Contraceptive DMPA-induced bone loss: A novel source of toxic metal lead exposure in young women

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PROJECT SUMMARY/ ABSTRACT The primary objective of this proposal is to examine an unintended consequence of depot medroxy- progesterone acetate (DMPA) induced bone loss: increased circulating toxic metal lead levels. DMPA is an important contraceptive option used by millions of women worldwide, including 54% of contracepting women in Uganda. However, an established side effect of DMPA use is bone loss, with the greatest bone mineral density (BMD) decline occurring during the first two years of use. We hypothesize that the skeletal effects of active DMPA use increase the release of lead stored in bone to plasma, resulting in increased circulating lead levels. Chronic exposure to lead is common worldwide, with high community lead exposure occurring in thousands of locations across the U.S. and globally, including Uganda. As over 90% of lead from exogenous exposure is stored in bone, bone becomes an endogenous lead source. Lead is mobilized to plasma, particularly during periods of higher bone turnover and loss. Plasma contains the most biologically active fraction of lead in circulation. No safe levels of lead exist; even at low doses, lead adversely affects all organ systems, due to its ability to replace calcium ions. The DMPA-lead association has only been tested in two cross-sectional studies, with both studies reporting an association. We propose to prospectively investigate DMPA use and circulating lead levels by building on the NICHD-funded Kampala Women’s Bone Study (KWBS) (R01HD089843, PI: Renee Heffron). KWBS, a 2-year longitudinal study of 499 women ages 16-25 years in Uganda, is investigating the impact of concurrent initiation of DMPA and tenofovir HIV pre-exposure prophylaxis (PrEP) on bone loss. Participants completed study visits every 3 months and were monitored with dual energy x-ray absorptiometry (DXA) scans of BMD and trabecular microarchitecture annually and markers of bone turnover, estrogen, and vitamin D at 5 time points over 24 months. Leveraging archived specimens, we will measure these markers at 4 additional time points to yield quarterly measurements. As lead measured in urine is indicative of bioactive circulating (plasma) lead, we will measure urinary lead concentrations every 3 months over 24 months. We will use this extensive data to achieve the following aims: (1) assess whether adolescent and young women initiating DMPA (n=268) have higher circulating lead levels compared to condom users (n=231) over 24 months; (2) investigate the mechanism of bone remodeling and loss on lead release from bone to plasma with DMPA use. We will examine in DMPA users and non-users quarterly bone remodeling indices, annual lumbar spine and total hip BMD, annual trabecular bone score, and quarterly estrogen levels and lead level change over 24 months; and (3) explore whether greater dietary calcium intake and sufficient vitamin D status reduce skeletal mobilization of lead to plasma. This robust prospective study builds on NICHD’s commitment to understanding the effects of contraception on human health, including DMPA-induced bone loss, and will generate vital data to inform the provision of safer contraception in adolescent, adult, and lactating women.