Up to 4% of women (1) are affected worldwide by Premature Ovarian Insufficiency (POI), a condition in which cessation of female gonadal function occurs before age forty years. POI is broadly categorised into spontaneous and iatrogenic POI. Spontaneous POI (s-POI) is idiopathic in most cases, but can be associated with chromosomal and genetic defects, environmental factors, autoimmune diseases (most commonly thyroid and adrenal disease) and various infections. In contrast, iatrogenic POI (i-POI) is secondary to medical and surgical causes such as chemotherapy, ionising radiotherapy, or bilateral oophorectomy (2).

POI is associated with increased mortality and morbidity due to the loss of oestrogen’s beneficial effects on various tissues and organs in the body, especially cardiovascular, neurocognitive, and musculoskeletal systems (3). Prompt diagnosis and management of POI and its sequelae can significantly reduce morbidity and mortality in this group.

While there is no unified definition of osteoporosis and osteopenia in adults aged < 50 years, researchers have indicated low bone mass and osteoporosis prevalence to be around 8-15% in women with POI (4, 5); the risk is dependent on the degree and duration of oestrogen deficiency. There is preferential loss of trabecular bone, leading to an almost 26% reduction in lumbar spine (LS) bone mineral density (BMD) compared with age-matched population controls (6). Although the exact prevalence of fractures remains unknown, it is anticipated to be high, with fractures occurring at a younger age (7). Small studies show that oestrogen can maintain and restore bone mineral density (BMD) in POI (8, 9) but the optimal formulation, dose and type of oestrogen replacement therapy (ERT) is unknown. Defining the musculoskeletal phenotype in POI, including BMD, fracture prevalence, body composition and effects of oestrogen on these indices, is important for the optimal management of these women.

Dual-energy X-ray absorptiometry (DXA) is routinely used to assess fracture risk, but it has disadvantages, including two-dimensional projection of areal-BMD (a-BMD), inability to differentiate between trabecular and cortical bone, and underestimation of BMD in women with short stature, such as Turner syndrome (TS). More recently, techniques such as trabecular bone score (TBS), can provide additional information relating to trabecular microarchitecture and are independent predictors of fracture risk.

TBS is computed from LS DXA images and constitutes a textural representation that assesses pixel grey‐level variations in the LS, providing an indirect analysis of trabecular microarchitecture (10). Despite data from longitudinal studies in older populations showing TBS predicts fractures independently of BMD and FRAX^® (11–14), data are limited in women with POI, in premenopausal women, and in younger men. In a small cohort of women with TS, a recognised genetic cause of POI, our group has previously reported an age-related decrease in TBS (15).

With recent insights gained from muscle-bone cross signaling (16), it is now evident that muscle plays an essential role in maintaining and preserving skeletal health. Studies in typical menopausal women suggest an accelerated decline in muscle mass, increase in abdominal adiposity, and reductions in lean body mass (LBM) due to oestrogen deficiency, with preservation in women using ERT (16). However, data in women with POI are scant and there is a growing need to analyse changes in body composition, as well as in bone variables in women with POI.

The aims of this study are to:

1) compare clinical and densitometric data, including skeletal and body composition assessments, between women with normal karyotype POI and age-matched healthy Australian women (controls) from the population-based Geelong Osteoporosis study (GOS), 2) analyse the longitudinal changes in the skeletal and body composition parameters in women with POI; and 3) investigate fracture prevalence in women with POI.

This study demonstrated that women with s-POI had the worst skeletal outcomes, including the lowest BMD at both the hip and spine and highest prevalence of abnormal TBS compared with women with i-POI or control women. Moreover, women in both POI subgroups demonstrated significantly lower lean mass (ALM and ALMI) regardless of cause. A 0.62%/year decline in FN-BMD was observed over 12 years, whereas no significant change was observed in LS-BMD, TBS, or FMI. Continued ERT use conferred a protective effect on both bone and body composition indices, with stable FN BMD and an increase in appendicular lean mass. Furthermore, a significant reduction in TBS of -0.51% was observed in POI women with interrupted ERT use.

An association of hypoestrogenism with impaired bone health has long been established, where researchers have focused on the impact on BMD. Congruent with previous studies of women with various causes of POI (5, 21, 22), our results also demonstrate lower LS and FN BMD in women with POI compared with control women. The reported prevalence of osteoporosis and low bone mass is consistent with the 8-15% reported in previous studies (4, 5).

Our novel finding of increased prevalence of abnormal TBS in s-POI women with normal karyotype is similar to data previously described by our group in a study of 60 women with Turner syndrome (TS), a genetic cause of POI, which showed that a third of these women had abnormal TBS (15). TBS provides an additional tool to predict fracture risk in older adults, including postmenopausal women. However, studies investigating TBS characteristics and its utility in predicting fracture risk in younger populations are limited. The natural trajectory of TBS can be delineated by a few small studies in pediatric and adolescent populations; Shawwa et al. concluded that TBS starts to increase from Tanner stage III in girls (23) and Dowthwaite et al. reported that the mean comparable adult TBS is attained by 12 months post-menarche (24). In a recent study of 565 participants, including 296 females aged between 4-19 years, Guagnelli et al. found that the TBS was highest for 18-year-old females when corrected for bone age, with an average score of 1.701 (25). Most studies in healthy premenopausal women aged between 20-50 years have described a slow decline (26–30) in TBS except for a North American study reporting stable TBS values in women aged 30-45 years, followed by a decrease thereafter (31). Studies assessing TBS in young females with anorexia nervosa have found a positive correlation between TBS and menstrual status (32, 33). The high prevalence of abnormal TBS in POI cohorts suggests an accelerated loss of microarchitectural integrity due to prolonged hypoestrogenism. It is known that the diagnosis of s-POI is often delayed due to its more insidious presentation, leading to late oestrogen commencement, which may explain the higher rates of abnormal TBS compared with those with i-POI in our study (34, 35).

Skeletal parameters remained stable in those women with POI who continued ERT, consistent with previous studies of both postmenopausal (36) and POI women (8, 9). Adverse bone outcomes were observed in POI women who did not use ERT regularly including a reduction in TBS. In contrast, a study of 60 women with TS aged between 20-50 years (15), showed that TBS remained stable over 10 years with ongoing use of ERT. Our findings affirm the role of oestrogen in maintaining BMD and microarchitecture.

Studies of body composition changes in postmenopausal women show increases in body fat mass with the accumulation of central and visceral adiposity, and a decline in appendicular lean body mass (37–40). A 2009 meta-analysis of 23 studies concluded that ERT had small beneficial effect on muscle strength in postmenopausal women (41). In addition, a recent clinical trial in postmenopausal women demonstrated increased muscle mass and function parameters with ERT plus resistance training versus resistance training alone (42). However, data are lacking regarding women with POI (16). Our study’s finding of lower muscle mass including ALM and ALMI in women with s-POI or i-POI is consistent with results from Luo et al., which reported a lower muscle distributing coefficient of the lower limbs (MD) in 240 women with POI compared with peri- or postmenopausal women, not on ERT (43). This contrasts with the case-control study of 140 participants by Freitas et al., which did not observe any difference in the TFM or TLM in women with POI (44); however, the use of ERT for 18 months by these participants may have prevented muscle loss. Similarly, in the longitudinal analysis of our POI cohort, an increase in lean mass (ALM, ALMI) was observed in those with continued ERT use over the follow-up period. Multiple pathophysiological oestrogenic influenced mechanisms potentially contribute to reduced muscle mass including: reduced muscle turnover, defective contractility, increased free radical-mediated apoptosis and impaired bone-muscle cross signaling due to compromised skeletal health in POI (16). Overall, these findings highlight the deleterious effects of oestrogen deficiency on muscle health and potential prevention with ERT.

Limited data are available regarding fracture risk and prevalence in women with POI (7). A case-control study showed an increased prevalence of Colles’ fracture in women with early menopause (45) and findings of increased fracture risk with earlier menopause were also seen Women’s Health Initiative observational study (46). However, prevalent fractures in our study were similar in all three groups, likely explained by our small study size. As fracture risk is time-dependent, increased fracture prevalence in POI women may become significant later in life. We were unable to determine the type of fracture (fragility or traumatic); however, recent data in postmenopausal women indicates increased fracture risk with both fracture types (47).

The strengths of this study include: (i) the use of a novel tool, TBS, for fracture risk assessment, (ii) the presence of an age- and BMI-matched control group for cross-sectional analysis, and (iii) the availability of longitudinal skeletal and body composition data for POI participants. Despite providing important new insights into musculoskeletal health in women with POI, our study also has some limitations. These include: (i) retrospective data collection, (ii) inclusion of BMD and TBS data from one s-POI patient with an L1 fracture could have affected the BMD analysis. However, whether TBS is affected by mild to moderate compression fractures is still debated (48) (iii) small sample size of the longitudinal POI cohort that may have underestimated the effects of ERT on the longitudinal skeletal and body composition parameters; and (iv) lack of a longitudinal control group. The small sample sizes and the use of different ERT preparations by the same woman also precluded the analysis of bone and body composition parameters according to type of ERT and we therefore restricted our analysis to ‘interrupted’ or ‘continued’ ERT use. These considerations highlight the need for adequately powered prospective studies, as currently occurring in the United Kingdom, or randomised clinical trials to answer the important question as to the optimal ERT for bone and muscle health in women with POI. Given the limitation of a small cohort, we could not identify an association between TBS and fractures in women with POI.

In this combined study of skeletal and body composition parameters, we demonstrate that lower BMD and spinal trabecular microarchitectural bone deficits, as assessed by TBS, are more common in POI women than healthy pre-menopausal women. Furthermore, these women are also at risk of losing muscle mass; ERT attenuates these changes. This study highlights the need to view bone and muscle health in unison, especially when bone microarchitectural and muscle assessments can be performed simultaneously with routine BMD assessment using commonly available DXA-based techniques.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

NS, HN, FM, AV, and PE contributed to conception and design of the study. NS and HN organised the database. NS and HN performed the statistical analysis. NS prepared the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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