Bone Health · Fracture Risk
Abstract
Background
Klinefelter syndrome (KS) frequently causes skeletal fragility characterized by profound alterations in bone microstructure with increased risk of fractures. Increased body fat mass associated with decreased body lean mass are frequent features of KS with possible detrimental effects on skeletal health. In this cross-sectional study, we evaluated the associations between body composition parameters, vertebral fractures (VFs) and trabecular bone score (TBS) in adult subjects with KS.
Methods
Seventy-one adult males (median age 41 years, range 18-64) with 47, XXY KS were consecutively enrolled by two Endocrinology and Andrology Units (IRCCS Humanitas Research Hospital in Milan and ASST Spedali Civili in Brescia). Dual-energy X-ray absorptiometry (DXA) was performed to assess bone mineral density (BMD) at lumbar spine, femoral neck and total hip, TBS and body composition. Prevalence of VFs was assessed by quantitative morphometry on lateral spine X-rays.
Results
VFs were detected in 14 patients (19.7%), without significant association with low BMD (p = 0.912). In univariate logistic regression analysis, VFs were significantly associated with truncal/leg fat ratio (OR 2.32 per tertile; 95% CI 1.05-5.15; p = 0.038), whereas impaired TBS (detected in 23.4% of subjects) was associated with older age at study entry (p = 0.001) and at diagnosis of disease (p = 0.015), body mass index (BMI; p = 0.001), waist circumference (p = 0.007), fat mass index (FMI; p < 0.001), FMI/lean mass index (LMI) ratio (p = 0.001). Prevalence of VFs was not significantly different between subjects with impaired TBS as compared to those with normal TBS (26.7 vs. 18.4%; p = 0.485). Skeletal end-points were not significantly associated with duration of testosterone replacement therapy and serum testosterone and 25hydroxyvitamin D values.
Conclusion
Body composition might influence bone quality and risk of VFs in subjects with KS.
Topics
By this author
Semen Analysis · Sperm Function Testing
Preimplantation genetic testing for male factor infertility: lights and shadows
Mazzilli R et al., 2026 · Journal of endocrinological investigation
Male factor could contribute, alone or in combination with female factor, to the inability to conceive in a couple in more than half of cases. The effect of male factor infertility (MFI) on embryological assisted reproductive technology (ART) outcomes remains an ongoing discussion. to evaluate the impact of MFI on embryo aneuploidy rates, to better understand the role and possible indication for Preimplantation genetic testing for aneuploidies (PGT-A), considering the role of sperm characteristics, paternal age, sperm DNA fragmentation and sperm aneuploidies. this narrative review included all available articles, published up to January 2026. Available evidence, often based on heterogeneous and old-fashioned methodologies, suggests that MFI may impair embryonic development, particularly in terms of fertilization rate and blastulation rate, more than embryo euploidy; however, a comprehensive evaluation of MFI should be integrated into clinical practice in the context of couple infertility, to also optimize the efficiency and outcomes of ART. Promising results emerged from sperm DNA fragmentation as a tool to predict embryo euploidy, but further investigations involving larger sample sizes and improved standardization are required.
Neoplastic Risk in Patients With Klinefelter Syndrome
Graziani A et al., 2026 · Andrology · Free to read
Besides gonadal involvement (hypogonadism, male factor infertility, and testicular hypotrophy), patients with Klinefelter syndrome (KS) may suffer from several extra-gonadic complications, including neoplastic events. The aim of this review is to summarize all major clinical evidence dealing with the association between KS and neoplastic diseases and provide practical suggestions for the management of patients with KS regarding neoplastic risk. This narrative review was conducted through a comprehensive search of the PubMed database, using combinations of the following keywords: "Klinefelter syndrome," "cancer," "neoplasm," "breast cancer," "germ cell tumor," "lymphoma," and "testosterone replacement therapy". KS is associated with a higher risk of breast cancer and mediastinal germ cell tumors and an apparent higher risk of hematological malignancies, in particular non-Hodgkin lymphoma and leukemia. Evidence on testicular cancer is limited, with no clear increase in risk attributable to KS, while prostate cancer has a lower risk and lower mortality rate. Given the complexity of the syndrome and the limited available evidence, regular clinical follow-up with targeted investigations when clinically indicated may facilitate early diagnosis and management of associated comorbidities.
Evidence Synthesis · Systematic Reviews
Body composition in male hypogonadism: practical considerations to the use of dual-energy x-ray absorptiometry
Delbarba A et al., 2026 · Reviews in endocrine & metabolic disorders · Free full text on PubMed Central
Male hypogonadism is associated with significant alterations in body composition, including reduced lean body mass (LBM), increased fat body mass (FBM), particularly visceral adiposity, and impaired muscle function, contributing to frailty and cardiometabolic risk. These changes reflect the disruption of a complex endocrine crosstalk among bone, muscle, and adipose tissue, mediated by cytokines such as osteokines, myokines, and adipokines. This dysregulation promotes the development of osteosarcopenic obesity, a condition characterized by the coexistence of low bone mass, sarcopenia, and excess adiposity. Testosterone (T) plays a central role in maintaining body composition by stimulating muscle protein synthesis, inhibiting adipogenesis, and preserving bone health. Its deficiency, irrespective of etiology, leads to rapid impairment of anabolic pathways, resulting in decreased lean mass and increased fat accumulation. Evidence from clinical and experimental models demonstrates that these alterations are partially reversible with T replacement therapy (TRT), although variability exists depending on the underlying cause of hypogonadism. Dual-energy X-ray absorptiometry (DXA) represents the gold standard for assessing bone mineral density (BMD) and a key tool for evaluating body composition through a three-compartment model. It allows precise quantification of fat and lean mass, as well as their regional distribution, with minimal radiation exposure. In this review, we provide a comprehensive and clinically oriented overview of body composition alterations in male hypogonadism, focusing on underlying pathophysiological mechanisms and the practical application of DXA across different clinical scenarios. We discuss evidence from conditions such as Klinefelter syndrome, Kallmann syndrome, androgen deprivation therapy, HIV infection, and transgender care, aiming to offer a pragmatic framework for integrating body composition assessment into routine practice and improving patient management.
Bone Mineral Density · Measurement
Impact of reference gender on bone mineral density and fracture risk assessment in transgender adults
Scala A et al., 2026 · Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA · Free full text on PubMed Central
In transgender adults, reference-gender choice alters Z-scores and fracture-risk estimates. Z-scores differ by 0.4-0.6 SD, with male references identifying more individuals with low BMD for age, especially in those assigned male at birth. Dual-reference reporting is advisable until further evidence becomes available. Transgender individuals, especially those assigned male at birth (AMAB), exhibit lower bone mineral density (BMD) compared with the cisgender population. Interpretation of densitometric data is challenging, as the choice of reference gender can significantly influence Z-scores and fracture risk scores. This study aims to evaluate the impact of the gender reference database (male or female) on the assessment of BMD and fracture risk in transgender adults prior to gender-affirming hormone therapy (GAHT). We conducted a cross-sectional analysis of 249 transgender individuals (153 assigned female at birth - AFAB and 96 AMAB) aged 18-43 years, recruited in the Hospitals of Padua and Brescia (Italy). Z-scores were calculated using both male and female reference databases and FRAX scores were computed using both gender inputs. Associations with anthropometric, biochemical, and hormonal parameters were explored. Z-scores differed systematically depending on the reference gender, with mean ΔZ ranging 0.4-0.6 SD across skeletal sites. Switching reference databases frequently led to reclassification of BMD status. AMAB individuals showed a higher prevalence of low BMD for age, particularly when assessed against male references (27.1%), whereas AFAB participants generally maintained normal BMD. However, FRAX scores remained low. BMI and 25-OH vitamin D levels were independent predictors of BMD and Z-scores in AMAB individuals. The choice of reference gender significantly influences densitometric interpretation in young transgender adults. Until further evidence becomes available, calculating Z-scores using both male and female reference databases is advisable. Early preventive interventions remain essential to preserve bone health.
Related research
Fracture Risk · Risk Factors
Prevalence and determinants of radiological vertebral fractures in patients with Klinefelter syndrome
Vena W et al., 2020 · Andrology
Klinefelter syndrome (KS) may induce skeletal fragility, but the studies so far published on this topic were mainly focused on the evaluation of bone mineral density (BMD) and bone microstructure, whereas data on fracture risk are still lacking. To evaluate the prevalence and determinants of vertebral fractures (VFs), that is, the hallmark of osteoporosis, in subjects with KS. Eighty-seven patients with KS (median age 41 years, range 18-64) were consecutively evaluated for radiological VFs (by quantitative morphometry) and lumbar spine and femoral neck BMD (by DXA). Fifty-five patients with KS were also evaluated by the fracture risk assessment (FRAX) tool. Low BMD was found in 22/87 (25.3%) patients [12 with osteopenia, three with osteoporosis and seven with "low BMD per age" (subject < 50 years with Z-score ≤-2.0 SD)] and VFs in 13/87 (14.9%) patients. In patients with VFs, the median spine deformity index was 2 (range 1-9). Prevalence of VFs was similar between healthy and low-BMD patients (15.9% vs 13.6%; P = .80). Noteworthy, patients with VFs had significantly higher age at diagnosis of KS as compared to patients who did not fracture (P = .039), without significant differences in age at the time of observation (P = .162), body mass index (P = .234), testosterone replacement therapy (P = .432), duration of testosterone therapy (P = .409), vitamin D therapy (P = 681), and serum testosterone levels (P = .338). Moreover, patients with VFs were more likely to complain back pain in comparison with those without VFs (33.3% vs 7.4%; P = .047). In 55 cases evaluated by the FRAX® tool, no significant differences in 10-year risk of major fracture (P = .270) and hip fracture (P = .860) were found between fractured and non-fractured patients. This study provides first evidence that KS may be associated with risk of VFs in close relationship with delay in disease diagnosis but independently of BMD values and serum testosterone levels or testosterone therapy.
Osteoporosis · Diagnosis and Treatment
Osteoporosis and bone metabolism in patients with Klinefelter syndrome
Grande G et al., 2023 · Endocrine connections · Free full text on PubMed Central
Low bone mass is common in men with Klinefelter syndrome (KS), with a prevalence of 6-15% of osteoporosis and of 25-48% of osteopenia. Reduced bone mass has been described since adolescence and it might be related to both reduced bone formation and higher bone resorption. Although reduced testosterone levels are clearly involved in the pathogenesis, this relation is not always evident. Importantly, fracture risk is increased independently from bone mineral density (BMD) and testosterone levels. Here we discuss the pathogenesis of osteoporosis in patients with KS, with a particular focus on the role of testosterone and testis function. In fact, other hormonal mechanisms, such as global Leydig cell dysfunction, causing reduced insulin-like factor 3 and 25-OH vitamin D levels, and high follicle-stimulating hormone and estradiol levels, might be involved. Furthermore, genetic aspects related to the supernumerary X chromosome might be involved, as well as androgen receptor expression and function. Notably, body composition, skeletal mass and strength, and age at diagnosis are other important aspects. Although dual-energy x-ray absorptiometry is recommended in the clinical workflow for patients with KS to measure BMD, recent evidence suggests that alterations in the microarchitecture of the bones and vertebral fractures might be present even in subjects with normal BMD. Therefore, analysis of trabecular bone score, high-resolution peripheral quantitative computed tomography and vertebral morphometry seem promising tools to better estimate the fracture risk of patients with KS. This review also summarizes the evidence on the best available treatments for osteoporosis in men with KS, with or without hypogonadism.
Hormones and Bone · Estrogen and Bone
Body Composition by DXA in Patients with Klinefelter and Kallmann Syndrome: The Kama Study
Buoso C et al., 2026 · The Journal of clinical endocrinology and metabolism · Free full text on PubMed Central
Klinefelter syndrome and Kallmann syndrome are 2 rare genetic disorders characterized by reduced testosterone (T) levels but differing in their gonadotrophin profiles. To date, no studies have directly compared body composition in these 2 syndromes. This work aimed to assess the prevalence of altered body composition parameters in patients with Klinefelter and Kallmann syndromes and to compare body composition between the 2 groups. Secondary objectives included evaluating associations between body composition, bone mineral density (BMD), and serum follicle-stimulating hormone (FSH) levels. This single-center, retrospective observational study included 50 patients, 29 with Klinefelter and 21 with Kallmann syndrome receiving T replacement therapy. Body composition was evaluated using whole-body dual-energy x-ray absorptiometry (DXA), which provided measurements of appendicular lean mass (ALM), total body fat (TBF), visceral adipose tissue (VAT), the ALM-to-height² ratio (appendicular lean mass index, ALMI), and the ALM-to-weight ratio. Radiologic sarcopenic obesity was identified in 7 patients (14%; 6/29 Klinefelter, 1/21 Kallmann), while osteosarcopenic obesity was found in 2 patients (4%), both with Klinefelter syndrome. Patients with Kallmann syndrome had significantly higher ALMI values than those with Klinefelter syndrome (8.37 ± 1.15 vs 7.28 ± 1.20 kg/m²; P < .001). Univariable analysis revealed an inverse association between FSH levels and ALMI (B = -0.026; P = .002), which remained statistically significant after adjustment for confounders (B = -0.030; P = .0022). This study demonstrated a significant difference in lean mass between Klinefelter and Kallmann syndromes, supporting a potential role for FSH in modulating muscle mass independently of T levels.
Hormones and Bone · Estrogen and Bone
Bone mass in subjects with Klinefelter syndrome: role of testosterone levels and androgen receptor gene CAG polymorphism
Ferlin A et al., 2011 · The Journal of clinical endocrinology and metabolism
Klinefelter syndrome (KS) is a chromosomal alteration characterized by supernumerary X-chromosome(s), primary hypogonadism, decreased pubertal peak bone mineral density (BMD), and accelerated bone loss during adulthood. Decreased bone mass has been traditionally related to low testosterone levels. However, testosterone replacement therapy does not necessarily increase bone mass in these patients, and low BMD can be observed also in patients with normal testosterone levels. The androgen receptor (AR) gene CAG polymorphism seems to modulate the sensitivity to testosterone and previous studies have related it to some clinical aspects of KS, to include BMD, gynecomastia, testes and prostate volume, and hemoglobin concentration. To analyze the relation between bone mass, testosterone, and AR CAG polymorphism in men with KS. Cross-sectional cohort study. University department. One hundred twelve consecutive treatment-naïve 47,XXY Klinefelter patients (mean age 33.5 ± 4.7 yr) and 51 age-matched normal male controls. Dual-energy x-ray absorptiometry, CAG repeat length polymorphism, X-chromosome inactivation, and testosterone levels. Forty-nine of 112 KS subjects (42.5%) had low bone mass (osteopenia or osteoporosis). Lumbar and/or femoral T-scores were lower in KS patients compared with controls. No significant relationship was observed between testosterone levels and bone parameters, and the prevalence of osteopenia/osteoporosis was similar in subjects with normal and low testosterone levels (43.7% and 40.5%, respectively). The mean CAG repeat length calculated after X-chromosome inactivation analysis showed no differences between patients with normal and low bone mass. Testosterone levels and AR CAG polymorphism are not associated with bone mass phenotype in KS.
Bone Health › Fracture Risk › Risk Factors
PMID 36030302 36030302 DOI 10.1007/s40618-022-01901-8 10.1007/s40618-022-01901-8 Vena et al. 2023, Vena 2023