## 1 Introduction  
In recent decades, global aging has outpaced historical trends, especially in developed nations, assisted by improved living conditions and advancements in medicine, that contribute to longer lifespans. This shift is significantly impacting healthcare systems as age-related pathologies surge, including osteoporosis. Osteoporosis is a systemic skeletal disorder characterized by reduced bone mineral density and microarchitectural deterioration bone tissue, often associated with aging, hormonal changes, and inadequate bone formation [1, 2]. Elderly individuals with osteoporosis are burdened by an elevated risk of experiencing fragility fractures after minor trauma, which is a primary contributor to reduced mobility and vulnerability among aging cohorts [3, 4]. Prevention strategies include a balanced diet rich in calcium and vitamin D, regular weight-bearing exercise, and pharmacological interventions aimed at preserving bone mass [1, 2]. Since pharmacological prevention only accounts for about 5% of the costs associated with osteoporosis [5] and considering that managing complications like fractures is considerably more challenging and costly, there is a heightened necessity and convenience for early identification of individuals at risk of developing osteoporosis. Achieving an early diagnosis and understanding the molecular and genetic factors contributing to osteoporosis are crucial for developing targeted therapies and improving overall bone health. In 1994, the World Health Organization proposed, dual X-ray absorptiometry (DXA) as the gold standard for the diagnosis of osteoporosis [6; 7] (Figure 1). To date, DXA is a widely accessible, well-standardized technique that quantifies bone mineral density (BMD-g/cm\({}^{2}\)) using two X-ray beams of different energies. Nevertheless, several studies have demonstrated that DXA's results can be hindered in assessing BMD [8], due to body composition variations, overlying soft tissue, and vascular calcification, which can cause distortions in the measurements [9; 10; 11; 12]. Clinical practice has relied on DXA to assess bone strength through the typical BMD in a specific region. However, because DXA also ignores 3D bone structure, the representative BMD cannot be a great standalone indicator of bone strength. Several reports have demonstrated that diverse bone architectures in patients with the same BMD might lead to different fracture risks. Some of these issues might potentially be solved by quantitative computed tomography (QCT), particularly by measuring the volumetric BMD of trabecular bone. This technique makes it easier to analyze localized BMD since it can distinguish between cortical and trabecular bone [13], and it also offers a precise volumetric BMD quantification measured in mg/cm\({}^{3}\) rather than g/cm\({}^{2}\) units [13; 14]. Moreover, QCT tests are not affected  
Figure 1: Dual-energy X-ray absorptiometry (DXA) for measuring BMD of the spine at the level of L1–L4 (**A**), femoral neck (**B**), and whole body (**C**). by common para-physiologic conditions, often observed in the elderly, such as osteophyte or aortic calcification [15]. The main limit is that these measurements cannot be applied retroactively, but rather they must be performed using calibration phantoms [16; 17; 18; 19]. Phantom-based QCT (PB-QCT), which encompasses synchronously calibrated QCT and asynchronously calibrated QCT, and phantomless QCT (PL-QCT) are the two primary categories of QCT. The PB-QCT examination requires a reference phantom made of materials such as K2 HPO4 with known densities to accurately quantify the BMD values. In contrast to PB-QCT, PL-QCT does not require simultaneous scanning of the external phantom to assess BMD. The aim of the review is to evaluate the feasibility and different approaches applied to achieve QCT BMD assessment with the phantomless calibration techniques.