The Role of Follicle-Stimulating Hormone in Bone Loss During Menopause Transition: A Narrative Review

The menopause transition (MT) may be an opportunity for early intervention to prevent rapid bone loss. To intervene early, we need to be able to prospectively identify pre- and perimenopausal women who are beginning to lose bone. This study examined whether estradiol (E2), or follicle-stimulating hormone (FSH), measured in pre- and perimenopausal women, can predict significant bone loss by the next year. Bone loss was considered significant if bone mineral density (BMD) decline at the lumbar spine (LS) or femoral neck (FN) from a pre- or early perimenopausal baseline to 1 year after the E2 or FSH measurement was greater than the least detectable change. We used data from 1559 participants in the Study of Women's Health Across the Nation and tested E2 and FSH as separate predictors using repeated measures modified Poisson regression. Adjusted for MT stage, age, race/ethnicity, and body mass index, women with lower E2 (and higher FSH) were more likely to lose BMD: At the LS, each halving of E2 and each doubling of FSH were associated with 10% and 39% greater risk of significant bone loss, respectively (p < 0.0001 for each). At the FN, each halving of E2 and each doubling of FSH were associated with 12% (p = 0.01) and 27% (p < 0.001) greater risk of significant bone loss. FSH was more informative than E2 (assessed by the area under the receiver-operator curve) at identifying women who were more versus less likely to begin losing bone, especially at the LS. Prediction was better when hormones were measured in pre- or early perimenopause than in late perimenopause. Tracking within-individual change in either hormone did not predict onset of bone loss better than a single measure. We conclude that measuring FSH in the MT can help prospectively identify women with imminent or ongoing bone loss at the LS. © 2019 American Society for Bone and Mineral Research.

BackgroundThe effects of elevated follicle-stimulating hormone (FSH) levels on physiological changes in the bone remain unclear. This study aimed to clarify the association between FSH concentrations and bone mineral density (BMD) and bone turnover markers (BTM) in late postmenopausal women.MethodsA total of 169 Korean women were enrolled. The participants’ ages ranged from 60 to 84 years (mean age, 69.0±5.1) and reported a mean duration of 19.4±6.6 years since menopause (YSM). The participants showed an average body mass index (BMI) of 24.4±2.8 kg/m2. Age, YSM, estradiol, testosterone, and BMI were confounders in the Pearson’s partial correlation. A test for trends across the quartiles of FSH levels was performed for each variable.ResultsThe mean FSH and estradiol concentrations were 61.5 IU/L and 2.9 pg/mL, respectively. Serum FSH concentration was not significantly associated with BMD (lumbar, r=0.09, P=0.30; total hip, r=0.00, P=0.96; and femoral neck, r=0.05, P=0.62). BTM across the FSH quartiles did not show any trend association (bone-specific alkaline phosphate, P=0.31; cross-linked C-terminal telopeptide of type I collagen, P=0.90). Instead, FSH levels were negatively correlated with BMI (r=−0.34, P=0.00). In the multivariate regression model adjusted for age, testosterone, and estradiol, only BMI showed a negative value across the FSH quartiles (β coefficient −0.11, P=0.00).ConclusionsThis study identified that high FSH concentrations were not associated with bone loss or high bone turnover in women in the late postmenopausal period.

The significance of high bone density in children

OBJECTIVES/SPECIFIC AIMS: Persons living with HIV (PLWH) are at increased risk for fragility bone disease. Current osteoporosis screening guidelines do not account for HIV status, and clinical risk assessment tools are not sensitive in PLWH. We examined the value of traditional osteoporosis risk factors, HIV-specific indices, and bone turnover biomarkers in predicting low bone mineral density (BMD) in PLWH. METHODS/STUDY POPULATION: Demographic and clinical characteristics, dual energy x-ray absorptiometry (DXA)-derived BMD, HIV indices (viral load, CD4 count, antiretroviral therapy [ART]), and biomarkers of bone turnover (C-terminal telopeptide of collagen [CTx], osteocalcin [OCN]) were evaluated in a cross-sectional analysis of PLWH (n=248) and HIV- controls (n=183). The primary outcome was low BMD, defined as osteopenia or osteoporosis by WHO criteria. Multivariable logistic and modified Poisson regression models were used to assess associations between low BMD and covariates of interest. RESULTS/ANTICIPATED RESULTS: Overall, median age was 44 years, 48% were male, 88% were black, median body mass index (BMI) was 28 kg/m2, 72% smoked cigarettes, and 53% used alcohol; characteristics did not differ by HIV status. PLWH had a mean CD4 of 408 cells/mm3, 55% were ART-naïve, and 45% had viral suppression on ART. Overall, 25% (109/431) had low BMD, including 31% of PLWH compared to 16% of HIV- controls. In multivariable models, HIV was significantly associated with low BMD (aOR 2.46, 95%CI 1.39-4.34; aRR 1.90, 95%CI 1.18-3.07). Adjusting for HIV, three traditional risks– age, race, and BMI– were independently associated with low BMD in the full cohort. However, bone turnover markers, CTx and OCN, were better able to discriminate low vs. normal BMD in PLWH compared to HIV- controls. In PLWH, mean serum CTx was 23% higher in low vs. normal BMD (mean CTx difference=0.06 ug/mL); in HIV- controls, no association with BMD was observed (mean CTx difference=0 ug/mL). In PLWH, mean serum OCN was 38% higher in those with low vs. normal BMD (mean OCN difference=2.48 ug/mL); in HIV- controls, mean serum OCN was only 16% higher in those with low vs. normal BMD (mean OCN difference=1.08 ug/mL). DISCUSSION/SIGNIFICANCE OF IMPACT: In PLWH as opposed to HIV- controls, serum biomarkers reflecting a high bone turnover state, may discriminate individuals with low versus normal BMD. Because changes in biomarkers precede changes in BMD, these markers should be explored further either alone or in combination with traditional risk assessment tools to improve early screening for osteoporosis in PLWH.

BackgroundElevated follicle‐stimulating hormone (FSH) is associated with an increased risk of postmenopausal osteoporosis. This study investigated the association of serum FSH with bone turnover markers (BTMs) and bone mineral density (BMD) in healthy women undergoing menopausal transition.MethodsA total of 487 healthy women (age 35–65 years, 50 ± 8.5 years) were enrolled in this study. Serum FSH, BTMs, and BMD at lumbar spine and total hip were measured in these subjects.ResultsFollicle‐stimulating hormone was positively correlated with various BTMs (r = 0.339–0.583, all p < 0.001) and negatively correlated with lumbar spine and total hip BMD (r = −0.629 and −0.514, all p < 0.001). After adjusting for age and body mass index, the partial correlation coefficients of FSH with BTMs and BMD remained significant. Estimating from the regression equation, for every 10 IU/L increase in serum FSH, BTMs increased by 0.38–3.6 units, and BMD decreased by 0.03–0.05 g/cm2, respectively. Multiple linear regression analysis showed that FSH was a positive factor for serum bone‐specific alkaline phosphatase, osteocalcin, and N‐telopeptide of collagen type 1 (β = 0.188–0.403, all p < 0.001), and a negative factor for lumbar spine BMD and serum C‐telopeptide of collagen type 1 (β = −0.629 and –0.183, all p < 0.001).ConclusionsThis study suggests that serum FSH levels are an independent risk factor for BTMs and BMD in menopause‐transitioning women, particularly for serum BAP and lumbar spine BMD.

: Background: The pro-inflammatory cytokines that are associated with the decline in ovarian function during menopause are involved in the pathophysiology of postmenopausal bone loss, which has not been examined in Indian postmenopausal women.Objectives: This study assessed the extent of changes in pro-inflammatory cytokines in relation to bone turnover markers, hormones, and bone mineral density (BMD) during menopausal transition in Indian women. Material/Patients and Methods: Levels of interleukin 1 (IL1 β), interleukin 6 (IL6), and tumor necrosis factor (TNF α); the bone markers osteocalcin (OC), bone-specific alkaline phosphatase (BSAP), carboxy terminal telopeptide (CTX), and deoxypyridoniline (DPD); and the hormones parathyroid hormone (PTH), follicle-stimulating hormone (FSH), and estrone glucuronide (E1G) were measured by enzyme linked immunosorbant assay (ELISA) in blood and urine samples of premenopausal (age: 21-40 years, n=124) and menopausal women (41-70 years, n=256) without fractures. Bone mineral density (BMD) in the femur and spine was measured by dual energy x-ray absorptiometry (DXA).Results: Of the cytokines that were measured, only IL6 increased significantly in all 3 groups of menopausal women (compared with premenopausal healthy women. The changes in IL6 paralleled changes in markers of bone resorption and correlated positively with bone turnover markers and negatively with BMD and E1G levels. In menopausal women, the rise in IL6, CTX, and DPD was high ( > 100%) and was associated with a decline in E1G ( > 75%) and BMD levels ( > 22%) during the first 5 years of menopause, indicating that bone loss is confined to the first decade of menopause. Conclusions: IL6 correlates negatively with estrogens and BMD and positively with bone resorption markers. Thus, IL6 levels, in conjunction with CTX, DPD, and estrogen levels, improve the prediction of bone loss in menopausal women. Implication for health policy/practice/research/medical education: The article will be help Clinicians in predicting and planning correct strategies for postmenopausal bone loss. Please cite this paper as: Desai M, Khatkhatay MI, Taskar V, Ansari Z. Changes in Cytokines, Biomarkers of Bone Turnover and Hormones Are Associated With Bone Loss in Postmenopausal Indian Women. Int J Endrocrinol Metab. 2012:10(1): 399-403. DOI: 10.5812/ijem.3339 Copyright©2012 Kowsar M. P. Co. All rights reserved

The menopause transition in women is a period of significant bone loss, with rapid declines in bone mineral density (BMD) commencing a year before the final menstrual period (FMP). Changes in menstrual bleeding patterns cannot reliably tell us if this rapid bone loss has begun or is imminent. We hypothesized that low circulating levels of anti-Mullerian hormone (AMH), which decline as women approach the FMP, would be associated with future and ongoing rapid bone loss. We used data from The Study of Women's Health Across the Nation, a multisite, multi-ethnic, prospective cohort study of the menopause transition to test this hypothesis. Adjusted for age, body mass index, race/ethnicity, and study site, every 50% decrement in AMH level in premenopause and early perimenopause was associated with 0.14% per year faster decline over the following 3 to 4 years in lumbar spine BMD and 0.11% per year faster decline in femoral neck BMD (p < 0.001 for both). AMH in late perimenopause was not associated with the rate of future BMD decline. AMH was also associated with the magnitude of ongoing bone loss, measured as percent of peak BMD lost by the end of the next 2 to 3 years. Every 50% decrement in AMH level was associated with 0.22% additional loss in spine BMD in premenopause, 0.43% additional loss in early perimenopause, and 0.50% additional loss in late perimenopause (p < 0.001 for all three). If a woman will lose more of her peak BMD than the site-specific least significant change (LSC) at either the lumbar spine or femoral neck by the next 2 to 3 years, then AMH below 100 pg/mL will detect it with sensitivity of 50% in premenopause, 80% in early perimenopause, and 98% in late perimenopause. These findings suggest that AMH measurement can help flag women at the brink of significant bone loss for early intervention. © 2022 American Society for Bone and Mineral Research (ASBMR).

Body composition in the Study of Women Entering and in Endocrine Transition (SWEET): A perspective of African women who have a high prevalence of obesity and HIV infection

Disclosure: E.H. Koh: None. S.K. Ewing: None. S. Sigurdsson: None. V. Guðnason: None. T.F. Hue: None. E. Vittinghoff: None. M. Zaidi: Research Investigator; Self; patents on FSH, bone, body fat and neurodegeneration. Held by Icahn School of Medicine and Mount Sinai. C.J. Rosen: None. C. Ohlsson: None. L. Grahnemo: None. Å. Tivesten: None. A.V. Schwartz: None. A.L. Schafer: None. Higher levels of follicle stimulating hormone (FSH) are associated with bone loss among women during the perimenopausal transition and among older men, independent of sex hormone levels. In vitro studies have shown bone remodeling via FSH-receptors on bone cells. Furthermore, treating ovariectomized mice with FSH-blocking polyclonal antibodies results in increased bone mineral density. However, it is uncertain whether this association of FSH elevation and bone loss translates to increased fracture risk. To examine the relationship between FSH and incident hip fracture, independent of sex hormone levels, we used a case-cohort design to sample from the AGES-Reykjavik cohort, a longitudinal cohort of 5764 older Icelandic adults designed to assess gene/environment interactions and their relationship to diseases in old age. Baseline visits took place from 2002 and through 2006. We excluded those with prior hip fracture, those whose quantitative computed tomography bone mineral density scan quality was unacceptable, or who were taking sex hormone replacement, sex hormone antagonists, or glucocorticoid medications. We randomly sampled, stratified by sex, 147 women and 148 men to form our subcohort. Our cases were comprised of a random sample, stratified by sex, of 133 women and 122 men (of whom 25 were in the subcohort) who sustained incident hip fracture within 10 years of the baseline visit. Fractures were adjudicated and recorded in the AGES-Reykjavik fracture registry. FSH and sex hormone binding globulin (SHBG) were measured on baseline serum by immunoassay and estradiol and total testosterone by mass spectrometry. Robust weighted Cox proportional hazards models were used to determine the relationship between FSH and subsequent risk of hip fracture, with adjustment for covariates. Among the subcohort, mean age was 76 years. In women, mean ± SD FSH was 64.4 ± 25.5 IU/L with estradiol 5.7 ± 4.2 pg/mL, testosterone 22.5 ± 10.4 ng/dL, and SHBG 74.0 ± 33.8 nmol/L. In men, mean FSH was 12.2 ± 11.9 IU/L with estradiol 21.3 ± 6.9 pg/mL, testosterone 457.9 ± 171.2 ng/dL, and SHBG 52.8 ± 17.5 nmol/L. No interaction was identified between FSH and sex for the relationship with fracture, so men and women were pooled for analysis. Higher levels of FSH were associated with a significant increased risk of incident hip fracture in models adjusted for age and sex [hazard ratio (HR) 1.24 (95% CI 1.04-1.48, p=0.02)] and after further adjustment for estradiol, testosterone, and SHBG levels [HR 1.20 (95% 1.01-1.44, p=0.04)] per sex-specific SD increase in FSH level. Our findings support a growing body of evidence for direct pleiotropic effects of FSH on bone. FSH may contribute to aging and disability independent of sex hormone levels. Presentation: Friday, June 16, 2023

Rates of bone loss across the menopause transition and factors associated with variation in menopausal bone loss are poorly understood. Our objective was to assess rates of bone loss at each stage of the transition and examine major factors that modify those rates. We conducted a longitudinal cohort study of 1902 African-American, Caucasian, Chinese, or Japanese women participating in The Study of Women's Health Across the Nation. Women were pre- or early perimenopausal at baseline. We assessed bone mineral density (BMD) of the lumbar spine and total hip across a maximum of six annual visits. There was little change in BMD during the pre- or early perimenopause. BMD declined substantially in the late perimenopause, with an average loss of 0.018 and 0.010 g/cm2.yr from the spine and hip, respectively (P<0.001 for both). In the postmenopause, rates of loss from the spine and hip were 0.022 and 0.013 g/cm2.yr, respectively (P<0.001 for both). During the late peri- and postmenopause, bone loss was approximately 35-55% slower in women in the top vs. the bottom tertile of body weight. Apparent ethnic differences in rates of spine bone loss were largely explained by differences in body weight. Bone loss accelerates substantially in the late perimenopause and continues at a similar pace in the first postmenopausal years. Body weight is a major determinant of the rate of menopausal BMD loss, whereas ethnicity, per se, is not. Healthcare providers should consider this information when deciding when to screen women for osteoporosis.

Calcium supplementation during pregnancy and lactation: Effects on the mother and the fetus

BackgroundBone loss in patients (pts) with early axial spondyloarthritis is insufficiently studied.ObjectivesTo assess 1-year bone mineral density (BMD) changes at the femoral neck (FN) and lumbar spine (LS) in pts...

To evaluate the occurrence of low bone mineral density (BMD) and its relationship with clinical and laboratorial characteristics in children and young adults with sickle cell anaemia living in Northeast-Brazil, and to assess the role of radiography in diagnosing low BMD. Bone mineral density of lumbar spine was measured by dual energy X-ray absorptiometry (DXA) in 27 patients with Sickle cell anaemia (SCA) aged 7-28years. Clinical history, calcium and calorie intake, laboratory measurements, anthropometrics and pubertal development were assessed, and X-rays were obtained. Z-scores and T-scores for weight, height, Body Mass Index (BMI) and BMD were calculated using age and gender matched reference data. Mean lumbar spine BMD Z-scores and T-scores were -1.81 SD in boys and -0.80 SD in girls. BMD Z-scores were below -2 SD in 33.3% of girls and in 46.7% of boys. Low BMD (<-2 SD) occurred significantly more in patients with low height-for-age (P=0.02), low weight-for-age (P=0.001) and low BMI-for-age (P=0.006). No significant relationships were found between BMD and other clinical and laboratory parameters. Radiography had a sensitivity of 75% and a specificity of 36% to detect low BMD, and was considered not useful in this context. Patients with low height and/or low weight-for-age seem to be at high risk for developing low BMD.

Menopausal hormone therapy and menopausal symptoms

Aim:The aim of this study is to determine the bone health in HIV-infected children on antiretroviral therapy (ART).Materials and Methods:This cross-sectional study was carried out in 31 HIV-infected children aged 5–18 years. Each patient underwent testing for serum calcium, phosphorous, alkaline phosphatase, and 25(OH) Vitamin D. Bone mineral density (BMD) was done using a DXA scanner. Patients' z scores for BMD of the lumbar spine and left femoral neck were noted. The factors associated with low BMD were analyzed.Results:Seven (22.6%) children had a low spinal BMD and 6 (19.4%) had low femoral neck BMD. Low serum calcium was seen in 6 (19.4%) patients and high alkaline phosphatase was seen in 15 (48.4%) patients. Low serum 25 (OH) Vitamin D levels were present in 30 (96.8%) patients, whereas all the patients had normal serum phosphorous. Duration of ART in those with low spinal BMD was 4.6 ± 3.4 years as compared to 6.4 ± 3.2 years in those with normal spinal BMD (P = 0.235) and for low left femoral neck BMD was 3.9 ± 2 years as compared to 6.5 ± 3.4 years for those with normal femoral neck BMD (P = 0.031). Mean 25(OH) Vitamin D levels were 8.4 ± 2.8 ng/ml in those with low femoral neck BMD as compared to 13.6 ± 8.3 ng/ml in those with normal femoral neck BMD (P = 0.015). Type of ART did not have any association with low BMD.Conclusion:Over 95% of HIV-infected children have low 25(OH) Vitamin D levels which affect the appendicular BMD. BMD is affected more in children who have been on ART for a shorter time. No particular ART regimen is associated with low BMD.