Tools
Biochemical Markers of Osteoporosis
Introduction
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]
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]
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]
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]
Specimen Collection
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Specimen Collection
Bone Turnover Biomarkers
One of the advantages of BTMs, which supports their increased use in clinical settings, is the relatively noninvasive nature of specimen collection using serum or urine. CTX-1 exhibits circadian rhythm fluctuations that are influenced by food intake, whereas P1NP is minimally affected by food and circadian rhythm.[5][19] If both CTX-1 and P1NP are to be assessed, the sample should be collected in the morning after an overnight fast.[20] When measuring only P1NP, the sample may be collected at any time, regardless of fasting.[21] Therefore, P1NP may be the preferred bone marker when samples cannot be collected in the early morning.[21]
However, P1NP does not elicit as rapid a response as CTX-1 when monitoring the effectiveness of antiresorptive therapies (eg, bisphosphonates), which makes P1NP more susceptible to false-negative results. Therefore, assessing CTX-1 levels should be prioritized whenever possible when monitoring patients on these medications.[22][23] On the other hand, P1NP is the superior choice for monitoring patients using anabolic treatments such as teriparatide or abaloparatide.[13]
Notably, nonfasting samples can be effectively used to monitor CTX-1 levels if multiple samples are collected from the same patient, with consistent timing (ie, at the same time of day and the same interval between the last meal and sampling). This sampling methodology allows for detecting relative fluctuations in levels, although these results cannot be compared to reference ranges established using fasting samples.[22][23]
The currently recommended specimens for measuring CTX-1 and P1NP levels are ethylenediaminetetraacetic acid (EDTA) plasma and serum, respectively.[13] Although CTX-1 can also be measured from serum, studies show that EDTA plasma is preferable due to its superior stability at elevated temperatures. Specimens for measuring CTX-1 levels require prompt handling and processing, as they are less stable compared to those for P1NP measurement.[21] Samples for CTX-1 assays should ideally be frozen to less than or equal to -20 °C within 2 hours of sampling collection. The exception is when levels are to be measured within 8 hours of acquiring the sample, in which case refrigeration at 4 °C is sufficient. Samples for CTX-1 and P1NP assays remain stable at less than or equal to -20 °C for at least 3 to 6 months. Both markers retain stability even with 2 cycles of freezing and thawing, if necessary. However, it is essential to mix the sample each time it is thawed to ensure homogeneous density.[24] Notably, icterus or lipemia in the sample does not interfere with the measurements, while hemolysis greater than 0.5 g/dL (moderate) can negatively impact CTX-1 and P1NP readings.[21]
MicroRNAs
Although BTMs offer valuable insights into the dynamics of bone turnover in patients, miRNAs hold promise in providing a more specific understanding of bone homeostasis. In particular, these markers offer the ability to shed light on osteoporotic processes at the cellular level, adding significant value to their potential use in clinical settings.[25]
As with BTMs, miRNA expression can be assessed using serum and plasma samples, typically derived from blood collected through venipuncture. RNA can be extracted using various solvents, then reverse transcribed and amplified using commercially available kits of choice.[26][27]
When using the OsteomiR® RUO assay for miRNA analysis, a starting sample size of 200 μL of plasma is recommended to ensure adequate RNA yield. After thawing and centrifuging the plasma samples for 5 minutes, synthetic RNA spike-in is mixed with the lysis buffer provided in the assay kit. RNA is then precipitated out of the solution with 100% isopropanol and glycogen. Finally, the OsteomiR® chemistry kit is used to perform reverse transcription and PCR amplification.[28]
Procedures
Bone Turnover Biomarkers
The analysis and measurement of CTX-1 and P1NP are conducted using both automated analyzer systems and manual assays.[24] Recent studies have exhibited a trend of researchers running both prominent commercial automated assays for each marker simultaneously. The primary reasons for this approach are the lack of data demonstrating superior accuracy and reproducibility between the tests, as well as evidence of significant discrepancies between the 2 assays in previous studies measuring BTM levels.[21]
As standardized reference values for BTMs have yet to be established, data from measurements obtained through this process are most useful in monitoring scenarios, where serial marker measurements from the same patient track relative changes over time. This approach is valuable for assessing pharmacological therapy response and adherence, as detailed below.[29] Baseline levels should be measured before starting treatment, allowing for comparison with BTM levels at specific intervals determined by the therapeutic agent used.[22]
To monitor the effectiveness of antiresorptive agents, such as IV bisphosphonates or denosumab, CTX-1 and P1NP levels should be checked after 1 and 3 months of treatment, respectively, to assess adequate suppression. For oral bisphosphonates, CTX-1 and P1NP levels should be measured at 3 and 6 months, respectively, after treatment initiation to confirm a decrease from baseline levels. This reduction indicates that the medications are working effectively. For anabolic agents, such as teriparatide, BTMs are expected to increase in response to treatment, with P1NP being the preferred marker. P1NP levels begin to rise immediately after treatment initiation, with peak levels typically occurring within 1 to 3 months.[29] Therefore, it is recommended to assess pretreatment P1NP levels and compare them to levels measured after 1 to 3 months of therapy.[23]
Serial measurements of BTMs are recommended for all therapies to ensure that therapeutic goals are met.[16][29] Although tracking relative levels at the individual patient level is useful for assessing changes in bone turnover rates, the lack of intra-laboratory and inter-laboratory standardization and reproducibility of BTM assay procedures remains a significant barrier to their routine use in clinical practice.[30][31][23]
MicroRNAs
Serum and plasma samples can be analyzed for miRNAs using various methods, including GeneChip™ miRNA Array, real-time polymerase chain reaction (PCR), next-generation sequencing (NGS), and OsteomiR® RUO assay.[32]
- The GeneChip™ miRNA Array profiles multiple miRNAs simultaneously, while real-time PCR quantifies specific miRNA targets.
- NGS provides a comprehensive analysis of the entire miRNA transcriptome, offering insights into both known and novel miRNAs involved in bone turnover processes.[33]
- For a more targeted approach, the OsteomiR® RUO assay is designed to quantify 19 specific miRNAs related to bone metabolism, making it a valuable tool for researching osteoporotic conditions and bone health. Each method enables precise miRNA expression measurement, offering the potential for more personalized and targeted diagnostic and therapeutic approaches in bone health management.[34]
Indications
Bone Turnover Biomarkers
Studies have shown that BTMs are valuable in identifying patients with accelerated bone turnover, predicting fragility fractures, and monitoring treatment efficacy and regimen adherence.[35][36][37] However, the lack of standardized reference values that account for the various preanalytic factors and comorbidities influencing turnover levels prevents the use of BTMs as independent diagnostic and fracture prognostic tools in daily clinical practice.[31] Despite this, BTMs are widely accepted for monitoring treatment response, particularly in the first year of treatment, when changes are not yet detectable through DXA scans.[16]
Monitoring treatment efficacy and adherence: BTMs are of considerable interest as a primary monitoring tool, even after a year of pharmacotherapy. However, despite the limitations of DXA scans, they remain the current gold standard for assessing treatment response. Serial imaging is expensive and often offers limited clinical value, as changes in bone mass are visually challenging to detect and are prone to human measurement error.
In contrast, BTMs respond rapidly to changes in bone turnover physiology and maintain stable levels during pharmacotherapeutic intervention. As a result, BTMs are clinically valuable for confirming continued patient compliance throughout the treatment period.[38] Moreover, BTMs' ability to capture information on bone turnover provides insights into the status of bone quality, the second key component of the osteoporotic disease process.[23]
MicroRNAs
MiRNAs have emerged as promising tools in osteoporosis management, similar to BTMs. MiRNAs are critical in regulating bone metabolism by influencing osteoblast and osteoclast activity. As noncoding RNA molecules, miRNAs offer a noninvasive means to assess bone health, including diagnosing patients with accelerated bone turnover, aiding in the prognosis of fragility fractures, and monitoring treatment efficacy and adherence.[39]
Identifying patients with accelerated bone turnover: Similar to BTMs, miRNAs have demonstrated potential in identifying patients with accelerated bone turnover. For example, miR-21 has been consistently associated with increased osteoclast activity—a critical factor in bone resorption. Elevated levels of miR-21 can indicate patients experiencing higher rates of bone turnover, which may contribute to increased fracture risk.[40]
Prognosis for fragility fractures: MiRNAs hold promise in providing prognostic insights for fragility fractures, similar to the role of BTMs. Specific miRNA profiles have been linked to increased fracture risk through their regulation of bone turnover pathways. For example, elevated levels of miR-203a have been associated with a higher likelihood of fractures in individuals with osteoporosis.[28] By utilizing miRNA biomarkers, clinicians may be able to predict fracture risk earlier and more accurately than with traditional diagnostic methods, such as BMD assessments alone.
Monitoring treatment efficacy and adherence: Similar to BTMs, miRNAs respond quickly to changes in bone turnover, making them useful for monitoring treatment efficacy and ensuring patient adherence to medication regimens. During pharmacotherapy, miRNA levels can reflect how well the treatment regulates bone metabolism. Specifically, miR-454-3p, miR-26b-5p, and miR-584-5p levels have been shown to accurately reflect the effects of denosumab on bone in osteoporotic patients. Elevated expression of these miRNAs was also associated with improvements in BMD, highlighting their potential role as monitoring tools for therapeutic response.[41]
Potential Diagnosis
Bone Turnover Biomarkers
Current literature demonstrates the potential of BTMs as valuable clinical tools in the management of osteoporosis. However, several limitations continue to hinder their widespread integration into clinical practice. Extensive research supports the use of these markers for confirming an adequate therapeutic response to anti-osteoporotic drugs, particularly for oral bisphosphonates. The reported compliance with oral bisphosphonate use drops to less than 50% within 1 year of treatment, largely due to the high-maintenance regimen of these medications and the relatively asymptomatic nature of osteoporosis.[42]
In patients who show insufficient response to treatment despite confirmed adherence, unchanging BTMs may help identify underlying issues, such as impaired medication absorption or underlying pathologies that contribute to disruptions in bone turnover.[43] However, data supporting the use of BTMs as independent diagnostic tools remain insufficient. Multiple studies are currently exploring BTMs' potential to serve as early indicators for identifying patients at increased fracture risk by detecting subtle changes in bone turnover. This could, in theory, enable earlier detection of osteoporosis and secondary causes of accelerated bone turnover.[44][23]
MicroRNAs
Recent studies highlight the significant potential of miRNAs as biomarkers for osteoporosis diagnosis and management, offering a more precise molecular approach compared to traditional BTMs. Specific miRNA patterns, such as the upregulation of miR-21, miR-24, and miR-100, and the downregulation of miR-24a, miR-103-3p, and miR-142-3p, have been strongly correlated with lower BMD in postmenopausal osteoporosis. These findings suggest that miRNAs could serve as early diagnostic tools and markers for disease progression.[26]
MiRNAs are additional markers that can provide valuable insights for the early diagnosis of osteoporosis and may also be used to monitor disease progression. OsteomiR® has demonstrated high accuracy, with miR-375 and miR-203a showing significant diagnostic value for patients at high risk of postmenopausal osteoporosis and fragility fractures, respectively.[45][28]
These miRNAs may offer clinicians earlier and more precise indicators of bone health, making them valuable tools for monitoring disease progression and guiding treatment decisions. Additionally, miRNAs can help track therapeutic efficacy, similar to BTMs, while offering insights into cellular-level bone homeostasis, which is essential for managing bone quality—one of the key factors in osteoporosis.
Normal and Critical Findings
Bone Turnover Biomarkers
Currently, BTM reference values are insufficiently standardized, leading the joint IOF and IFCC Working Group on Bone Marker Standards (WG-BMS) to conclude that these markers are currently unsuitable for routine clinical practice. Established in 2012, the IFCC-IOF Working Group for the Standardization of Bone Marker Assays aims to enhance the standardization of CTX-1 and P1NP assays for clinical use. This group is currently conducting a study to facilitate the availability of standardized testing and reference values for osteoporosis clinics worldwide.[46]
The interpretation of bone turnover marker concentrations remains a challenge due to the lack of consensus on universal reference interval values. This absence of standardized ranges makes it difficult to categorize bone turnover rates as low, normal, or high. Individual studies have established country-specific reference ranges for P1NP and CTX-1, with values obtained from cohorts in Europe, Asia, and North America showing consistency across regions.[38][47][48][49][50][51][52][53][54][55][56][57][58][59] This suggests that reference values may be universal; however, further research is needed to conclude the effect of ethnicity and geography on variability.
Moreover, most studies have focused on determining BTM reference intervals in premenopausal, healthy individuals, with the assumption that these values can be applied to assess derangements in postmenopausal patients. However, reference ranges for CTX-1 (approximately 100-700 ng/L) and P1NP (approximately 15-70 µg/L) vary widely and show geographic differences. In addition, it has been proposed that controlling for preanalytical factors may help mitigate these variations, but further studies are needed to determine the root cause more definitively.[29][13]
Studies examining the risk of fracture in healthy, untreated postmenopausal women have consistently shown that those with higher BTMs are at an increased risk of fragility fractures. A study reported that participants with BTM levels in the highest quartile were twice as likely to experience a bone fragility fracture within the next 5 years compared to those in the first, second, and third quartiles.[60] However, studies examining BTM levels have yet to provide conclusive, universal recommendations for reference ranges to identify abnormalities in postmenopausal patients. Literature has also shown a notable lack of data in examining BTM levels in men.
When evaluating CTX-1 and P1NP values to monitor adherence and effective response to anti-osteoporotic regimens, conclusions on absolute values indicating adequate treatment are also lacking. Most studies have focused on establishing reference intervals for oral bisphosphonates, which are first-line medications in osteoporosis treatment and have a high noncompliance rate. Several studies recommend that the goal of bisphosphonate therapy in postmenopausal women should be to achieve BTM levels within the lower half of the reference interval established for healthy premenopausal women.[13][38] However, this approach depends on the proper establishment of universal reference values. When determining the change from pretreatment values that would indicate an adequate response to treatment, it is crucial to establish the least significant change (LSC) value. A change in BTM levels that exceeds the LSC is considered significant.[29] Fortunately, studies have shown that BTMs exhibit minimal arbitrary fluctuation at the individual level, enhancing the accuracy of this value.[13]
The LSC for CTX-1 and P1NP varies by study, but overall results are consistent with values reported in the TRIO study on postmenopausal women with osteoporosis undergoing oral bisphosphonate therapy. This study found that at 12 weeks of treatment, the LSC for CTX-1 and P1NP, as well as observed effect values, were measured using 2 prominent automated assays currently available on the market. For CTX-1 and P1NP, the LSC and premenopausal reference intervals were found to be -56% and 0.13 to 0.81 µg/L, and -38% and 15 to 54 µg/L, respectively. However, several limitations were identified, in addition to the need for larger-scale validation of these findings. These include some patients already exhibiting BTM levels in the lower half of the reference interval before treatment initiation. Additionally, the LSC method requires the establishment of baseline pretreatment levels, which is not currently standard clinical practice.[43]
When evaluating BTM levels, it is important to consider the various preanalytical factors and comorbid conditions that can influence these levels, including, but not limited to, diabetes, thyroid disorders, bariatric surgery, and sudden weight loss.[61][62][63][64][65] Osteoporotic patients presenting with severely elevated initial BTM values, defined as 3 SD above the mean, are atypical in osteoporosis and should prompt an evaluation for other causes such as recent fracture, hyperparathyroidism, hyperthyroidism, Paget disease, chronic kidney disease, or cancer.[66][31]
MicroRNAs
Several studies have investigated changes in the expression of specific miRNAs and their correlation with BMD values. A study examining bone loss in premenopausal women found that miR-21, miR-24, and miR-100 were significantly elevated in patients with mild-to-moderately low BMD. Additionally, this study reported notably lower levels of miR-24a, miR-103-3p, and miR-142-3p in patients diagnosed with osteoporosis.[26]
The specific normal ranges for miRNA expression, as well as those indicating osteoporosis or an increased risk of osteoporosis, are still being established. Currently, miRNA expression levels in osteoporosis are primarily used for relative comparisons (ie, higher or lower levels) rather than fixed numerical ranges. Further research is needed to define standardized cutoff points for clinical diagnostics.[32]
Interfering Factors
Bone Turnover Biomarkers
Bone turnover marker levels can be affected by multiple factors that contribute to preanalytical variability. Controllable factors, which can be adjusted or minimized, include circadian rhythm fluctuations, food intake, exercise level, alcohol consumption, seasonal variations, and medications such as oral glucocorticoids and aromatase inhibitors. On the other hand, uncontrollable factors that contribute to preanalytical variability include age, mobility status (or immobility), ethnicity, history of fractures, and menopausal status.[67]
Other factors that can confound BTM measurements include the presence of conditions that accelerate bone turnover, such as hyperparathyroidism, as well as conditions that lower BTMs, such as hypothyroidism. Additionally, conditions that dissociate the typically synchronized processes of bone formation and resorption, such as rheumatoid arthritis or multiple myeloma. Current literature advises that BTM sampling should be performed in an environment that minimizes interference from controllable factors. Additionally, it is important to remain mindful of uncontrollable factors and potential confounders.[21][68]
MicroRNAs
Similar to BTMs, miRNA levels are influenced by various physiological conditions such as age, ethnicity, mobility, and menopausal status, as well as other uncontrollable contributors to bone turnover variability. Additionally, serum miRNA levels reflect pathophysiological processes across multiple tissue types, not solely bone homeostasis. A comprehensive evaluation requires interpreting the miRNA profile associated with osteoporosis alongside patient history and other diagnostic tools.[69]
Complications
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]
Patient Safety and Education
The use of BTMs and miRNAs as additional tools to identify patients at higher fracture risk, monitor anti-osteoporosis treatment efficacy and adherence, and investigate potential secondary causes of osteoporosis can help reduce the significant financial, physical, and psychological burdens associated with fragility fractures. Clinicians should emphasize the importance of screening through DXA, either alone or in combination with BTM and miRNA measurements, to identify at-risk patients before fracture incidence.[29]
Integrating miRNAs and BTMs into clinical practice has the potential to significantly improve patient outcomes by enabling earlier identification of individuals at higher fracture risk and providing more precise tools for monitoring treatment efficacy. Patient education on the importance of osteoporosis screening and adherence to anti-osteoporotic therapies, such as bisphosphonates, is essential, given the common challenge of poor adherence due to the disease's asymptomatic nature until fractures occur. Physicians should also highlight the value of BTMs and miRNAs in detecting poor treatment response or underlying causes of increased bone turnover, facilitating timely interventions to prevent severe hip and spine fractures, which are associated with high morbidity and mortality.
Clinical Significance
Osteoporosis is a condition characterized by loss of bone mass and structural integrity, leading to fragility fractures associated with high morbidity and mortality. As osteoporosis remains clinically silent until a fracture occurs, validated methods to identify individuals at elevated risk are essential for fracture prevention. Current gold-standard tests can radiographically detect significant bone mass loss but do not assess bone quality, which is equally crucial in determining fracture risk. BTMs and miRNAs show promise as valuable tools for identifying patients with accelerated bone turnover, even in those without observable osteoporotic changes on imaging or in situations where imaging may not be available.
Moreover, BTMs and miRNAs are highly effective for monitoring treatment, as they respond rapidly to changes in bone physiology. These markers enable physicians to assess treatment efficacy, identify patients requiring therapy adjustments due to suboptimal response, and confirm adherence to medication regimens—particularly beneficial for patients on demanding treatments such as bisphosphonates. Additionally, in some cases, BTMs and miRNAs can help detect abnormal bone turnover rates in patients indicative of secondary pathologies, facilitating earlier diagnosis and management by clinicians.
The potential of BTMs and miRNAs as additional tools to assess medication efficacy, predict fracture risk, and investigate the causes of osteoporosis is highly promising. These tools could help healthcare professionals improve patient outcomes and reduce the overall cost of the disease. However, effectively using BTMs to manage osteoporosis in older men remains a challenge and is still some time away.
Bone Turnover Markers in Monitoring Pharmacotherapy Response
Persistent derangements in BTMs in the setting of pharmacotherapy treatment for osteoporosis can help identify patients who may require alternative treatments and may indicate an independent underlying condition affecting bone turnover rates.[29] Significantly elevated BTM levels (>3 SD above the normal reference range) can assist clinicians in identifying patients who require further evaluation for secondary causes of increased bone turnover. However, a universal reference range must still be established to implement this approach as standard practice in clinical settings.[31] Further studies are needed to identify and validate normal reference ranges, which are crucial for standardizing the use of BTMs in osteoporosis management, from initial diagnosis through the final stages of treatment.[13]
MicroRNAs in Monitoring Pharmacotherapy Response
Elevated levels of specific miRNAs, such as miR-454-3p, miR-26b-5p, and miR-584-5p, have been strongly associated with adherence to denosumab therapy. These miRNAs are also linked to improvements in BMD. As a result, miRNAs can serve as valuable biomarkers for monitoring medication adherence and assessing the effectiveness of pharmacotherapy.[41]
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