# Therapeutic Potential of Chrysin in Improving Bone Health
## 1 Introduction  
Currently, the magnitude of musculoskeletal diseases is emerging systematically among all age groups, affecting the social life of people and leading to pain and disability [1]. Osteoporosis is the most discussed burden of approximately 1 in 3 women and 1 in 5 men [2]. The predominant risk factors projecting bone diseases such as osteoporosis are age, sex, genetic defects, sedentary lifestyle, vitamin D deficiency/insufficiency, minimal intake of calcium, and early menopause [3]. However, the possible aspects that can reduce the intensity of skeletal disorders can be the recognition of the disease in its early stage followed by an effective treatment that includes ingestion of appropriate vitamin D and calcium supplements to combat bone loss [4]. Vitamin D is broadly recognized as a \"bone vitamin\" for its magnificent impact on osseous tissue. Conversely, its insufficient distribution leads to vitamin D deficiency, which has a tremendous effect on skeletal healthand worsens pathological conditions such as osteoporosis [5,6]. It was formerly known that the imperative relationship between active vitamin D and transcellular calcium uptake is necessary for maintaining bone architecture [7]. The observational findings on calcium kinetics specified that systematic absorption of calcium is approximately 30-40% in the case of adequate vitamin D (>32 ng/mL) and elicits only 10-15% in the case of low vitamin D (<15 ng/mL) [8].  
On the other hand, although hypovitaminosis D is a modifiable risk factor, the medical community is facing several challenges in terms of maintaining or achieving optimum serum vitamin D\({}_{3}\) levels and retaining bone mass [9]. Respective research strategies are implemented to conquer vitamin D insufficiency by targeting sunlight exposure and climatic conditions [10], gut absorption of vitamin D supplements [11], vitamin D receptor (VDR) genotyping [12], and metabolic expression of cytochrome P450 (CYP450) enzymes and their interplay with vitamin D [13,14]. CYP450 enzymes are the major class of catabolic enzymes that play a decisive role in the pharmacokinetics of drugs as well as endogenous substances. Since CYP enzymes metabolize 90% of medicinal drugs, numerous investigations implying CYP450 have become crucial for revealing unveiled drug-drug interactions [15]. It is possible that the interactions caused by enzymatic inhibition/induction result in diminished/enhanced metabolic compounds, which may have a greater emphasis on the kinetic and dynamic profiles of therapeutic targets [16]. In this regard, we focused on the multifunctional class of enzymes CYP3A4, which catalyzes 25-hydroxylated-mediated conversion of the active form of vitamin D into its inactive form [14]. Interestingly, research studies revealed that therapeutic substrates (inducers/inhibitors) of CYP3A4 enzymes may contribute to altering the 1,25(OH)\({}_{2}\)D\({}_{3}\) levels in the serum [15]. Various systematic studies have indicated that higher doses of vitamin D\({}_{3}\) fail to achieve optimum serum 25-OH-D\({}_{3}\) levels in humans [17]. From this perspective, subsequent inhibition of vitamin D metabolism by CYP3A4 substrates may show an ameliorative effect on hypovitaminosis D. We hypothesized to enhance 25-OH-D\({}_{3}\) levels by incorporating the well-established CYP3A4 inhibitor chrysin [18], as shown in Figure 1. Chrysin is a natural flavonoid with beneficial pharmacological effects, such as anticancer, neuroprotective, hepatoprotective, cardioprotective, and antiarthritic effects [19,20]. It has also shown a promising outcome in osteopororotic rats [21]. Our research aimed to study the impact of chrysin on low-dose vitamin D\({}_{3}\) supplementation and its further implications on vitamin D deficiency conditions and bone health.  
Figure 1: Chrysin CYP3A4 inhibition pathway: impact of chrysin on vitamin D and bone health.