EC Orthopaedics

Osteoporosis is a multifactorial skeletal disorder traditionally explained by the estrogen-deficiency model. However, recent evidence indicates that bone loss begins earlier than menopause and is influenced by multiple age-related mechanisms beyond hormonal decline. Objective of the paper is to highlight less recognized determinants of osteoporosis and fragility fractures, focusing on bone aging, oxidative stress, and early trabecular bone loss independent of bone mineral density (BMD). Early trabecular and cortical bone loss has been observed in both men and women before the onset of sex hormone deficiency. Senescence-related alterations and accumulation of reactive oxygen species (ROS), advanced glycation end products (AGEs), and advanced oxidation protein products (AOPPs) emerge as central mechanisms of skeletal deterioration.

 Keywords: Osteoporosis; Fracture; Old Age

1. Vincenzo Rochira., et al. “The endocrine role of estrogens on human male skeleton”. International Journal of Endocrinology (2015): 165215.
2. Hui SL., et al. “Age and bone mass as predictors of fracture in a prospective study”. Journal of Clinical Investigation 6 (1988): 1804-1809.
3. Riggs BL., et al. “Effects of estrogen therapy on bone marrow adipocytes in postmenopausal osteoporotic women”. Osteoporosis International 9 (2008): 1323-1330.
4. Slemenda C., et al. “Sex steroids, bone mass, and bone loss. A prospective study of pre-, peri-, and postmenopausal women”. Journal of Clinical Investigation 1 (1996): 14-21.
5. Seifert-Klauss V., et al. “Bone loss in premenopausal, perimenopausal and postmenopausal women: results of a prospective observational study over 9 years”. Climacteric5 (2012): 433-440.
6. Jeffrey Kiernan., et al. “Concise review: Musculoskeletal stem cells to treat age-related osteoporosis”. Stem Cells Translational Medicine 10 (2017): 1930-1939.
7. Patrick Coipeau., et al. “Impaired differentiation potential of human trabecular bone mesenchymal stromal cells from elderly patients”. Citotherapy 5 (2009): 584-594.
8. He L., et al. “A shorter telomere is the key factor in preventing cultured human mesenchymal stem cells from senescence escape”. Histochemistry and Cell Biology 3 (2014): 257-267.
9. Bowen Wang and Deepak Vashishth. “Advanced glycation and glycoxidation end products in bone”. Bone 176 (2023): 116880.
10. Zeng J., et al. “Advanced oxidation protein products aggravate age‑related bone loss by increasing sclerostin expression in osteocytes via ROS‑dependent downregulation of Sirt1”. International Journal of Molecular Medicine 6 (2021): 108.
11. Mohamad NV., et al. “Are oxidative stress and inflammation mediators of bone loss due to estrogen deficiency? a review of current evidence”. Endocrine, Metabolic and Immune Disorders - Drug Targets 9 (2020): 1478-1487.
12. Manolagas SC. “From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis”. Endocrine Reviews 3 (2010): 266-300.
13. Weinstein RS., et al. “Endogenous glucocorticoids decrease skeletal angiogenesis, vascularity, hydration, and strength in aged mice”. Aging Cell2 (2010): 147-161.
14. Balaban RS., et al. “Mitochondria, oxidants, and aging”. Cell 4 (2005): 483-495.
15. Chien KR and Karsenty G. “Longevity and lineages: toward the integrative biology of degenerative diseases in heart, muscle, and bone”. Cell4 (2005): 533-544.