Key determinants of postmenopausal osteoporosis: A mini-review of current insights

INTRODUCTION

Osteoporosis is a serious health concern that mostly affects elderly people. It is a complicated systemic bone disorder marked by reduced bone mineral density (BMD) and the breakdown of bone architecture that leads to enhanced bone fragility.^[1] With ageing, BMD gradually decreases, which can result in primary osteoporosis. This condition predominantly affects women 10– 15 years after menopause and men aged 75–80. As the global population ages, osteoporosis is emerging as a prime health challenge, placing considerable financial pressure on healthcare systems. Research shows that osteoporosis affects over ~200 million people globally.^[2] The World Health Organization (WHO) characterizes natural menopause as the permanent end of menstrual cycles lasting at least 12 continuous months without being influenced by any physiological or pathological conditions. Data show that the mean age for normal menopause in developed countries is 51, while in less developed or non-industrialized regions, it typically occurs around the age of 48.^[3] With life expectancy reaching approximately 70 years, a large fraction of women will live over 1/3^rd of their lives following transition through menopause. Furthermore, the number of women experiencing menopause is rising due to the fast-aging global population. Due to this, ensuring the health and well-being of menopausal women has become a pressing issue worldwide.^[4] The WHO data show that osteoporosis affects 30% of women after menopause.^[5] In India, around 61 million people are reported to have the condition, with women accounting for 80% of those affected.^[6] In India, osteoporosis tends to develop 10–20 years earlier than in Western countries, creating a significant strain on health and economic resources.^[7,8] Data on the incidence of postmenopausal osteoporosis (PMO) and the associated risk factors are limited, especially in India, where the condition affects one in three women and one in eight men.^[6]

As BMD decreases with advancing age, the prevalence of osteoporosis among women rises significantly. This condition is striking by diminished bone density and an intensified risk of fractures above the age of 50 years, affecting ~1 in three and five in women and men, respectively. The relationship between aging and osteoporosis underscores the importance of monitoring bone health as individuals grow older, particularly since the likelihood of fractures increases with lower BMD levels.^[9] The diagnosis of osteoporosis is mainly made through BMD evaluation using X-ray absorptiometry. As per the WHO criteria, osteoporosis and osteopenia are characterized by a T-score of −2.5 or lower and between −1.0 and −2.5, respectively. The femoral neck and lumbar spine are critical anatomical areas for assessing bone health.^[5]

FACTORS INVOLVED IN PMO: (AGE, QUALITY OF LIFE, HORMONE, POLLUTION)

Research on osteoporosis generally emphasizes factors such as physical activity, lifestyle, age, chronic stress, environmental factors, and diet [Figure 1]. However, the effects of air pollution on osteoporosis remain largely unexamined. Osteoporosis is a skeletal disorder associated with aging, noticeable by a decrease in bone mass and the weakening of bone microarchitecture, which causes heightened bone fragility. The WHO defines osteoporosis using BMD measurements, describing it as a condition where BMD is 2.5 standard deviations or more below the reference level for an adult.^[10] Therefore, BMD is used as a diagnostic marker for osteoporosis. In postmenopausal women and older men, however, BMD consistently drops with age. The risk of osteoporosis-related fractures rises significantly for women over 55 and for men over 65, underscoring the detrimental impact of aging on bone health. Aging influences bone remodeling differently in men and women, resulting in higher rates of bone resorption in women and decreased bone formation and turnover in men.^[11] In postmenopausal women, appropriate sleep duration and good sleep quality were positively associated with lower BMD.^[12]

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Figure 1:

Role of key molecular determinants (urine and serum-based diagnostic biomarkers) and associated risk factors influencing the progression of osteoporosis in postmenopausal women. The symbols (↑) and (↓) represent upregulation and downregulation, respectively. C-terminal telopeptide of collagen type I, β-CrossLaps, N-terminal telopeptide of collagen type I, and high sensitivity C-reactive protein. ICTP: Cross-linked C-terminal Telopeptide of Type I Collagen, B-CTX: beta-C-terminal telopeptide, NTX: N terminal telopeptide, hs-CRP: High sensitivity C reactive protein.

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Hormonal influences on osteoblast and osteoclast metabolism extend beyond sex hormones. Pre-clinical evidence indicates several other hormones, whose levels fluctuate with age, also impact bone metabolism. Increases in cortisol, parathyroid hormone, cortisol, and follicle-stimulating hormone are factors that contribute to bone loss in older adults, whereas decreases in testosterone, vitamin D, insulin-like growth factor 1, and estrogen, testosterone, and vitamin D are factors that contribute to bone mass preservation.^[13] Osteoporosis significantly affects women’s quality of life by increasing the risk of fractures, notably at the hip and spine, which can lead to reduced mobility and long-term disability. Nearly half of postmenopausal women experience at least one stereoscopic fracture, resulting in higher mortality rates, diminished quality of life, and an escalating burden on healthcare systems and society.^[14] Beyond fractures, osteoporosis also raises the likelihood of chronic pain and dependency. Several factors contribute to the onset of osteoporosis in postmenopausal women, including hormonal changes such as aging, genetic factors, estrogen deficiency, lifestyle choices like smoking, metabolic disorders, and the side effects of certain medications.^[15] Osteoporosis is a widespread condition that affects women after menopause and is closely linked to a significant decline in their quality of life.^[4] The primary cause of osteoporosis in women is estrogen deficiency, which becomes particularly significant after menopause. In many postmenopausal women, reduced estrogen levels accelerate bone loss by disrupting the equilibrium between bone resorption and formation. Thus, hormonal imbalance, coupled with increased bone turnover, results in a rapid decrease in bone mass, rendering bones more fragile and susceptible to fractures.^[16] Besides estrogen deficiency, other contributing factors to this bone deterioration include insufficient calcium intake and reduced physical activity.

Estrogen is vital for bone remodeling, helping to regulate bone resorption and strengthen areas with lower density. During menopause, the decline in estrogen disrupts this balance, accelerating bone loss in vulnerable areas such as the spine and hips and reducing overall bone strength.^[17]

By attaching itself to its receptors, estrogen influences bone metabolism by promoting the production of osteoprotegerin (OPG) and reducing the activity of the receptor-activator of nuclear factor kappa-B ligand (RANKL). This action limits the formation of osteoclasts and decreases bone resorption. In addition, estrogen activates the Wnt/b-catenin signaling pathway, which is imperative for bone formation, and enhances bone morphogenetic protein signaling, guiding mesenchymal stem cells toward developing into osteoblasts rather than adipocytes. In the absence of estrogen, pro-inflammatory cytokines (interleukin [IL]-1 and IL-6) and tumor necrosis factor are released more often, contributing to additional bone loss. OPG binding prevents RANKL from attaching to its receptor RANK (receptor activator of nuclear factor kappa-B), which activates osteoclasts.^[16,18]

Estrogen regulates the balance between RANKL and OPG by promoting OPG expression, which reduces bone resorption [Figure 1]. Furthermore, estrogen plays a role in regulating bone health, hinders osteoclast differentiation, and stimulates osteoclast apoptosis through the amplified synthesis of transforming growth factor beta. Without sufficient estrogen, RANKL expression is elevated, which stimulates osteoclastogenesis, resulting in enhanced bone resorption and loss of bone density. In addition, the deficiency of estrogen reduces the signaling mechanisms that promote osteoclast cell death, further contributing to the imbalance in bone remodeling.^[19]

People residing in elevated stages of particulate matter 2.5 (PM2.5) air pollution are at superior risk of developing osteoporotic fractures. While air pollution is already the leading environmental cause of mortality, recent studies have also associated it with an enhanced risk of osteoporosis, highlighting its impact on bone health. Prolonged exposure to polluted air may accelerate bone loss, particularly in older adults, adding a new aspect to the health risks associated with air quality.^[20] Bones are long-term storage sites for heavy metals [cadmium (Cd), mercury, lead, and aluminum], which bind to calcium in the hydroxyapatite matrix. More than 90% of the lead accumulates in bones and teeth in the body, where it can disrupt bone health by lowering vitamin D levels, inhibiting the function of bone-forming osteoblasts, and promoting the action of bone-resorbing osteoclasts. This imbalance accelerates bone loss and increases the frequency of developing osteoporosis. Long-term exposure to these heavy metals can further impair BMD, compounding the incidence of fractures and bone-related disorders.^[21,22] A cohort study revealed that increased air pollution accelerates bone loss in postmenopausal women affected by osteoporosis, with the lumbar spine being particularly affected. Nitrogen oxides were found to be especially harmful, causing a rate of bone loss in the lumbar spine that is twice as fast as that caused by normal aging. This pollution exposure was linked to a 1.22% annual decrease in BMD, highlighting the significant impact of environmental factors on bone health in older women.^[23] In addition, these factors suggest that air pollution may significantly raise fracture risk in exposed populations (the elderly and those with co-morbid conditions) and potentially increasing their susceptibility to injuries from falls. Enhancing air quality could be crucial in protecting these individuals from additional health complications.

CLIMATE CHANGE RELATED TO PMO

CONCLUSION

Understanding the various factors that influence PMO is crucial for the effective prevention and management of this widespread condition. The emerging topic of how environmental factors influence bone health is an exciting area of exploration. Getting a sample of functional bone as an organ presents significant challenges. Developing artificial bone microenvironments offers a promising avenue for advancing our knowledge. These engineered systems can be designed to replicate the biochemical and physical conditions found in human bones, providing a controlled platform for experimentation by simulating different environmental scenarios such as variations in temperature, nutrient concentrations, or physical loading. By examining these factors, we can gain valuable insights into their impact on bone health over time. In addition, hormonal changes, genetic predispositions, nutritional deficiencies, and lifestyle choices significantly influence bone health during and after menopause. By addressing these factors through proactive measures such as diet, exercise, and medical interventions, women can better mitigate their risk of developing osteoporosis. Continued research and awareness are essential to empower women to make informed decisions about their bone health, ultimately leading to improved life quality and well-being in their postmenopausal years.