International Journal of Molecular Medical Science, 2025, Vol.15, No.4, 185-194 http://medscipublisher.com/index.php/ijmms 189 4.3 Similarities and differences with past research results The current findings are consistent with the results of some recent high-quality meta-analyses and large-scale studies (randomized trials), which also failed to demonstrate that vitamin D supplementation alone has a preventive effect on fractures in elderly people living at home or in general health (Zhao et al., 2017; LeBoff et al., 2022; Khatri et al., 2023; De Souza et al., 2024a; De Souza et al., 2024b). However, these results differ from some earlier studies and summary analyses, which suggested that it might be effective, especially when vitamin D is taken together with calcium, or for people living in institutions such as nursing homes who are inherently deficient in vitamin D (Chapuy et al., 1992; Weaver et al., 2015; Yao et al., 2019; Chakhtoura et al., 2021). The differences in research results are largely due to variations in the research subjects (population), the initial vitamin D levels, supplementation methods (plans), and whether calcium supplementation was carried out simultaneously. The latest and most comprehensive analyses all emphasize that vitamin D alone should not be recommended for the prevention of fractures in the elderly, especially those who are not deficient in vitamin D and have no other risk factors for fractures (Zhao et al., 2017; LeBoff et al., 2022; Khatri et al., 2023; De Souza et al., 2024a; De Souza et al., 2024b). 5 The Differential Effects of Supplementary Plans and Population Characteristics 5.1 Subgroup analysis results based on dose levels and supplementation frequencies Subgroup analysis showed that both daily supplementation and periodic (weekly or monthly) supplementation of vitamin D could effectively increase the concentration of serum 25 (OH) D, and when the cumulative dosage was the same, the effect and safety were similar. For instance, taking the same total dose of vitamin D3 daily, weekly or monthly (such as 1000-1500 international units per day, or calculating the amount to be taken weekly or monthly based on this) will lead to similar improvements in the status of vitamin D. Simple supplementary plans may make people more willing to persist, especially the elderly or those with chronic diseases (Płudowski, 2023). However, there is some evidence suggesting that taking an unusually large dose at one time (for instance, ≥300 000 international units at a time) may increase the risk of adverse conditions such as falls or fractures, especially for frail elderly people. So for safety reasons, it is recommended to take an appropriate dose daily or weekly (Giustina et al., 2022; Xu and Li, 2025). Although daily supplementation and supplementation at intervals have similar effects in improving vitamin D deficiency, the choice of which option to use depends on the patient's preference, the extent to which they can persist, and the actual condition of their illness. For instance, simple weekly or monthly supplementation regimens may be more practical when it is difficult to adhere to daily supplementation on a regular basis. However, doctors should avoid giving patients too many doses at one time to minimize potential risks (Giustina et al., 2022; Płudowski, 2023). 5.2 Changes in risk in populations with different baseline vitamin D levels For those who are deficient in vitamin D from the very beginning (serum 25 (OH) D<30 nanomoles per liter), the benefit of vitamin D supplementation in reducing the risk of fractures is the most obvious. After supplementation, the risk of bone problems, including fractures and bone loss, can be reduced (Figure 2) (Amrein et al., 2020; Giustina et al., 2022). In contrast, for those whose initial vitamin D levels were not low (serum 25 (OH) D>50 nanomoles per liter), supplementing vitamin D usually did not have an additional preventive effect on fractures. Both large-scale randomized trials and Mendel-based randomization studies have demonstrated this point (Bouillon et al., 2021; Sofianopoulou et al., 2021;Giustina et al., 2022). For those who were severely deficient in vitamin D at the beginning, not only did their vitamin D levels improve more significantly after supplementation, but the probability of death and illness also decreased considerably. Therefore, supplementing calcium for people with low vitamin D levels at the beginning not only has clinical effects but is also cost-effective. However, regular calcium supplementation for people with adequate vitamin D levels is unlikely to bring significant benefits to bones (Amrein et al., 2020; Bouillon et al., 2021; Sofianopoulou et al., 2021). 5.3 The regulatory effect of calcium supplementation on fracture risk Calcium supplementation can significantly alter the impact of vitamin D on the risk of fractures. Many consensus
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