Insights and implications of sexual dimorphism in osteoporosis

Abstract

Osteoporosis, a metabolic bone disease characterized by low bone mineral density and deterioration of bone microarchitecture, has led to a high risk of fatal osteoporotic fractures worldwide. Accumulating evidence has revealed that sexual dimorphism is a notable feature of osteoporosis, with sex-specific differences in epidemiology and pathogenesis. Specifically, females are more susceptible than males to osteoporosis, while males are more prone to disability or death from the disease. To date, sex chromosome abnormalities and steroid hormones have been proven to contribute greatly to sexual dimorphism in osteoporosis by regulating the functions of bone cells. Understanding the sex-specific differences in osteoporosis and its related complications is essential for improving treatment strategies tailored to women and men. This literature review focuses on the mechanisms underlying sexual dimorphism in osteoporosis, mainly in a population of aging patients, chronic glucocorticoid administration, and diabetes. Moreover, we highlight the implications of sexual dimorphism for developing therapeutics and preventive strategies and screening approaches tailored to women and men. Additionally, the challenges in translating bench research to bedside treatments and future directions to overcome these obstacles will be discussed.

Fig. 1

The prevalence of osteoporosis in men and women throughout their lifetimes. a Left: The prevalence of osteoporosis in women and men aged 50 and older in selected countries. The sex-specific prevalence rates of osteoporosis in the world, China, European Union (EU) countries, and the United States (US) are presented for women and men aged 50 years and older. The criterion of the World Health Organization was applied for the diagnosis of osteoporosis. The following data sources were used to determine osteoporosis prevalence: osteoporosis prevalence worldwide and in EU countries (https://www.osteoporosis.foundation/facts-statistics/epidemiology-of-osteoporosis-and-fragility-fractures); osteoporosis prevalence in China, the survey of the China Ministry of Health; and osteoporosis prevalence in the US, The Centers for Disease Control and Prevention. Middle: The sex-specific prevalence of osteoporotic fractures in selected countries. Unlike osteoporosis, the population-based prevalence of osteoporotic fractures is difficult to obtain for men and women by country due to the lack of standard diagnostic criteria. The data represent the proportions of hip fractures in men and women worldwide, China, EU countries, and the US. Data on hip fractures in China were adopted from a study in Hefei, China. Data for hip fractures worldwide, in EU countries, and in the US originated from the following data source: (https://www.osteoporosis.foundation/facts-statistics/epidemiology-of-osteoporosis-and-fragility-fractures). Right: The cumulative mortalities among male hip fracture patients were higher than those of female patients at 6, 12, and 36 months. Data were adopted from the study in Denmark. b The balance of bone formation and bone resorption changes during a lifetime due to decreased sex steroids, increased glucocorticoids, T2DM, and aging. Bone resorption can outweigh formation because of decreased osteoblastogenesis, enhanced osteoclastogenesis, reduced bone remodeling, and cell senescence. c Bone mass (upper), average sex hormone production (upper middle), prevalence of T2DM (lower middle), and urine cortisol levels (below) in men and women throughout their lifetime. The dots representing 24 h urine cortisol levels, shown as the 2.5th and 97.5th percentiles, were adapted from a study in Switzerland. SASP senescence-associated secretory phenotype

Fig. 2

X-linked osteoporosis in males. X-linked osteoporosis is most likely more common in males, given the higher rates of mutation in genes, such as PLS3 and factor VIII (FVIII), that are located on the X chromosome. PLS3 deficiency induces an imbalance between bone resorption and formation, resulting in insufficient mineralization in osteoblasts, increased bone resorption in osteoclasts, and dysregulation of mechanosensing in osteocytes. A missing or defective clotting protein, factor VIII (FVIII), may directly disrupt bone homeostasis via the RANK/RANKL/OPG pathway in hemophilia A (HA) patients. The FVIII/VWF complex inhibits RANKL and increases the activity of OPG, thereby promoting osteogenesis. Activated FVIII detaches from VWF, binds to FIX, and then activates FX to FXa, which is responsible for the conversion of prothrombin into thrombin. Thrombin binds to PRL-1 to increase the production of IL-6, which further enhances the expression of RUNX2 and osteocalcin, decreasing the expression of RANKL. FVIII or FIX regulates the Wnt/β-catenin pathway and reduces the production of sclerostin to further inhibit the Wnt signaling pathway. OPG osteoprotegerin, RANKL receptor activator of nuclear factor-kappa B ligand, TNF-α tumor necrosis factor α, IFN-γ interferon-γ; IL-1β, interleukin-1β, IL-6 interleukin-6, MAPK mitogen-activated protein kinase, COX-2 cyclooxygenase 2, PGE2 prostaglandin E2, EP4 PGE2 receptor 4, RUNX2 runt-related transcription factor 2

Fig. 3

Mechanisms of sex steroid hormones on bone homeostasis. a Mechanism of estrogen action on bone cells. Estrogen is the most important sex hormone in women who undergo a hormonal shift in 17β-estradiol levels, transitioning from perimenopause to early postmenopause. The declining estrogen levels after menopause directly enhance the apoptosis of osteocytes to reduce bone remodeling, indirectly decrease osteoblastogenesis, and increase osteoclastogenesis by regulating RANKL. Estrogen regulates RANKL by acting on stromal cells and immune cells by changing cytokine profiles. b Schematic of the effects of male sex hormones on bone cells. The male sex hormone testosterone is an important regulator of bone cells, mainly osteoblasts and osteoclasts. Decreased testosterone levels in older men induce a decrease in DHT, which further represses the proliferation and differentiation of osteoblasts, increases apoptosis of osteoblasts, and reduces the synthesis of EMP. The decline in testosterone results in reduced estrogen levels, which further directly or indirectly decreases osteoblastogenesis and increases osteoclastogenesis to reduce BMD. ALP alkaline phosphatase, Bcl-2 B-cell lymphoma-2, ERα estrogen receptor alpha, ERβ estrogen receptor beta, FasL Fas ligand, IL-1 interleukin-1, IL-6 interleukin-6, IL-7 interleukin-7, IFN-γ interferon-γ, RANKL receptor activator of nuclear factor kappa B ligand, TNF-α tumor necrosis factor-alpha, Akt serine/threonine-protein kinase, AR androgen receptor, 5-AR congenital 5-alpha-reductase, BMD bone mineral density, DHT dihydrotestosterone, EMP erythromyeloid progenitor, PI3K phosphatidylinositol-3 kinase

Fig. 4

The role of sex hormone-mediated oxidative stress and protective autophagy in osteoporosis. a Glucocorticoids, diabetes, and aging induce reactive oxygen species (ROS) and increase oxidative stress, which is a major mechanism of osteoporosis. Excessive oxidative stress disrupts bone homeostasis by promoting bone resorption and inhibiting bone formation and remodeling. Sex steroids, especially estrogen, can promote protective autophagy to enhance bone formation. b 17β-estradiol promotes protective autophagy in osteoblasts and osteocytes via FOXO3 and mTOR signaling to enhance bone formation. Estrogen also inhibits excessive autophagy in osteoblasts via JNK signaling to decrease apoptosis. Excessive ROS increase protective autophagy in osteoclasts to promote survival and bone resorption. c Aging, diabetes, glucocorticoids, and estrogen deficiency all increase ROS to induce excessive oxidative stress to repress osteoblastogenesis through TCF/LEF signaling. Oxidized lipids in bone marrow further enhance adipogenesis by activating PPARγ signaling. Crosstalk between ROS and p66^Shc promotes the apoptosis of osteoblasts and osteocytes, which can be repressed by E2 and DHT. d Schematic illustration of autophagy from initiation, elongation, maturation, and autophagosome. Key molecules under the regulation of sex hormone receptors, AR and ESR1, are indicated by dotted lines. ROS reactive oxygen species, AR androgen receptor, ER estrogen receptor, ESR1 estrogen receptor 1, E2 17β-estradiol, DHT dihydrotestosterone, 4-HNE 4-hydroxynonenal, TCF/LEF T-cell factor/lymphoid enhancer-binding factor, JNK c-Jun n-terminal kinase, AMPK adenosine 5’-monophosphate (AMP)-activated protein kinase, MAPK mitogen-activated protein kinases, ERK extracellular regulated protein kinases, TFEB transcription factor EB, PI3k phosphoinositide 3-kinase, FOXO forkhead Box O, ULK1 unc-51-like kinase 1, PPARγ peroxisome proliferator-activated receptor γ

Fig. 5

Pathological mechanisms of osteoporosis induced by diabetes, glucocorticoids, and psychological stress. a Glucocorticoid (GC) inhibits the proliferation and increases the apoptosis of osteoblasts by downregulating Wnt signaling, repressing the production of sex steroids, decreasing calcium absorption, and reducing growth factors. GC decreases the differentiation of adipocytes in bone marrow by decreasing the Wnt/β-catenin pathway. GCs also promote the apoptosis of osteocytes by increasing the influx of Ca²⁺. GCs decrease apoptosis and promote the survival of osteoclasts by upregulating RANKL and downregulating M-CSF. b T2DM-associated osteoporosis is characterized by decreased bone turnover and impaired microarchitecture, which has a complex pathological mechanism and involves multiple signaling pathways. T2DM affects bone metabolism, demineralization, bone marrow adiposity, and calcium balance through hyperglycemia. Other coexisting conditions in T2DM, such as obesity, impaired renal function, hypercalciuria, reactive oxygen species (ROS), more advanced glycation end products (AGEs) accumulation, inflammation, and peptides in the gastrointestinal (GI) tract, contribute to the higher prevalence of osteoporosis in T2DM patients. Estrogen and androgen can scavenge ROS directly or indirectly by changing cytokine profiles and exert protective effects by nonskeletal mechanisms such as the regulation of adipose tissues. Estrogen protects pancreatic β cells and increases insulin production to indirectly alleviate diabetic osteoporosis. c Psychological stress contributes to osteoporosis through the hypothalamic‒pituitary‒adrenal (HPA) axis and the brain-immune connection. Psychological stress promotes bone loss by regulating growth hormones, glucocorticoids, sex hormones, and pro-inflammatory cytokines. MSCs mesenchymal stem cells, M-CSF macrophage colony-stimulating factor, OPG osteoprotegerin, RANKL receptor activator of nuclear factor kappa-B ligand, AGEs advanced glycation end products, ROS reactive oxygen species, SOST sclerostin, GLP-1 glucagon-like peptide-1, GI tract gastrointestinal tract, GIP gastric inhibitory polypeptide, IGF insulin-like growth factor, GC glucocorticoid, CRH cortisol-releasing hormone, GnRH gonadotrophin-releasing hormone, GHRH growth hormone-releasing hormone, SNS sympathetic nervous system, NPY neuropeptide Y, NMU neuromedin U, ACTH adrenocorticotrophic hormone, GH growth hormone, FSH follicle-stimulating hormone, LH luteinizing hormone, PICs pro-inflammatory cytokines

Fig. 6

Overview of current mainstream treatments for osteoporosis. Numerous endocrine system hormones, including the hypothalamic‒pituitary‒adrenal (HPA) axis, PTH, androgen, estrogen, and glucocorticoid, all tightly regulate bone homeostasis and may be powerful targets for osteoporosis treatment. Current mainstream treatments for osteoporosis are indicated in green. CRH cortisol-releasing hormone, GnRH gonadotrophin-releasing hormone, ACTH adrenocorticotrophic hormone, TSH thyroid stimulating hormone, FSH follicle-stimulating hormone, LH luteinizing hormone, PTH parathyroid hormone, T3 triiodothyronine, ER estrogen receptor, RANKL receptor activator of nuclear factor kappa-B ligand