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.

项目总结/摘要 本提案的主要目的是检查长效甲羟孕酮的非预期后果- 醋酸孕酮（DMPA）诱导的骨丢失：增加循环中有毒金属铅水平。DMPA是一个 世界各地数百万妇女使用的重要避孕选择，其中包括54%的避孕妇女， 乌干达然而，DMPA使用的一个既定副作用是骨丢失，骨密度最大 (BMD)在使用的头两年出现下降。我们假设，骨骼的影响，积极 DMPA的使用增加了储存在骨骼中的铅向血浆的释放，导致循环铅水平增加。 慢性铅暴露在世界范围内很常见，在成千上万的人中， 在美国和全球各地，包括乌干达。由于超过90%的外源性铅暴露是 储存在骨中，骨成为内源性铅源。铅被动员到血浆中，特别是在 高骨转换和丢失的时期。血浆中含有最具生物活性的铅， 流通铅的安全水平是不存在的;即使在低剂量下，铅也会对所有器官系统产生不利影响， 取代钙离子的能力。DMPA与铅的相关性仅在两项横断面研究中进行了测试， 两项研究都报告了相关性。我们建议前瞻性调查DMPA的使用和循环 通过建立在NICHD资助的坎帕拉妇女骨骼研究（KWBS）（R 01 HD 089843，PI： Renee Heffron）。KWBS是对乌干达499名16-25岁妇女进行的一项为期两年的纵向研究， 同时开始DMPA和替诺福韦HIV暴露前预防（PrEP）对骨丢失的影响。 参与者每3个月完成一次研究访问，并通过双能X线吸收测量法进行监测 (DXA)每年扫描骨密度和骨小梁微结构，以及骨转换、雌激素和 维生素D在24个月内的5个时间点。利用存档的标本，我们将测量这些标记， 4个额外的时间点，以产生季度测量结果。由于尿中测得的铅表明 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 利用这一广泛的数据实现以下目标：（1）评估青少年和年轻妇女是否 与24岁以上使用避孕套者（n =231）相比，开始使用DMPA者（n=268）的循环铅水平更高 （2）研究骨重建和骨丢失对铅从骨释放到血浆的机制， DMPA使用。我们将检查DMPA使用者和非使用者的季度骨重建指数，年度腰椎骨重建指数， 脊柱和全髋骨密度、年度骨小梁评分以及季度雌激素水平和铅水平变化 （3）探讨是否更多的膳食钙摄入量和足够的维生素D状态减少 铅的骨骼移动到血浆中。这项强有力的前瞻性研究建立在NICHD承诺的基础上， 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、成年人和哺乳期妇女提供更安全的避孕措施提供信息。