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 may aff ect bone® Dowdendensity Health Media 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) obgmanagement.com Vol. 21 No. 11 | November 2009 | OBG Management 21 For mass reproduction, content licensing and permissions contact Dowden Health Media. 21_r1_OBGM1109 21 10/23/09 3:46:23 PM UPDATE osteoporosis 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. ROB FLEWELL FOR OBG MANAGEMENT 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 22 OBG Management | November 2009 | Vol. 21 No. 11 22_r1_OBGM1109 22 10/23/09 3:46:28 PM UPDATE osteoporosis 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, dis- continued, 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.