Abstract

Abstract
Osteoporosis is a widespread disease of old age, and every fifth elderly person in the world has it, and women after menopause are particularly exposed to it. The condition has a high chance of creating fractures that can lead to severe complications or even death. Available pharmacological interventions (bisphosphonates, RANKL inhibitors, and hormone replacement therapy) are capable of reducing the risk of fractures, but compliance with regular treatment is often a problem among patients, and these medications are associated with such side effects as GI upset, atypical fractures, and other health problems related to hormone activity. In comes Ashwagandha (Withania somnifera), an ancient Ayurvedic plant commonly referred to as a Rasayana. Its extracts contain withanolides, which have anti-inflammatory and antioxidant effects. What actually caught our attention, however, is that preclinical studies revealed that the estrogen-like withanolides in Ashwagandha prevented bone loss in estrogen-depleted rats. In addition to that, laboratory work indicates that the plant regulates endocrine pathways in a way that is beneficial to bone health: it reduces cortisol and increases testosterone. The molecules responsible for these effects are equally interesting from a mechanistic perspective. A major withanolide, Withaferin-A, drives osteoblast proliferation and differentiation via the activation of Runx2 and prevents osteoclast differentiation by inhibiting NF-kappa B and RANKL. It also helps to prevent degradation of Runx2 by Smurf2, which maintains osteoblast activity intact. In vitro, osteoblasts and osteoclasts incubated with Ashwagandha extracts remain healthier: they do not release Runx2 and Smad complexes, and cytokines that drive bone inflammation are reduced. The situation is no brighter in living models. Ashwagandha also blocked the loss of bone density and reversed microarchitecture and biomechanical strength in ovariectomized rats. This is beginning to be supported by limited human studies. A recent RCT combined Ashwagandha with Asparagus racemosus and observed that the combination was able to decrease the bone-turnover markers and inflammatory biomarkers in postmenopausal women in a dose-dependent manner. The findings are promising yet premature; bigger studies are required before such results can be extrapolated. In conclusion, the multi-faceted effect of Ashwagandha, osteogenic, anti-resorptive, anti-inflammatory, and antioxidant, in combination with its low-adverse-effect profile, makes it a potential supplement to existing osteoporosis therapies. In case these initial data are confirmed in prospective studies, Ashwagandha may be used as an adjunct to conventional treatment, which may reduce side effects and enhance patient outcomes in osteoporosis.

Key words: Osteoporosis, Ashwagandha, Withanolides, Osteoblast, Signaling