Prevalence of osteopenia and osteoporosis in middle-aged and older Korean men with testosterone deficiency syndrome: a cross-sectional study

1. Introduction

In diseases characterized by low bone mineral density (BMD), such as osteopenia and osteoporosis, there is an imbalance between bone mineral loss and bone remodeling, where the rate of bone mineral loss exceeds the rate of bone remodeling [1]. Although reduced bone density may not be a direct risk factor for mortality in older adults, it can contribute to increased mortality as a secondary cause. Fragility fractures, especially those occurring in the hip, can result in long-term limitations in independent mobility and have been linked to a mortality rate of 25% within one year following the fracture. In addition, vertebral fractures are associated with a 2.7-fold higher risk of mortality [2]. Osteoporosis is more prevalent in women than men, while osteopenia is more frequently observed in men. The global aging of populations has led to an increased incidence of bone density disorders in both genders. According to a study by Kaushal et al. [3], the prevalence of osteoporosis was observed to be 11.1% in women and 4.2% in men, while the prevalence of osteopenia was 40.3% in women and 29.9% in men.

The primary cause of BMD in men is the natural process of aging. However, there are also secondary factors that contribute to this decline, including inadequate nutrition, low levels of vitamin D, low body mass index (BMI), high alcohol consumption, low physical activity (PA) and muscle strength, as well as decreased testosterone levels [4]. Testosterone is a key male sex hormone primarily produced by the testicles and plays a significant role in regulating fertility, muscle mass, personality traits and bone density. As men age, testosterone levels gradually decrease at a rate of approximately 1–2% per year. When testosterone levels consistently fall below 3.5 ng/mL, it is referred to as testosterone deficiency syndrome (TDS), which requires hormone therapy and careful monitoring [5, 6]. While the incidence of osteoporosis is lower in men compared to women, the decline in testosterone levels is not as drastic as the decline in estrogen levels observed in postmenopausal women. As a result, TDS incidence in men ranges from 10–40% [7, 8]. Decreased testosterone levels are associated with increased bone density loss and fracture risk. Kacker et al. [9] reported that men with TDS or sexual dysfunction had a 3.79-fold higher risk of osteoporosis, and an increase in spinal bone density was observed in 43 men following testosterone treatment.

Androgens, including testosterone, play a crucial role in maintaining bone density by promoting bone mass anabolism and stimulating periosteal apposition, which increases bone size and strength [4]. Despite ongoing research, the exact physiological effects of testosterone on BMD remain partially understood. The incidence of both TDS and low BMD increases with age, and these conditions are influenced by various health behaviors, making their relationship complex. According to a study by Ko et al. [10], TDS prevalence was 1.6 times higher in smokers and decreased by 7.7% with high-intensity exercise. Additionally, the frequencies of alcohol consumption and strength training differed significantly between individuals with healthy BMD and those with low BMD [11].

However, despite some studies highlighting low BMD in men with TDS, research focusing on the prevalence of osteoporosis and osteopenia in this population remains scarce. Therefore, we designed this study to assess the prevalence of osteoporosis and osteopenia in Korean men with and without TDS and explore the relationship between TDS and health behaviors such as physical fitness, PA, alcohol consumption and smoking.

2. Materials and methods

2.1 Research process and participants

The present study involved the analysis of data from a total of 4707 men who voluntarily visited the healthcare center of a hospital in Korea. Only data from participants who provided consent for analysis and publication were included. The age range of the participants was between 40 and 79 years, with 2769 individuals classified as middle-aged men (40–59 years) and 1938 individuals as older men (60–79 years). This study followed a cross-sectional design.

The inclusion and exclusion criteria for participant selection are detailed in Fig. 1. Initially, we had a pool of 5936 patients. Among them, 1229 patients were excluded for various reasons: 125 were receiving medication for diseases related to our study, 1003 did not undergo the necessary tests or had missing data, and 101 either declined to participate, underwent surgery due to severe illness, or displayed psychological instability.

Fig. 1.Flowchart illustrating the study inclusion and exclusion criteria for participant selection. BMD: bone mineral density; TDS: testosterone deficiency syndrome.

The healthcare center examination was conducted as follows: Participants arrived at the hospital before 9 AM for identification, examination guidance and protocol explanations. On the examination day, they had consultations with physicians regarding their health conditions and their consent for the examination was reconfirmed. They were instructed to fast for 8 hours before undergoing blood tests and also completed a questionnaire about their medical history and health behaviors, including physical activity, alcohol consumption and smoking. Body measurements (height, weight and body composition), electrocardiography and blood pressure assessments were conducted, followed by blood sampling, BMD and physical fitness measurements. Ethics approval and consent from the participants were obtained for this study.

2.2 BMD and testosterone

Dual-energy X-ray absorptiometry (Lunar Prodigy iDXA; General Electric Healthcare, Waukesha, WI, USA) was used to measure BMD. Measurements were taken at the lumbar spine (L1–L4) and femoral neck with participants in the supine position (Fig. 2). The T-score was calculated, with values of ≤−1.0 indicating osteopenia and ≤−2.5 indicating osteoporosis [12].

Fig. 2.Bone mineral density location at X-ray at the (a) femoral neck and (b) lumbar spine 1–4.

For blood collection, the participants were required to fast for >8 h and instructed to avoid excessive exercise and overexertion for 7 days prior to the collection. A radioimmunoassay kit (TESTO CT2; Cisbio Bioassays, Codolet, France) was used to determine total serum testosterone levels. Blood samples were collected at 8 AM by a trained nurse and analyzed using an automated analyzer (TBA-200FR; Toshiba, Tokyo, Japan) employing the enzymatic method. Based on previous literature, patients with total serum testosterone levels of ≤3.5 ng/mL were classified as TDS, while those with levels >3.5 ng/mL were classified as non-TDS (NTDS) [6].

3. Results

4. Discussion

Testosterone, being primarily produced in the Leydig cells of the testicles, is widely recognized as a key male sex hormone and an androgen steroid hormone. It circulates throughout the body via the bloodstream and plays an important role in promoting sexual characteristics such as the growth and maturation of reproductive organs, the stimulation of body hair growth, and an increase in musculoskeletal size [8].

The findings of this study indicate an increased risk of osteopenia in men with TDS, which is consistent with previous research. Numerous studies have consistently emphasized that hypogonadism, or low testosterone levels, is a secondary contributor to bone loss in men, accounting for 16–30% of cases of osteoporosis development and up to 50% of osteoporotic fractures [9, 18]. A Korean study examining the association between testosterone and bone density in 144 male identical twins and 1070 family members found a positive correlation between testosterone levels and BMD and also identified a significant genetic influence on testosterone levels and BMD [19]. However, it should be noted that a few studies have reported either no association or a negative relationship between testosterone levels and BMD. For instance, in the US multiracial National Health and Nutrition Examination Survey, there was no negative association between BMD and total testosterone levels when they were <500 ng/dL in men aged 40–60 years. However, among non-Hispanic White, non-Hispanic Black, and Mexican American populations, total testosterone levels >500 ng/dL exhibited a negative association with BMD [20].

Given the potential impact of testosterone on BMD, numerous studies have examined the effects of hormone therapy to further investigate this relationship. One randomized trial conducted at six centers in Australia administered testosterone or a placebo for 2 years on men aged ≥50 years and investigated the difference in BMD between them. The results showed that compared with the control group, the experimental group had significantly increased tibial and radial cortex and total tibial and radial BMD [21]. However, these effects of testosterone therapy were reported to be obvious in middle-aged men while only partially present in older men. In a meta-analysis of seven randomized controlled trials comprising 800 patients, it was found that testosterone therapy did not significantly change the BMD of the whole body but induced significant changes in that of the spine, femoral neck and total hip [22].

The findings of our present study align with previous research, showing significant associations between TDS and BMD in the middle-aged group, while only the femoral neck exhibited significant associations in the older men group. These observations might be attributed to multiple factors influencing bone density beyond those considered in this study. Hence, while primary osteoporosis is related to senescence, secondary osteoporosis is influenced by various risk factors and causes [12, 23], suggesting that factors such as nutritional status and other underlying diseases could significantly impact bone density, particularly in older men. For instance, people with diabetes were reported to have a 4–5 times higher risk of osteoporosis than those without diabetes [24].

Testosterone therapy is not widely recommended as a primary treatment for low BMD. Testosterone therapy is recommended if low testosterone levels are the obvious cause of osteoporosis but not if the testosterone level is normal [25]. Testosterone and androgens have a complex relationship with bone-related cells. Androgen receptors are expressed in bone-associated osteoblasts, osteoclasts and osteocytes. Thus, loss of androgen receptors in osteoblasts can decrease trabeculae and trabecular bone mass [26], resulting in the low bone density observed in patients with androgen insensitivity syndrome and androgen receptor deficiency [27, 28]. Therefore, testosterone can potentially affect osteoblasts by promoting trabecular bone and osteocyte formation via androgen receptors [18]. However, while there is some understanding of the role of androgens in osteoblasts, there is a lack of studies exploring the relationship between androgens and osteoclasts. Further research is needed to investigate the pathophysiological mechanisms involved.

The present study observed a significant increase in the prevalence of osteopenia but not osteoporosis among the participants. It is worth noting that the incidence of osteoporosis in men is generally low, and severe complications such as osteoporotic fractures are rare, making it challenging to conduct comprehensive studies on such topics. As a result, guidelines for the treatment of osteoporosis in young men often recommend regular follow-ups rather than immediate active treatment in the absence of osteoporotic fractures [25].

In the present study, significant differences were observed in exercise-related variables such as VO_2peak, grip strength and PA between the NTDS and TDS groups in both age ranges. These findings align with a study conducted by Ko et al. [10], which focused on older men and found that the OR for TDS increased by 1.7-fold in the group with low muscle mass, while the risk of TDS decreased by 7.7% in the group engaging in frequent strength training. Numerous studies have demonstrated a correlation between testosterone levels and muscle mass and strength. For instance, in a study involving older men receiving hormone therapy, the experimental group exhibited improvements in muscle mass and strength compared to the placebo [29]. Moreover, testosterone levels were reported to be increased after 8 weeks of weight training [30]. These findings highlight the potential impact of testosterone on muscle-related variables and suggest that testosterone therapy and strength training may have beneficial effects on muscle mass and strength in older individuals.

Health experts commonly highlight the detrimental effects of smoking and alcohol consumption on both bone and sexual health. In the present study, although smoking and alcohol consumption did not show significant associations with TDS in the middle-aged groups, they were significant in the older groups. However, previous studies have yielded inconsistent results regarding the relationship between smoking, alcohol consumption and testosterone levels. For instance, one study reported a 1.6-fold increased OR for low testosterone in smokers, but the OR did not reach significance for smoking alone. Additionally, heavy drinkers were found to have a 4.37-fold increased risk of testosterone deficiency than non-drinkers [10, 31]. However, another study by Haik et al. [32] found no significant differences in testosterone and sex hormone-binding globulin levels between smokers and non-smokers. Although further research is needed to better understand the underlying physiological pathways and mechanisms involved, it is important to note that smoking and excessive alcohol consumption are recognized as risk factors for various health issues beyond their potential effects on testosterone levels.

In our present study, we observed that the TDS group had higher BMI and body fat percentage than the NTDS group, consistent with previous studies that reported similar associations. One possible physiological mechanism for this association could be that obesity can inhibit testosterone production and hypothalamic-pituitary-gonadal function by activating aromatase [33]. Further investigations could explore the relationship between TDS and cardiovascular risks, including obesity.

Our study also had several limitations. First, the participants were volunteers, so it cannot be determined whether individuals with limited access to healthcare facilities and lower health awareness would yield similar results. Additionally, considering the cross-sectional design of this study, we could not establish causality between low BMD and TDS. Furthermore, the pathophysiological mechanisms or pathways underlying the observed associations could not be elucidated, and the use of memory-dependent test methods, such as questionnaires, might have introduced the possibility of over- or under-estimation in the data. Future studies should consider employing various methods, such as measuring free testosterone and BMD at different skeletal sites like the wrist, total hip and trochanter, and increasing the sample size to enhance the generalizability of the findings.

5. Conclusions

The present study revealed that middle-aged and older men with TDS had lower BMD than NTDS individuals. Age, BMI, PA and VO_2peak were identified as significant factors affecting testosterone levels. Compared to the NTDS group, the TDS group had an increased risk of osteopenia in the lumbar spine and femoral neck among middle-aged men and an increased risk of femoral neck osteopenia in older men, highlighting the importance of managing BMD-related health in men with TDS.

Availability of Data and Materials

The subject institution of the data prohibits external export to protect patient information.

Author contributions

ZBW and YK—Conceptualization; YK and YC—methodology, writing–review and editing; YK—formal analysis, investigation; ZBW and YC—writing—original draft preparation, supervision.

Ethics approval and consent to participate

This study was conducted in accordance with the principles outlined in the Declaration of Helsinki with the approval of the Institutional Review Board of Asan medical center (approval number: S2015-2252). Participants submitted a handwritten consent form.

Acknowledgment

We sincerely thank Gangneung-Wonju National University and Asan medical center for administrative support for this study.

Funding

This research was funded by research funds for newly appointed professors of Gangneung-Wonju National University in 2022.

Conflict of interest

The authors declare no conflict of interest.