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

摘要 本提案的主要目的是对同时使用的骨安全性进行全面研究 基于替诺福韦（TDF）的暴露前预防（PrEP）用于预防艾滋病毒和长效甲羟孕酮 醋酸（DMPA）用于预防妊娠。同时使用这些药物的骨安全性极低， 这与艾滋病毒负担高和经常使用DMPA的环境中的年轻妇女有关，如乌干达。 作为单一干预措施，这两种药物都已知会降低骨矿物质密度，这是骨折的关键标志 风险。骨折通常会导致工资损失和经济稳定，对年轻女性造成严重后果。 此外，25岁之前骨量的减少可导致峰值骨量减少，这是一种常见的骨质疏松症。 与日后的骨质疏松性骨折有关。撒哈拉以南非洲国家最近批准的基于TDF-PrEP 药品管理部门将加速其推广，研究其与其他药物一起使用时的效果 对公共卫生信息传递来说非常及时和重要。我们假设有直接的联系， 同时使用TDF和DMPA治疗亚临床肾损伤或雌激素过少引起的骨丢失， 全面评估两种机制途径的标志物。我们将招募400名艾滋病毒感染者- 在乌干达的坎帕拉，16-25岁的未感染妇女开始使用DMPA和避孕套，并向所有 他们使用放射学、生物化学和流行病学方法，将解决以下具体目标： 1)在骨采集的直接调查中，我们将使用双能X射线吸收法（DXA）评估 使用基于TDF-PrEP和DMPA的年轻女性在24小时内是否同时获得较低的峰值骨量， 与单独使用或单独使用药物的女性相比， 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）骨转换率较高，是骨丢失的直接前兆，2）区分两种 TDF和DMPA使用与骨量之间的机制途径：亚临床肾损伤和 低雌激素血症; 3）使用中介分析，我们将确定在何种程度上的途径，通过 亚临床肾损伤和低雌激素血症可同时解释女性骨密度变化 使用基于TDF的PrEP和DMPA。这项研究将是第一个全面评估和模型减少 在骨量，骨代谢的变化，以及骨和肾功能之间的途径和骨， 在骨的关键时间点期间，通过同时启动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.