Impact of Concurrent Initiation of DMPA Contraception and Tenofovir PrEP on Bone Loss in Young Women

摘要 这项建议的主要目标是在同时使用的情况下对骨骼安全性进行全面研究 替诺福韦(TDF)为基础的暴露前预防(PrEP)预防HIV和储存甲羟孕酮 醋酸盐(DMPA)用于避孕。同时使用这些制剂对骨骼的安全性是非常高的 适用于艾滋病毒负担高且经常使用DMPA的环境中的年轻女性，如乌干达。 作为单一的干预措施，这两种药物都能降低骨密度，而骨密度是骨折的关键标志 骨折通常会导致工资损失和经济稳定，这对年轻女性来说是严重的后果。 此外，在25岁之前减少骨量可能会导致峰值骨量减少，这是一种常见的 与晚年骨质疏松性骨折的相关性。撒哈拉以南非洲国家最近批准了基于TDF的PrEP 药品当局将加快其推广速度，研究其与其他药物一起使用时的效果 对于公共卫生信息来说，这是非常及时和重要的。我们假设有直接的联系来自 同时使用TDF和DMPA治疗亚临床肾损伤或雌激素减退所致的骨丢失 综合评估这两条机械路径的标志物。我们将招募400名艾滋病病毒感染者- 在乌干达坎帕拉，16-25岁未受感染的妇女开始使用DMPA和避孕套，并向所有 他们。使用放射学、生化和流行病学方法，将解决以下具体目标： 1)在骨获取的直接调查中，我们将使用双能x射线骨密度仪(Dxa)来评估 同时使用基于TDF的PrEP和DMPA的年轻女性是否获得了超过24小时的较低峰值骨量- 一个月的时间内，有证据表明微结构被破坏，相对于单独使用药物或 两种药物都没有；2)我们将调查年轻女性是否同时使用基于TDF的PrEP和DMPA 经验：1)更高的骨转换率，骨丢失的直接先兆；2)区分两种骨丢失的标志 TDF和DMPA使用与骨量之间的机制途径：亚临床肾损伤和 和3)使用中介分析，我们将确定途径通过的程度 亚临床肾损伤和雌激素减退同时引起女性骨密度改变 使用基于TDF的PrEP和DMPA。这项研究将是第一个全面评估和模拟减排的研究 在骨量方面，骨代谢的变化，以及骨和肾功能与骨代谢之间的通路 在骨骼的关键时间点同时启动PrEP和DMPA而改变的雌激素 年轻女性的成熟。

ABSTRACT The primary objective of this proposal is to conduct a comprehensive study of bone safety with concurrent use of tenofovir (TDF)-based pre-exposure prophylaxis (PrEP) for HIV prevention and depot medroxyprogesterone acetate (DMPA) use for pregnancy prevention. Bone safety with the concurrent use of these agents is extremely relevant for young women in settings with high HIV burden and frequent use of DMPA, such as Uganda. As single interventions, both of these agents are known to reduce bone mineral density, a key marker for fracture risk.Bone fractures often result in lost wages and economic stability, severe consequences for young women. Furthermore, reductions in bone mass before the age of 25 can yield reduced peak bone mass, a frequent correlate of osteoporotic fracture later in life. Recent approvals of TDF-based PrEP from Sub-Saharan African drug authorities will accelerate its roll-out, making studies of its effects when added on top of other agents extremely timely and important for public health messaging. We hypothesize that there are direct links from concurrent TDF and DMPA use to bone loss through subclinical kidney injury or hypoestrogenism and will comprehensively assess markers of both mechanistic pathways. We will enroll a prospective cohort of 400 HIV- uninfected women ages 16-25 years initiating DMPA and condoms in Kampala, Uganda, and offer PrEP to all of them. Using radiologic, biochemical, and epidemiologic methods, the following specific aims will be addressed: 1) In a direct investigation of bone acquisition, we will use dual energy x-ray absorptiometry (DXA) to assess whether young women using TDF-based PrEP and DMPA concurrently attain lower peak bone mass over a 24- month period and have evidence of disrupted microarchitecture, relative to women using either agent singly or neither agent; 2) We will investigate whether young women concurrently using TDF-based PrEP and DMPA experience: 1) higher rates of bone turnover, a direct precursor to bone loss and 2) markers distinguishing two mechanistic pathways between TDF and DMPA use and bone mass: subclinical kidney injury and hypoestrogenism; and 3) Using mediation analysis, we will identify the degree to which the pathways through subclinical kidney injury and hypoestrogenism account for changes in bone density among women concurrently using TDF-based PrEP and DMPA. This study will be the first to comprehensively evaluate and model reductions in bone mass, changes in bone metabolism, and the pathways between bone and kidney function and bone and estrogen that are altered by the simultaneous initiation of PrEP and DMPA during a critical time point of bone maturation for young women.