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

避孕药 DMPA 引起的骨质流失：年轻女性有毒金属铅暴露的新来源

• 批准号: 10714991
• 负责人: Kristen Upson
• 金额: $ 60.56万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714991
• 关键词: 25-hydroxyvitamin D; Adherence; Adolescent; Adult; Affect; Age; Air; Bone Density; Bone remodeling; Calcium ion; Cardiovascular Diseases; Cessation of life; Child; Chronic Kidney Failure; Circulation; Communities; Contraceptive Agents; Contraceptive methods; Cross-Sectional Studies; Cyclophosphamide; Data; Dietary Calcium; Dose; Dual-Energy X-Ray Absorptiometry; Dust; Estrogens; Food; Funding; Glean; Goals; HIV; Half-Life; Health; Human; Hypertension; Ingestion; Inhalation; Injectable; Injections; Investments; Lactation; Lead; Lead levels; Location; Longitudinal Studies; Measurement; Measures; Medroxyprogesterone 17-Acetate; Modeling; Monitor; National Institute of Child Health and Human Development; Oral; Organ; Ovarian; Participant; Plasma; Predisposition; Prevention; Production; Prospective Studies; Reporting; Research; Serum; Source; Tenofovir; Testing; Time; Toxic effect; Trabecular Bone Score; Uganda; Urine; Vertebral column; Visit; Vitamin D; Water; Woman; biological specimen archives; body system; bone; bone imaging; bone loss; bone turnover; calcium intake; chronic Pb exposure; cigarette smoke; cognitive function; condoms; contaminated water; dietary; follow-up; hip bone; hormonal contraception; indexing; lead acetate; lead exposure; negative affect; novel; pre-exposure prophylaxis; pregnancy prevention; prospective; side effect; skeletal; substantia spongiosa; toxic metal; unintended pregnancy; urinary; young woman

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.

项目概要/摘要 该提案的主要目的是检查长效甲羟孕酮的意外后果- 醋酸黄体酮 (DMPA) 引起的骨质流失：循环有毒金属铅水平增加。二甲基苯丙胺 (DMPA) 是一种 全球数百万女性使用的重要避孕选择，其中 54% 的女性采取避孕措施 乌干达。然而，使用 DMPA 的一个已确定的副作用是骨质流失，骨矿物质密度最大 (BMD) 下降发生在使用的头两年内。我们假设积极的骨骼效应 DMPA 的使用增加了骨骼中储存的铅向血浆的释放，导致循环铅水平增加。 慢性铅暴露在世界范围内很常见，数千人的社区铅暴露率很高 遍布美国和全球（包括乌干达）的地点。由于超过 90% 的铅来自外源性暴露 储存在骨骼中，骨骼成为内源性铅源。铅被迁移到血浆中，特别是在 骨转换和骨丢失较高的时期。血浆中含有最具生物活性的铅成分 循环。不存在安全的铅含量；即使在低剂量下，铅也会对所有器官系统产生不利影响，因为它 具有置换钙离子的能力。 DMPA-先导关联仅在两项横断面研究中进行了测试， 这两项研究都报告了关联。我们建议前瞻性地调查 DMPA 的使用和流通 基于 NICHD 资助的坎帕拉女性骨骼研究 (KWBS)（R01HD089843，PI： 蕾妮·赫夫隆）。 KWBS 是一项针对乌干达 499 名 16-25 岁女性的为期 2 年的纵向研究，正在进行调查 同时启动 DMPA 和替诺福韦 HIV 暴露前预防 (PrEP) 对骨质流失的影响。 参与者每 3 个月完成一次研究访问，并通过双能 X 射线吸收测定法进行监测 每年进行一次 BMD 和小梁微结构 (DXA) 扫描，以及骨转换、雌激素和骨代谢标志物 24 个月内 5 个时间点的维生素 D。利用存档的样本，我们将在以下位置测量这些标记： 4 个额外的时间点可产生季度测量结果。由于尿液中的铅含量表明具有生物活性 循环（血浆）铅，我们将在 24 个月内每 3 个月测量一次尿铅浓度。我们将 利用这些广泛的数据来实现以下目标：(1) 评估青少年和年轻女性是否 与安全套使用者 (n=231) 相比，初始 DMPA (n=268) 的循环铅水平高于 24 岁以上 月； (2) 研究骨重塑和铅从骨释放到血浆的损失机制 二甲基苯丙胺的使用。我们将检查 DMPA 用户和非用户的季度骨重塑指数、年度腰椎指数 脊柱和总髋部 BMD、年度骨小梁评分、季度雌激素水平和铅水平变化 超过 24 个月； (3) 探讨膳食钙摄入量增加和维生素 D 充足状态是否会降低 骨骼将铅动员到血浆中。这项强有力的前瞻性研究建立在 NICHD 的承诺之上 了解避孕对人类健康的影响，包括 DMPA 引起的骨质流失，并将 生成重要数据，为青少年、成人和哺乳期妇女提供更安全的避孕措施提供信息。