STUDY QUESTION

研究问题

What is the frequency of, and predictors for, osteoporosis, fractures, and osteoporosis management (investigation, treatment) in women with premature ovarian insufficiency (POI; menopause <40 years) and early menopause (EM; menopause 40–44years)?

在卵巢功能不全（POI；绝经年龄<40岁）和早期绝经（EM；绝经年龄介于40- 44岁）女性中，骨质疏松症、骨折和骨质疏松症管理（预防和治疗）的发生率和预测因素是什么？

SUMMARY ANSWER

结论

Over the 23-year follow-up duration, at a mean age of 68 years, women with POI/EM had higher osteoporosis/fracture risk and prevalence, higher osteoporosis screening and anti-osteoporosis medication use compared to women with usual age menopause; increasing age was predictive of increased risk of osteoporosis/fracture and menopause hormone therapy (MHT) prior to or at study entry (aged 45–50 years) was protective.

在为期23年的跟踪观察期内，平均年龄为68岁的POI/EM女性与正常绝经年龄的女性相比，POI/EM女性的骨质疏松/骨折风险和患病率较高，骨质疏松筛查和抗骨质疏松药物使用率较高。年龄增加可预测骨质疏松/骨折风险增加，并且在进入研究之前或进入研究时（年龄45-50岁）进行绝经激素治疗（MHT）具有保护作用。

WHAT IS KNOWN ALREADY

已知内容

Women with POI/EM have increased risk of osteoporosis and fractures with limited data regarding risk factors for reduced bone density and fractures. Clinical guidelines recommend screening with dual X-ray absorptiometry (DXA) and treatment with MHT for most women with POI/EM to reduce osteoporosis and fracture risk; however, studies indicate gaps in osteoporosis knowledge, guideline uptake, and management adherence by clinicians and women.

患有POI/EM的女性患骨质疏松症和骨折的风险增加，有关骨密度降低和骨折的风险因素的数据有限。临床指南建议对大多数患有POI/EM的女性进行双重X线吸收测定法（DXA）筛查和MHT治疗，以降低骨质疏松症和骨折风险。然而，研究表明临床医生和女性在骨质疏松症知识，指南学习和管理依从性方面存在差距。

STUDY DESIGN, SIZE, DURATION

研究设计、规模、持续时间

The Australian Longitudinal Study on Women’s Health is a prospective longitudinal study of Australian women. This study uses the cohort of women born between 1946 and 1951, surveyed nine times between 1996 and 2019. Data from the Australian administrative health records, including hospital admissions data (fractures, osteoporosis), Medicare Benefits Schedule (DXA), and the Pharmaceutical Benefits Scheme (PBS; MHT, anti-osteoporosis medication, available only from 2002) were linked to survey data.

澳大利亚妇女健康纵向研究是一项针对澳大利亚妇女的前瞻性纵向研究。这项研究使用了1946年至1951年出生的女性队列，在1996年至2019年期间进行了9次调查。来自澳大利亚行政健康记录的数据，包括入院数据（骨折、骨质疏松症）、医疗保险福利计划（DXA）和药物福利计划（PBS; MHT，抗骨质疏松症药物，仅从2002年开始提供），与调查数据相关联。

PARTICIPANTS/MATERIALS, SETTING, METHODS

参与者/材料、设置、方法

Survey respondents with self-reported age of menopause were included. POI/EM was defined as menopause <45 years. T-test or chi-square were used for comparisons at baseline (P < 0.05 indicates significance). Generalized estimating equations for panel data explored predictors for the longitudinal outcomes of osteoporosis, fractures, DXA rates, MHT use, and anti-osteoporosis medication (in women with osteoporosis/fracture, from Survey 4 onwards only). Univariable regression was performed, and variables retained where P < 0.2, to form the multivariable model, and bootstrapping with 100 repetitions at 95% sampling of the original dataset to ensure robustness of results.

参与者包括自我报告绝经年龄的调查对象。POI/EM定义为绝经年龄<45岁。基线特征使用T检验或卡方检验进行比较（P<0.05表示差异具有统计学意义）。面板数据的广义估计方程探索了骨质疏松、骨折、DXA率、MHT使用和抗骨质疏松药物（骨质疏松/骨折女性，仅从调查第4项开始）纵向结局的预测因素。进行单变量回归分析，并且在P<0.2时保留变量，以形成多变量模型，并且在原始数据集的95%采样下重复进行100次，以确保结果的稳定性。

MAIN RESULTS AND THE ROLE OF CHANCE

主要结果

Eight thousand six hundred and three women were included: 610 (7.1%) with POI/EM. Mean (SD) baseline age was 47.6 (1.45) years in the entire cohort and mean (SD) age of menopause was 38.2 (7.95) and 51.3 (3.04) years in women with POI/EM and usual age menopause, respectively (P < 0.001). Over the 23 years, of women with POI/EM, 303 (49.7%) had osteoporosis/fractures, 421 (69.0%) had DXA screening, 474 ever used MHT (77.7%), and 116 (39.1%) of those with osteoporosis/fractures used anti-osteoporosis medication. Of women with usual age menopause, 2929 (36.6%) had osteoporosis/fractures, 4920 (61.6%) had DXA screening, 4014 (50.2%) used MHT, and 964 (33.0%) of those with osteoporosis/fractures used anti-osteoporosis medication. Compared to women with menopause at age ≥45 years and after adjusting for other risk factors, women with POI/EM had increased risk of osteoporosis (odds ratio [OR] 1.37; 95% CI 1.07–1.77), fractures (OR 1.45; 1.15–1.81), DXA testing (OR 1.64; 1.42–1.90), MHT use (OR 6.87; 5.68–8.30), and anti-osteoporosis medication use (OR 1.50; 1.14–1.98). In women with POI/EM women, increasing age was associated with greater risk of osteoporosis/fracture (OR 1.09; 1.08–1.11), and MHT prior to or at study entry (aged 45–50 years), was protective (OR 0.65, 0.45–0.96). In women with POI/EM, age (OR 1.11; 1.10–1.12), fractures (OR 1.80, 1.38–2.34), current smoking (OR 0.60; 0.43–0.86), and inner (OR 0.68; 0.53–0.88) or outer regional (OR 0.63; 0.46–0.87) residential location were associated with DXA screening. In women with POI/EM, increasing age (OR 1.02; 1.01–1.02), and currently consuming alcohol (OR 1.17; 1.06–1.28), was associated with having ever used MHT. In the 299 women with POI/EM and osteoporosis/fractures, only 39.1% ever received treatment with an anti-osteoporosis medication. Increasing age (OR 1.07; 1.04–1.09) and lower BMI (OR 0.95; 0.92–0.98) were associated with greater likelihood of treatment with anti-osteoporosis medication.

一共8603名女性被纳入研究，610名女性（占比7.1%）患有POI/EM。整个队列的平均（SD）基线年龄为47.6岁（1.45），POI/EM女性和正常年龄绝经女性的平均（SD）绝经年龄分别为38.2岁（7.95）和51.3岁（3.04）（P<0.001）。在23年中，303例（49.7%）POI/EM女性患有骨质疏松/骨折，421例（69.0%）进行了DXA筛查，474例曾使用MHT（77.7%），116例（39.1%）骨质疏松/骨折患者使用抗骨质疏松药物。在正常年龄绝经的女性中，2929例（36.6%）患有骨质疏松症/骨折，4920例（61.6%）进行了DXA筛查，4014例（50.2%）使用了MHT，964例（33.0%）骨质疏松症/骨折患者使用了抗骨质疏松症药物。与绝经年龄≥45岁的女性相比，在调整其他风险因素后，POI/EM女性患骨质疏松症的风险（比值比[OR] 1.37; 95% CI 1.07-1.77），骨折（OR 1.45; 1.15-1.81），DXA检测（OR 1.64; 1.42-1.90），MHT使用（OR 6.87; 5.68-8.30）和抗骨质疏松药物使用（OR 1.50; 1.14-1.98）均增加。在患有POI/EM的女性中，年龄增加与骨质疏松/骨折的风险增加相关（OR 1.09; 1.08-1.11），在进入研究之前或进入研究时（年龄45-50岁），使用MHT具有保护作用（OR 0.65，0.45-0.96）。在POI/EM女性中，年龄（OR 1.11; 1.10-1.12），骨折（OR 1.80，1.38-2.34），当前吸烟（OR 0.60; 0.43-0.86）和内部（OR 0.68; 0.53-0.88）或外部区域（OR 0.63; 0.46-0.87）居住位置与DXA筛查相关。在POI/EM女性中，年龄增加（OR 1.02; 1.01-1.02）和目前饮酒（OR 1.17; 1.06-1.28）与曾经使用过MHT相关。在299名患有POI/EM和骨质疏松症/骨折的女性中，只有39.1%的人接受过抗骨质疏松症药物治疗。年龄增加（OR 1.07; 1.04-1.09）和BMI降低（OR 0.95; 0.92-0.98）与抗骨质疏松药物治疗的可能性增加相关。

LIMITATIONS, REASONS FOR CAUTION

局限性，谨慎的原因

Survey data including age of menopause were self-reported by participants; fracture questions were not included in the 2001 survey, and location or level of trauma of self-reported fractures was not asked. Additional risk/protective factors such as vitamin D status, calcium intake, and exercise were not able to be included. Due to sample size, POI and EM were combined for all analyses, and we were unable to differentiate between causes of POI/EM. PBS data were only available from 2004, and hospital admissions data were state-based, with all of Australia were only available from 2007.

包括绝经年龄的调查数据是由参与者自我报告的；骨折问题未包括在2001年的调查中，自我报告的骨折的位置或创伤程度未被询问。其他风险/保护因素，如维生素D状态，钙摄入量和运动无法纳入。由于样本量的原因，所有分析均合并POI和EM，我们无法区分POI/EM的原因。PBS数据仅从2004年起可用，医院入院数据以州为基础，澳大利亚所有地区仅从2007年起可用。

WIDER IMPLICATIONS OF THE FINDINGS

研究意义

This study supports previous literature indicating increased risk of osteoporosis and fractures in women with POI, and adds evidence for women with POI/EM, where there was a relative paucity of data. This is the first study to analyse a variety of clinical and demographic risk factors for osteoporosis and fractures in women with POI/EM, as well as analysing investigation and treatment rates. In these women, using MHT prior to or at study entry, aged 45–50 years, was protective for osteoporosis/fractures; however, having ever used MHT was not, highlighting the importance of early treatment with MHT in these women to preserve bone strength. Although women with POI/EM and osteoporosis or fractures were more likely to use anti-osteoporosis medications than those with usual age menopause, overall treatment rates are low at <40%, demonstrating a significant treatment gap that should be addressed to reduce future fracture risk.

这项研究支持既往文献所示POI女性骨质疏松和骨折的风险增加，并为POI/EM女性相关研究提供了更多证据，因为这方面数据相对较少。这是第一项分析POI/EM女性骨质疏松和骨折的各种临床和人口统计学风险因素以及分析调查和治疗率的研究。在这些年龄在45-50岁的女性中，在研究入组前或入组时使用MHT对骨质疏松症/骨折具有保护作用。然而，曾经使用过MHT的女性则没有，凸显了这些女性早期使用MHT治疗以保持骨强度的重要性。尽管患有POI/EM和骨质疏松症或骨折的女性比正常年龄绝经的女性更有可能使用抗骨质疏松药物，但总体治疗率较低，<40%，表明需要解决这种明显的治疗差距，以降低未来骨折的风险。

参考文献：

A R Jones, J Enticott, P R Ebeling, G D Mishra, H T Teede, A J Vincent, Bone health in women with premature ovarian insufficiency/early menopause: a 23-year longitudinal analysis, Human Reproduction, Volume 39, Issue 5, May 2024, Pages 1013–1022, https://doi.org/10.1093/humrep/deae037