As the most common metabolic bone disease worldwide, osteoporosis and its associated morbidities have garnered significant attention as a public health concern and economic burden. The condition is characterized by progressive loss of bone mass and destruction of bone microarchitecture, both of which are independent risk factors for skeletal fragility and fracture. The primary goal of managing osteoporosis is the prevention of these fractures, termed fragility or low-trauma fractures, as they are the disease’s main source of morbidity and mortality. Consequently, the primary goal of osteoporosis management is fracture prevention, with early diagnosis being crucial. Unfortunately, osteoporosis is commonly indetectable clinically before a fracture event, and early indicators of disease are difficult to assess radiographically. This highlights the need for methods that allow early detection of loss of bone integrity to mitigate further disease progress and subsequent fracture.
The pathogenesis of osteoporosis stems from detrimental alterations in the homeostasis of bone turnover, leading to decreased bone strength by loss of mass and quality. There are multiple known mechanisms capable of causing such derangement of the balance between bone breakdown and formation and are dependent on the individual risk factors of each patient, such as low estrogen state, advanced age, long term corticosteroid use or other disease states such as systemic inflammation, thyroid, and parathyroid disease.
The most commonly utilized method for identifying osteoporosis is through T-score determination, a quantified measure of bone marrow density (BMD) using dual-energy x-ray absorptiometry (DXA). A BMD, represented by T-score, of the spine or hip greater than or equal to 2.5 standard deviations below the average for that of healthy young women is considered diagnostic. BMD values are also used to determine and monitor management, in addition to establishing fracture risk, despite profuse data showing that the majority of patients experiencing fragility fractures do not have a T-score indicating osteoporotic bone density. As a result, it is recognized that BMD is insufficient as a sole means for comprehensively evaluating bone strength. Moreover, BMD is not particularly useful as a singular surveillance tool of treatment response, as changes in density may be slow or minimal. This is particularly apparent within the first year of treatment, where serial DEXA scans are ineffective at detecting BMD change. Due to the limitations of BMD, researchers have explored other possible tools to support osteoporosis management, with bone turnover markers being a topic of particular interest.
Bone turnover biomarkers (BTMs) are byproducts produced from the bone remodeling process that can be measured in urine or serum and are indicative of the rate of bone turnover. BTMs are classified as either markers of bone formation such as total alkaline phosphatase (total ALP, bone-specific alkaline phosphatase (B-ALP), procollagen type 1 N-terminal propeptide (P1NP), osteocalcin (O), and procollagen type 1 C-terminal propeptide (P1CP), or as markers of bone resorption such as hydroxyproline (HYP), pyridinoline, tartrate-resistant acid phosphatase 5b (TRAP 5b), deoxypyridinoline (DPD), carboxy-terminal cross-linked telopeptide of type 1 collagen (CTX-1), and amino-terminal cross-linked telopeptide of type 1 collagen (NTX-1).
There is limited specificity with these markers, as BTMs are reflective of the rate of bone turnover in general. However, unlike DXA measurements, BTM levels show appreciable, rapid response to changes in turnover rate, making them of great use clinically for monitoring treatment response and adherence in osteoporotic patients from the onset of treatment initiation.
Although all BTMs can shift in response to osteoporotic disease processes, the International Osteoporosis Foundation (IOF) and International Federation of Clinical Chemistry (IFCC) have recommended serum P1NP and CTX-1 as bone formation and resorption reference markers, respectively, for use in fracture risk prediction and monitoring of osteoporosis treatment. Studies looking at BTMs in various cohorts have shown that elevated markers are associated with increased bone turnover, which increases the deterioration of bone quality and, thus, the risk of fragility fracture. This correlation shows promise in osteoporosis management, where bone turnover biomarkers (BTMs) have already proved to be of clinical use as adjuvant tools for fragility fracture risk stratification and treatment response, as well as adherence monitoring. However, there is currently insufficient evidence to establish their ability to fulfill these roles without the concomitant assessment of BMD with DXA, nor their use as an independent diagnostic tool. As such, more research is needed to establish their utility, as well as how to adjust for the multiple physiological and pathological factors that can influence levels.
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