Primary osteoporosis is closely linked to hormone deficiency, which disrupts the balance of bone remodeling. It affects postmenopausal women but also significantly impacts older men. Estrogen can promote the production of osteoprotegerin, a decoy receptor for RANKL, thereby preventing RANKL from activating osteoclasts. Furthermore, estrogen promotes osteoblast survival and function via activation of the Wnt signaling pathway. Likewise, androgens play a critical role in bone metabolism, primarily through their conversion to estrogen in men. Estrogen deficiency accelerates bone resorption through a rise in pro-inflammatory cytokines (IL-1, IL-6, TNF-α) and RANKL, which promote osteoclastogenesis. In the classic genomic pathway, estrogen binds to estrogen receptors in the cytoplasm, forming a complex that migrates to the nucleus and binds to estrogen response elements on DNA, regulating gene transcription. Androgens can be defined as high-affinity ligands for the androgen receptor; their combination can serve as a ligand-inducible transcription factor. Hormone replacement therapy has shown promise but comes with associated risks and side effects. In contrast, the non-genomic pathway involves rapid signaling cascades initiated at the cell membrane, influencing cellular functions without directly altering gene expression. Therefore, the ligand-independent actions and rapid signaling pathways of estrogen and androgen receptors can be harnessed to develop new drugs that provide bone protection without the side effects of traditional hormone therapies. To manage primary osteoporosis, other pharmacological treatments (bisphosphonates, teriparatide, RANKL inhibitors, sclerostin inhibitors, SERMs, and calcitonin salmon) can ameliorate osteoporosis and improve BMD via actions on different pathways. Non-pharmacological treatments include nutritional support and exercise, as well as the dietary intake of antioxidants and natural products. The current study reviews the processes of bone remodeling, hormone actions, hormone receptor status, and therapeutic targets of primary osteoporosis. However, many detailed cellular and molecular mechanisms underlying primary osteoporosis seem complicated and unexplored and warrant further investigation.
Keywords: osteoporosis, estrogen, androgen, osteoprotegerin, Wnt signaling pathway
1. IntroductionWith an escalating global population of elderly individuals, osteoporosis, significantly associated with the likelihood of fragility fractures that lead to various patient complications, is quickly emerging as one of the most prevalent medical conditions, with estimates that it will affect 500 million individuals worldwide by 2025 [1]. Moreover, osteoporosis is often referred to as a ‘silent disease’ because it usually does not produce noticeable symptoms until it leads to fractures. According to the statistics presented by The International Osteoporosis Foundation (IOF), up to half of all women and one in five men aged 50 or older are likely to experience a fragility fracture during their lifetime [2]. Osteoporosis is often viewed as a disease predominantly affecting women, and this perception is largely due to the substantial increase in its incidence and fracture risk among women post-menopause as a result of hormonal changes. It is indisputable that women he a higher tendency to develop osteoporotic fractures than men [3]. Although men experience fractures less frequently than women, they face higher mortality rates following a fracture [4]. Hence, we should never neglect the importance of deficiencies in both androgen and estrogen, and how they affect bone metabolism in both genders respectively and collectively.
Osteoporosis is defined by a decrease in bone density, which gives rise to microarchitecture deterioration, and constitutes both significant public health and economic issues; it is characterized by its high occurrence rate and the severe clinical outcomes associated with it. According to a report regarding the burden and management of fragility fractures completed by Borgström et al. in 2020 that compared fragility fracture-related DALYs (disability-adjusted life years) with 16 other prevalent non-communicable diseases across six European countries, osteoporotic fractures ranked as the fourth most burdensome condition, exceeded only by ischemic heart disease, dementia, and lung cancer [5]. According to one 2021 meta-analysis review by Nader et al., the prevalence of worldwide osteoporosis was reported to be 18.3%. Under the different pooling sample sizes, women accounted for 23.1% while men constituted 11.7% in the general population, respectively [6]. Also, the highest prevalence of osteoporosis in the eldery was reported to be 24.3% in Asia [6]. A nationwide population-based study in Taiwan by Lee et al., utilizing data from Taiwan’s National Health Insurance Research Database from 2008 to 2019, found that the age-standardized incidence rates were 640 and 1372.5 per 100,000 people, respectively [7]. In the United States, osteoporosis leads to around 1.5 million fractures annually, with most of these incidents occurring in women who he gone through menopause [8]. A 50-year-old white woman’s lifetime risk for a hip fracture is estimated at 15–20%, with a 50% chance of incurring any osteoporotic fracture [8,9]. Frailty fractures due to osteoporosis primarily occur in the hip and spine, but can also be found in the proximal humerus, wrist, ribs, ischiopubic branches, and even in the ankle [10]. Among these fractures, vertebral and hip fractures are associated with an increased risk of death [11]. Moreover, women aged 50 and older experience osteoporosis at a rate four times greater and osteopenia at a rate twice as high as men, while men tend to he a greater risk of mortality after a hip fracture [12].
Therefore, with today’s increase in life expectancy, enhanced awareness regarding the prevention and recognition of osteoporosis among physicians and patients is beneficial for public health. Certain risk factors of osteoporosis-related fractures should be identified, such as aging, sex steroid hormone deficiency, low body mass, prolonged immobility, parental history of hip fracture, smoking and alcohol habits, chronic use of glucocorticoids, and vitamin D insufficiency [13]. The modifiable and non-modifiable risk factors of osteoporosis are listed in Table 1.
Table 1.Modifiable and non-modifiable risk factors of osteoporosis.
Modifiable Risk Factors Description Smoking Nearly doubles the risk of hip fracture by reducing bone density and vascular health. Excessive alcohol intake More than 2 units daily increases fracture risk by weakening bone structure. Low body mass index BMI below 19 is linked to decreased bone mass and higher fracture risk. Poor nutrition Low intake of calcium, protein, fruits, and vegetables compromises bone health, especially in older adults. Low dietary calcium intake Insufficient calcium intake, worsened by age-related absorption decline, weakens bones. Vitamin D deficiency Common in older adults with limited sun exposure, leading to poor calcium absorption and lower bone density. Inactivity (not enough exercise) Physical inactivity accelerates bone loss and muscle weakening, increasing fracture risk. Eating disorders Disorders like anorexia lead to weight loss, estrogen deficiency, and rapid bone loss, especially in young women. Frequent falls Frequent falls heighten fracture risk in those with compromised bone health. Non-Modifiable Risk Factors Description Age Advanced age is strongly linked to osteoporosis, with most fractures occurring in those over 65. Gender Women he a higher risk due to hormonal factors and lower peak bone mass. Ethnicity Individuals of Caucasian and Asian descent he a higher risk of developing osteoporosis compared to those of African or Hispanic descent. Family history ofosteoporosis A family history increases susceptibility due to genetic and lifestyle influences. Body frame size Individuals with smaller skeletal frames he a lower baseline bone mass, increasing their vulnerability to osteoporosis and fractures as they age. Open in a new tabIn clinical practice, osteoporosis can be classified into primary and secondary causes. Primary osteoporosis, a kind of osteoporosis that develops independently of other health conditions, is often related to aging and the decreased sex hormone levels that occur after menopause in women and andropause in men.
Primary osteoporosis can be further classified into type 1, type 2, and idiopathic types. Type 1 involutional osteoporosis, also referred to as postmenopausal osteoporosis, is a condition resulting from estrogen deficiency, and mainly impacts the spongy, trabecular bone [13]. Although this condition affects both men and women, it predominantly occurs in women aged 51 to 75, who are characterized by accelerated bone loss during this period [14]. Type 2 involutional osteoporosis, also referred to as senile osteoporosis, typically affects individuals aged 75 and older. As a result of the aging process, this condition leads to the degeneration of both the trabecular and cortical bone [13]. Idiopathic osteoporosis is a heterogenous type affecting both sexes in young adults. It involves compromised bone structure and strength, which is largely due to reduced osteoblast activity and inadequate bone formation during growth phases [15].
On the other hand, secondary osteoporosis results from numerous medical conditions or treatments deemed to be external factors that disrupt the bone turnover processes and negatively affect bone density and strength. Potential causes include prolonged use of glucocorticoids, thyroid dysfunction, or chronic diseases affecting nutrient absorption or hormone levels, and others [16]. Table 2 summarizes the possible medical conditions or treatments that can induce secondary osteoporosis.
Table 2.Possible medical conditions or treatments that can induce secondary osteoporosis.
Contributors Examples/Conditions Lifestyle Changes Alcohol abuse, excessive thinness, excess vitamin a, frequent falling, high salt intake, immobilization, inadequate physical activity, low calcium intake, smoking (active or passive), vitamin D insufficiency/deficiency Genetic Diseases Cystic fibrosis, Ehlers-Danlos, Gaucher’s disease, hemochromatosis, hypophosphatasia, hypophosphatemia, Marfan syndrome, Menkes steely hair syndrome, osteogenesis imperfecta, parental history of hip fracture, porphyria, homocystinuria Gastrointestinal Disorders Celiac disease, gastric bypass, gastrointestinal surgery, malabsorption, inflammatory bowel disease, pancreatic disease, primary biliary cirrhosis Thyroxotoxicosis (Specific examples were not listed, but this would include any condition leading to excess thyroid hormone.) Hematologic Disorders Hemophilia, leukemia and lymphomas, sickle cell disease, multiple myeloma, monoclonal gammopathies, systemic mastocytosis, thalassemia Endocrine Disorders Obesity, Cushing’s syndrome, diabetes mellitus (types 1 and 2), hyperparathyroidism Hypogonadal States Anorexia nervosa, androgen insensitivity, female athlete triad, hyperprolactinemia, hypogonadism, panhypopituitarism, premature menopause (