet to attain peak bone mass. use or in later years,” the committee opinion noted. CONTINUED ON PAGE 24

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Study explores bone gains after DMPA OCs (20 μg ethinyl estradiol), compared with Berenson and associates measured BMD a gain of 1.9% at the lumbar spine and 0.6% every 6 months for as long as 3 years in 703 at the femoral neck in nonusers of hormonal white, African-American, and Hispanic wom- contraception. en who used an OC, DMPA, or nonhormonal Women who made a transition from contraception. Th ey also measured BMD for DMPA to a very-low-dose OC recovered bone up to 2 additional years in 68 women who mass slowly. After DMPA was discontinued, discontinued DMPA. Th ey found no diff er- women who selected nonhormonal contra- ences between races—although they did fi nd ception recovered BMD (4.9% at the spine, the expected DMPA-associated bone loss. 3.2% at the femoral neck)—unlike those who Th ey also found a small amount of bone chose a very-low-dose OC, who regained loss (0.5% at the lumbar spine and 1.3% at BMD at the spine (2.3%) but not the femoral the femoral neck) in users of very-low-dose neck (–0.7%).

Denosumab nears FDA approval for treatment of osteoporosis

Cummings SR, San Martin J, McClung MR, et al; Trial: Denosumab versus placebo FREEDOM trial. Denosumab for prevention of Cummings and colleagues reported the fi nd- fractures in postmenopausal women with ings of the Fracture Reduction Evaluation of osteoporosis. N Engl J Med. 2009;361:756–765. Denosumab in Osteoporosis Every 6 Months Kendler DL, Roux C, Benhamou CL, et al. Eff ects of (FREEDOM) trial, which involved 7,868 New vertebral denosumab on bone mineral density and bone turn- women 60 to 90 years old who had a BMD over in postmenopausal women transitioning from T-score between –2.5 and –4.0 at the lumbar fractures occurred alendronate therapy. J Bone Miner Res. 2009 [Epub at a rate of 2.3% ahead of print]. spine or total hip. Participants were random- among women ly assigned to receive 60 mg of denosumab or Miller PD, Bolognese MA, Lewiecki EM, et al, for the taking denosumab, placebo subcutaneously every 6 months for Amg Bone Loss Study Group. Eff ect of denosumab on 36 months. Th e primary endpoint was new versus 7.2% among bone density and turnover in postmenopausal women vertebral fracture. Secondary endpoints in- those taking placebo with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized cluded nonvertebral and hip fractures. blinded phase 2 clinical trial. Bone. 2008;43:222–229. Findings included: • Denosumab reduced the risk of new, n FDA panel advising the Division of radiographically detected vertebral AReproductive and Urologic Products fracture, with a cumulative incidence of voted to approve denosumab (proposed 2.3%, versus 7.2% in the placebo group brand name: Prolia) as a treatment for os- (risk ratio, 0.32; P<.001). teoporosis. Th e drug is a fully human mono- • Denosumab reduced the risk of hip clonal antibody to the receptor activator of fracture, with a cumulative incidence nuclear factor-B ligand (RANKL), a cytokine of 0.7% in the denosumab group, versus that is essential for the formation, func- 1.2% in the placebo group (hazard ratio, tion, and survival of osteoclasts. By binding 0.60; P=.04). RANKL, denosumab prevents interaction • Denosumab reduced the risk of nonver- between RANKL and its receptor, RANK, on tebral fracture, with a cumulative inci- osteoclasts and osteoclast precursors and dence of 6.5% in the denosumab group, thereby inhibits osteoclast-mediated bone versus 8.0% in the placebo group (haz- resorption. Its eff ects are reversible. ard ratio, 0.80; P=.01). CONTINUED ON PAGE 26

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• Th ere was no increase in the risk of can- women continuing on alendronate cer, infection, cardiovascular disease, (P<.0001). delayed fracture healing, or hypocalce- • Women making a transition to deno- mia, and no cases of osteonecrosis of the sumab also gained signifi cantly more jaw or adverse reaction to injection of BMD at 12 months at the lumbar spine, the drug. femoral neck, and the distal third of the radius (all P<.0125). How does denosumab compare • Th e transition to denosumab reduced with alendronate? bone turnover to a greater degree than Kendler and associates explored a clini- did continuing alendronate. cally relevant question: What are the eff ects of switching from a bisphosphonate (in this What happens when denosumab case, alendronate) to denosumab? is discontinued? Th ey studied 504 postmenopausal Miller and colleagues randomized post- women who were at least 55 years old, had menopausal women who had a lumbar spine a T-score between –2 and –4, and had been T-score of –1.8 to –4.0 or a proximal femur taking alendronate for at least 6 months. T-score of –1.8 to –3.5 to one of the following Th ese women were randomized in double- arms: blinded, double-dummy fashion to 60 mg of • denosumab every 3 months (6, 14, or subcutaneous denosumab or a continuation 30 mg) of 70 mg of oral alendronate. Follow-up was • denosumab every 6 months (14, 60, 100, 12 months. or 210 mg) Findings included: • open-label oral alendronate every week • Among the women making a transition (70 mg) to denosumab, total hip BMD increased • placebo. by 1.9% at 12 months, versus 1.05% in After 24 months, women taking deno- Among women sumab either: who switched from • continued treatment at 60 mg every alendronate to WHAT THIS EVIDENCE MEANS 6 months for an additional 24 months FOR PRACTICE denosumab, BMD • discontinued therapy increased by 1.9% • discontinued treatment for 12 months Among postmenopausal women who and then reinitiated denosumab at at the hip over 12 have low bone mineral density (BMD), 60 mg every 6 months for an additional months, versus long-term treatment with denosumab 12 months. 1.05% in those leads to gains in BMD and a reduction of Th e placebo cohort was maintained who continued on markers of bone turnover. These effects throughout this period. alendronate are fully reversible upon discontinuation of the drug, but reoccur when treatment is Continuous, long-term denosumab in- restored. creased BMD at the lumbar spine (9.4% to In addition, switching from alendro- 11.8%) and total hip (4.0% to 6.1%). In con- nate to denosumab produces a greater trast, discontinuation of denosumab was as- reduction in bone turnover than does sociated with a decrease in BMD of 6.6% at continuation on the bisphosphonate. the lumbar spine and 5.3% at the total hip Denosumab is a safe, extremely potent within the fi rst 12 months. Retreatment with agent that will undoubtedly ﬁ nd a place denosumab increased lumbar spine BMD in the ObGyn armamentarium, where it by 9% from the original baseline values. will join bisphosphonates, selective Levels of bone turnover markers increased estrogen receptor modulators, and hormone therapy. The long dosing upon discontinuation of denosumab and interval (every 6 months) should help decreased with retreatment. Adverse events increase compliance. occurred at similar rates in all treatment groups.

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Bolognese M, Krege JH, Utian WH, et al. or low bone mass to receive 20 mg invasive breast cancer in post- Effects of arzoxifene on bone mineral density of arzoxifene or placebo daily for menopausal women, “the study and endometrium in postmenopausal women 2 years. failed to demonstrate a statisti- with normal or low bone mass. J Clin Endo- crinol Metab. 2009;94:2284–2289. The trial also found that changes cally signifi cant difference in key in breast density were neutral or secondary effi cacy endpoints, such slightly decreased in the arzoxifene as nonvertebral fractures, clinical The benzothiophene derivative group, and there was no evidence of vertebral fractures, cardiovascu- arzoxifene, which has been in endometrial hyperplasia or carci- lar events, and cognitive func- development for the prevention noma, based on central review of tion, compared with placebo.” and treatment of osteoporosis, as baseline and follow-up endometrial The release went on to say: “In well as for reduction of the risk of biopsies. Nor were there any signifi - addition, certain adverse events, invasive breast cancer in postmeno- cant differences between groups in including venous thromboembolic pausal women, has been pulled endometrial thickness, as assessed events, hot fl ushes, and gyneco- from the regulatory approval pro- by transvaginal ultrasonography, or logical-related events, were reported cess by its manufacturer, Eli Lilly. in the incidence of uterine polyps, more frequently in the arzoxifene This move is somewhat surprising vaginal bleeding, and hot fl ushes. group, compared with placebo.”5 because, in a phase 3 trial, arzoxifene Nevertheless, Lilly issued a press Arzoxifene therefore joins an signifi cantly increased bone mineral release in late August announcing expanding list of selective estrogen density at the lumbar spine (2.9%) that arzoxifene would not be submit- receptor modulators (SERMs) that and total hip (2.2%), compared with ted to the FDA for regulatory review.5 did not make it out of clinical trials: placebo. It also decreased levels of It appears that, although initial results idoxifene, droloxifene, levormeloxi- biochemical markers of bone from the “pivotal” 5-year, phase 3 fene, and lasofoxifene (approved in metabolism. GJAD “Generations” trial indicated Europe, however), to name a few. In the trial, Bolognese and associ- that the drug had met the primary The fall of arzoxifene again under- ates randomly assigned 331 post- endpoints of signifi cantly reducing scores the notion that “not all menopausal women who had normal the risk of vertebral fracture and SERMs are created equal.”6

TSEC, a novel compound, enters development Lindsay R, Gallagher JC, Kagan R, Pickar JH, with raloxifene and 17β-estradiol. Th e ideal Constantine G. Effi cacy of tissue-selective estrogen SERM–estrogen combination would have the complex of bazedoxifene/conjugated estrogens for positive attributes of both classes of drugs osteoporosis prevention in at-risk postmenopausal women. Fertil Steril. 2009;92:1045–1052. with fewer, or none, of the undesired eff ects. An appropriate TSEC would therefore allevi- ate hot fl ushes, treat vulvar and vaginal atro- lthough raloxifene is the only selective phy, and protect against bone loss without Aestrogen receptor modulator (SERM) stimulating the endometrium and increasing approved by the FDA for prevention and the risk of breast cancer. treatment of osteoporosis, numerous other One third-generation SERM that has SERMs have been explored for this appli- been investigated for its utility in this regard cation. One new category of drug is the tis- is bazedoxifene (BZA), which produced sue selective estrogen complex (TSEC), endometrial thickness and amenorrhea which pairs a SERM with an estrogen. Th is rates comparable to those of placebo. It was previously attempted unsuccessfully also produced greater gains in BMD at the

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lumbar spine in a 2-year, randomized, double-blind, placebo-controlled trial.3 Th e WHAT THIS EVIDENCE MEANS incidence of new vertebral fracture was sig- FOR PRACTICE nifi cantly lower with BZA than with placebo Bazedoxifene is a potential therapeutic in a study of postmenopausal women with agent for menopausal women that may 4 osteoporosis. protect the endometrium while preventing Given these favorable data, a TSEC con- bone loss in a population at higher risk of taining BZA and conjugated equine estrogen osteoporosis. It is not yet approved for this was designed as a potential new compre- indication; further investigation is needed. hensive menopausal therapy. The combination of an estrogen and a selective estrogen receptor modulator to Substudies suggest bazedoxifene potentially relieve vasomotor symptoms, has promise prevent vulvovaginal atrophy, and preserve Lindsay and associates reported on two os- bone mass without stimulating the endometrium or increasing the risk of breast teoporosis substudies of the Selective estro- cancer or venous thromboembolism is gen Menopause and Response to Th erapy very exciting—and just might revolutionize (SMART) Trial. Th e main study, which evalu- treatment of menopausal women. ated the incidence of endometrial hyperplasia at 12 months, will be reported elsewhere; match the placebo, as was raloxifene. Sub- it was a multicenter, double-blind, random- jects were directed to take one tablet orally ized, placebo-controlled phase 3 trial that at approximately the same time each day for enrolled 3,397 women. 2 years. Th e primary outcome for both sub- Substudy I involved women who were studies was a change in BMD at the lumbar more than 5 years postmenopausal, and spine, as measured by dual-energy x-ray Substudy II included women who were be- absorptiometry. tween 1 and 5 years postmenopausal. Eligible In both substudies, BMD increased to a The combination of screened subjects were randomly assigned to greater degree at the lumbar spine and total bazedoxifene and one of the following treatment groups: hip at all BZA-estrogen dosages than with conjugated equine • bazedoxifene (10, 20, or 40 mg), each placebo, and it increased to a greater degree estrogen increased with conjugated equine estrogen (0.625 at the lumbar spine at most BZA-estrogen BMD at the lumbar or 0.45 mg) dosages, compared with raloxifene. • raloxifene (60 mg) Osteocalcin and N-telopeptide signifi - spine and total hip • placebo. cantly decreased at all BZA-estrogen dos- to a greater degree To maintain blinding, the combination ages, compared with placebo, and at most than placebo did of BZA and conjugated equine estrogen was BZA-estrogen dosages, compared with ral- provided as a single, encapsulated tablet to oxifene.

References 1. Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM. 4. Silverman SL, Christiansen C, Genant HK, et al. Effi cacy Change in bone mineral density among adolescent women of bazedoxifene in reducing new vertebral fracture risk in using and discontinuing depot medroxyprogesterone acetate postmenopausal women with osteoporosis: results from a 3-year, contraception. Arch Pediatr Adolesc Med. 2005;159:139–144. randomized, placebo- and active-controlled clinical trial. J Bone 2. Polatti F, Perotti F, Filippa N, Gallina D, Nappi RE. Bone mass Miner Res. 2008;23:1923–1934. and long-term monophasic oral contraceptive treatment in young 5. Based on preliminary phase III GHAD study results, Lilly women. Contraception. 1995;51:221–224. concludes arzoxifene’s clinical profi le does not support regulatory 3. Miller PD, Chines AA, Christiansen C, et al. Eff ects of submission [press release]. Available at http://newsroom.lilly. bazedoxifene on BMD and bone turnover in postmenopausal com/releasedetail.cfm?ReleaseID=403905. Accessed October 2, women: 2-year results of a randomized, double-blind, placebo-, 2009. and active-controlled study. J Bone Miner Res. 2008;23 6. Goldstein SR. Not all SERMs are created equal. Menopause. 525–535. 2006;13:325–327.

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