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Osteoporosis is the most common metabolic bone disease globally, drawing significant attention due to its public health impact and economic burden. This condition is characterized by a progressive loss of bone mass and deterioration of bone microarchitecture, both of which independently increase the risk of skeletal fragility and fractures.[1] The pathogenesis of osteoporosis arises from detrimental alterations in bone turnover homeostasis, resulting in reduced bone strength due to loss of both mass and quality. Several mechanisms contribute to this imbalance between bone resorption and formation. These mechanisms vary depending on individual risk factors such as low estrogen levels, advanced age, long-term corticosteroid use, and other secondary conditions, including systemic inflammation and thyroid or parathyroid disorders.[2] The primary goal in managing osteoporosis is to prevent osteoporosis-related fractures, commonly referred to as fragility or low-trauma fractures, which are the leading contributors to its morbidity and mortality.[3][4] Early diagnosis is crucial for achieving this objective. However, osteoporosis often goes clinically undetected until a fracture occurs, and early signs are challenging to identify through radiographic imaging. This underscores the need for alternative diagnostic tools and methods to enable early detection of bone loss, predict disease progression, and assess fracture risk.[5] The T-score is the most commonly used method for diagnosing osteoporosis, as it quantifies bone mineral density (BMD) through dual-energy x-ray absorptiometry (DXA). A BMD, which is represented by a T-score of the spine or hip that is 2.5 SD or more below the average for a healthy young adult, is considered diagnostic for osteoporosis. BMD measurements are also used to monitor disease progression and assess fracture risk. However, substantial evidence shows that most individuals who experience fragility fractures do not have T-scores indicating osteoporotic bone density.[5][6][7][8] As a result, BMD alone is recognized as insufficient for comprehensively evaluating bone strength.[9]

The T-score is the most commonly used method for diagnosing osteoporosis, as it quantifies bone mineral density (BMD) through dual-energy x-ray absorptiometry (DXA). A BMD, which is represented by a T-score of the spine or hip that is 2.5 SD or more below the average for a healthy young adult, is considered diagnostic for osteoporosis. BMD measurements are also used to monitor disease progression and assess fracture risk. However, substantial evidence shows that most individuals who experience fragility fractures do not have T-scores indicating osteoporotic bone density.[5][6][7][8] As a result, BMD alone is recognized as insufficient for comprehensively evaluating bone strength.[9] Moreover, BMD is not particularly effective as a standalone surveillance tool for monitoring treatment response, as significant changes in BMD tend to be minimal or occur slowly. This limitation is especially evident during the first year of treatment when serial DXA scans often fail to detect meaningful BMD changes. Given these constraints, researchers have investigated alternative tools to enhance osteoporosis management, with bone turnover markers emerging as a key area of interest.[10] Bone Turnover Biomarkers Bone turnover markers (BTMs) are byproducts of the bone remodeling process and can be measured in urine or serum. BTMs are categorized as markers of bone formation or bone resorption. Markers of bone formation include total and bone-specific alkaline phosphatase (ALP), procollagen type 1 N-propeptide (P1NP), osteocalcin, and procollagen type 1 C-propeptide (P1CP). Markers of bone resorption include hydroxyproline, pyridinoline, tartrate-resistant acid phosphatase 5b, deoxypyridinoline, the carboxy-terminal cross-linked telopeptide of type 1 collagen (CTX-1), and the amino-terminal cross-linked telopeptide of type 1 collagen (NTX-1).[11][12] BTMs have limited specificity, as they reflect overall bone turnover rather than specific sites. However, unlike DXA measurements, BTMs respond quickly and noticeably to changes in bone turnover rates. This makes them highly valuable in clinical practice for monitoring treatment response and ensuring adherence to medication therapy.[13]

BTMs have limited specificity, as they reflect overall bone turnover rather than specific sites. However, unlike DXA measurements, BTMs respond quickly and noticeably to changes in bone turnover rates. This makes them highly valuable in clinical practice for monitoring treatment response and ensuring adherence to medication therapy.[13] Although all BTMs can shift in response to osteoporotic disease processes, the International Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry (IFCC) recommend serum P1NP and CTX-1 as the preferred markers for bone formation and resorption, respectively, for fracture risk prediction and monitoring osteoporosis treatment.[14] Studies evaluating BTMs in various cohorts have demonstrated that elevated BTM levels are associated with increased bone turnover, which accelerates the deterioration of bone quality and heightens the risk of fragility fractures. This correlation highlights the potential of BTMs in osteoporosis management, where they have already demonstrated significant clinical value as adjunct tools for fragility fracture risk stratification, monitoring treatment response, and assessing medication adherence.[15] However, there is currently insufficient evidence to support their ability to perform these roles independently of BMD assessment via DXA or as standalone diagnostic tools.[10][16] Further research is needed to validate their utility and address the multiple physiological and pathological factors that can influence BTM levels. MicroRNAs MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression post-transcriptionally and play an essential role in various biological processes, including bone metabolism. Emerging research on miRNAs presents a promising opportunity to enhance the diagnosis and management of osteoporosis. Circulating miRNAs in serum have been shown to correlate with bone metabolism and osteoporosis. These miRNAs influence the differentiation and activity of osteoblasts and osteoclasts, thereby affecting bone formation and resorption. Moreover, commercial panels such as OsteomiR®, which assess a set of 19 bone-related miRNAs, highlight their potential for clinical application.[17]

MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression post-transcriptionally and play an essential role in various biological processes, including bone metabolism. Emerging research on miRNAs presents a promising opportunity to enhance the diagnosis and management of osteoporosis. Circulating miRNAs in serum have been shown to correlate with bone metabolism and osteoporosis. These miRNAs influence the differentiation and activity of osteoblasts and osteoclasts, thereby affecting bone formation and resorption. Moreover, commercial panels such as OsteomiR®, which assess a set of 19 bone-related miRNAs, highlight their potential for clinical application.[17] Integrating miRNAs with traditional diagnostic tools has the potential to transform osteoporosis management by facilitating earlier detection of bone loss, improving risk stratification, and enabling more personalized treatment strategies. As research progresses, miRNAs could emerge as key biomarkers in the comprehensive evaluation and management of osteoporosis, addressing limitations of conventional methods such as BMD and BTMs.[18]

Potential Patient Complications The collection of samples for bone turnover marker and miRNA analysis is relatively noninvasive; thus, it carries a low risk of medical complications for the patient. Complications in Establishing Bone Turnover Markers as a Gold Standard in Osteoporosis Management Although promising research aims to validate the use of BTMs in osteoporosis management, several limitations must be addressed before these markers can be integrated into clinical practice as adjuncts or standalone tools in standard care. Compiling data for large meta-analyses is a significant challenge due to the inherent heterogeneity in study protocols and data analysis methods across different research efforts. Standardization in the analytical methods used in studies to establish reference levels for bone turnover markers and in protocols for specimen collection and their associated assay is absent.[70] Until reference values for bone turnover markers are validated in the literature, their clinical utility remains limited. This also hinders the ability of studies to effectively address and minimize false positives and negatives caused by potential interfering factors.[21] Complications in Establishing MicroRNAs as a Gold Standard in Osteoporosis Management The development of miRNA-targeting drugs as an intervention for osteoporosis progression is complicated by certain limitations. Notably, a single miRNA can influence multiple pathways by targeting various genes, which may lead to unintended adverse effects. Furthermore, while miRNAs hold promise as diagnostic markers and tools for monitoring disease progression, the lack of comprehensive understanding of the precise mechanisms through which miRNAs regulate bone homeostasis and osteoporotic processes hinders their clinical application. Further research is needed to characterize the mechanisms by which miRNAs influence pathophysiological processes in osteoporosis.[32]