Bone turnover: markers of bone formation and resorption

Bone is not a "static" tissue. Even in healthy adults, it is constantly being renewed: some old bone tissue is broken down by osteoclasts, and in its place, osteoblasts form new bone matrix. This continuous cycle is called bone remodeling. Laboratory markers of bone turnover reflect the rate and direction of this process, helping to understand how actively bone is being built and broken down in the body. [1]

The importance of these tests stems from the fact that they change much more rapidly than bone mineral density. Densitometry shows the cumulative effect of bone loss or preservation, while bone turnover markers can change within weeks or months of starting therapy. Therefore, they are particularly useful in cases where the physician needs to not only confirm the presence of osteoporosis, but also understand whether the body is responding to treatment and whether the patient is adhering to the prescribed regimen. [2]

However, bone turnover markers are almost never used as a standalone diagnostic test for osteoporosis. The American Association of Clinical Endocrinology's clinical guidelines explicitly state that they do not alone provide a diagnosis, although elevated values may indicate faster bone loss and a higher risk of fractures. Densitometry, the presence of low-trauma fractures, age, clinical risk factors, and a general assessment of fracture risk still play a key role in diagnosis. [3]

Current international consensus confirms that in postmenopausal women, higher concentrations of bone turnover markers are associated with a higher risk of fractures. However, this association is not yet standardized enough to incorporate these markers into risk models with the same confidence as age, previous fractures, or densitometry parameters. Therefore, their clinical role today is primarily supplementary, rather than primary. [4]

In practice, bone turnover markers are best understood as a "dynamic layer" of information. They don't replace imaging or densitometry, but they do help to understand the rate of processes: whether resorption is progressing rapidly, whether it is being suppressed by medication, whether bone formation has increased with anabolic therapy, whether the picture is distorted by chronic kidney disease, a recent fracture, or poor preparation for analysis. It is in this role that they have become an important part of modern metabolic osteology. [5]

Table 1. What bone turnover markers can and cannot show

What markers help to assess	What they can't reliably replace
Bone remodeling rate	Densitometry
Early biological response to treatment	Comprehensive diagnosis of osteoporosis
Indirect assessment of therapy adherence	Assessing bone strength with a single number
Risk of accelerated bone loss	Determining the cause of osteoporosis without further examination
Features of metabolism in chronic kidney disease and some metabolic bone diseases	Morphological assessment of bone in complex cases

The data are summarized from modern reviews and clinical guidelines. [6]

What markers are considered bone formation markers?

Bone formation markers reflect the activity of osteoblasts, the cells that synthesize bone matrix and participate in its mineralization. Three of the most well-known markers are the N-terminal propeptide of procollagen type I, bone alkaline phosphatase, and osteocalcin. Each is associated with new bone formation, but not all are equally useful for routine clinical practice. [7]

Today, the N-terminal propeptide of procollagen type I is considered the primary reference marker for bone formation. The International Osteoporosis Foundation and the International Federation of Clinical Chemistry and Laboratory Medicine proposed its use as a basic marker in research and practice back in 2011, and the 2025 consensus confirmed this position. This is because this indicator accurately reflects the synthesis of type I collagen, the main protein of the bone matrix, and is relatively convenient for monitoring treatment. [8]

Bone alkaline phosphatase is also a marker of formation. It reflects osteoblast activity and mineralization processes. This indicator is particularly interesting in situations where standard collagen markers become less reliable, such as in chronic kidney disease, because bone alkaline phosphatase is less dependent on renal excretion. This is why it is named one of the preferred markers in the updated consensus for chronic kidney disease. [9]

Osteocalcin has historically been a very popular marker of formation, but it is now used more cautiously. It is more dependent on the measurement method, renal function, and a number of physiological factors. For this reason, osteocalcin has given way to the N-terminal propeptide of procollagen type I as the standard marker for monitoring osteoporosis in most clinical and research protocols. [10]

From a practical standpoint, elevated bone formation markers do not always indicate disease. They can be expected and desirable, for example, during anabolic therapy, when treatment stimulates new bone formation. However, they can also occur in Paget's disease, hyperparathyroidism, fracture recovery, and other conditions with accelerated remodeling. Therefore, any elevated level should be considered in the context of symptoms, medical history, age, renal function, and other laboratory data. [11]

Table 2. Main markers of bone tissue formation

Marker	What does it reflect?	Material	Practical features
N-terminal propeptide of procollagen type I	Synthesis of type I collagen by osteoblasts	Blood	The main reference marker for bone formation
Bone alkaline phosphatase	Osteoblast activity and mineralization	Blood	Useful for chronic kidney disease
Osteocalcin	Functional activity of osteoblasts	Blood	Depends more on the method and renal function

The classification is based on contemporary reviews and consensus documents.[12]

What markers are considered bone resorption markers?

Resorption markers reflect the activity of osteoclasts, cells that break down bone tissue. This group is particularly important in the treatment of osteoporosis, as most common first-line therapy drugs are antiresorptive and should rapidly reduce bone loss. When physicians want to see the early effects of bisphosphonates or denosumab, they most often look to resorption markers. [13]

The primary reference marker for bone resorption in routine osteoporosis practice is the β-isomerized C-terminal telopeptide of type I collagen. This marker is formed during the breakdown of type I collagen and is a good indicator of bone resorption intensity. The 2025 consensus reaffirmed its status as a basic marker for monitoring therapy in patients with normal renal function. [14]

Another well-known indicator is the N-terminal telopeptide of type I collagen. It can be measured in blood or urine, but urinary assays are less commonly used in modern practice because they are more variable and more dependent on renal function, hydration, and the technical aspects of sample collection. As laboratory diagnostics became standardized, the emphasis increasingly shifted toward serum and plasma tests. [15]

Tartrate-resistant acid phosphatase 5b is another resorption marker that reflects osteoclast activity. Its particular value lies in the fact that it is much less dependent on renal function than β-isomerized C-terminal telopeptide of type I collagen. Therefore, in the setting of chronic kidney disease, this indicator is considered one of the most promising resorption markers. [16]

As with formation markers, an elevated resorption marker does not automatically indicate osteoporosis. It can rise in thyrotoxicosis, hyperparathyroidism, Paget's disease, after a fracture, during immobilization, and in other metabolic conditions. However, if a patient with confirmed osteoporosis experiences a significant decrease in the resorption marker after initiation of antiresorptive therapy, this is generally considered a positive early biological response to treatment. [17]

Table 3. Main markers of bone resorption

Marker	What does it reflect?	Material	Practical features
β-isomerized C-terminal telopeptide of type I collagen	Collagen type I breakdown during resorption	Blood plasma or serum	The main reference marker for resorption
N-terminal telopeptide of type I collagen	Collagen breakdown during resorption	Blood or urine	More variable, especially in urine
Tartrate-resistant acid phosphatase 5b	Osteoclast activity	Blood	Less dependent on kidney function, important in chronic kidney disease

The classification is based on major reviews and updated international consensus.[18]

When are these tests prescribed and what do they actually tell the doctor?

The most common indication is monitoring osteoporosis treatment. Clinical guidelines from the American Association of Clinical Endocrinology recommend considering bone turnover markers during the initial evaluation and follow-up of patients with osteoporosis. Their value lies in the fact that they respond to treatment before changes in bone mineral density occur. This provides a convenient way for the physician to determine whether the medication is working and whether the patient is taking it regularly. [19]

The second indication is to determine the rate of bone loss and the risk of accelerated remodeling. Elevated marker levels may accompany more rapid bone loss and be associated with a higher risk of fractures, especially in postmenopausal women. However, their role here is supportive: they enhance the clinical picture and do not replace densitometry and risk factor assessment. [20]

A third important task is working with patients who have concerns about treatment adherence. The 2025 International Consensus emphasizes that bone turnover markers can improve communication with patients, aid motivation, and serve as a convenient feedback tool. If the expected decrease or increase in markers does not occur, this prompts an investigation into the cause: incorrect medication administration, non-compliance with the instructions for administration, malabsorption, laboratory errors, or the need to change the treatment regimen. [21]

The fourth clinical area is denosumab discontinuation and follow-up. The UK National Osteoporosis Group 2024 guidelines recommend that after denosumab discontinuation, zoledronic acid should be administered after 6 months and that serum β-isomerized C-terminal telopeptide of type I collagen should be monitored to determine the timing of further interventions. This is a very important practical scenario, as denosumab discontinuation may lead to a rapid increase in bone resorption and an increased risk of vertebral fractures. [22]

The fifth area is chronic kidney disease and so-called chronic kidney-associated osteoporosis. Here, markers are needed not only for monitoring but also for understanding the type of remodeling, as these patients may have bone in either a high- or low-turnover state. This is important when choosing therapy, as the same treatment may be beneficial in one setting and undesirable in another. [23]

Finally, bone turnover markers can be used in Paget's disease, hyperparathyroidism, thyrotoxicosis, fracture healing, and a number of other conditions where it is important for the physician to monitor bone remodeling activity. However, even here, they should not be considered in isolation. Their clinical value is revealed only in conjunction with symptoms, imaging, calcium-phosphorus metabolism biochemistry, and the overall disease picture. [24]

Table 4. When bone turnover markers are particularly useful

Clinical task	What are the benefits of markers?
Starting treatment for osteoporosis	Allows early detection of biological response
Monitoring adherence to therapy	Helps to understand whether the patient is taking the treatment correctly
Assessing the rate of bone loss	Complement fracture risk assessment
Denosumab discontinuation	Helps control rebound resorption and the timing of further therapy
Chronic kidney disease	They help to evaluate the type of remodeling and choose an approach
Paget's disease and other metabolic bone diseases	Show remodeling activity in dynamics

The table summarizes clinical scenarios from current guidelines and reviews.[25]

How to take tests correctly and why the results are so often misleading

The most common cause of misinterpretation is not disease, but preanalytical variability. For the β-isomerized C-terminal telopeptide of type I collagen, the time of day and the presence of food intake are particularly important. The National Project for Standardization of Bone Metabolism Markers explicitly recommends taking this test in the morning on an empty stomach and, if possible, under the same conditions each time, as otherwise, differences between the two results may reflect sampling conditions rather than treatment. [26]

The situation is somewhat simpler for the N-terminal propeptide of type I procollagen. This marker is much less susceptible to circadian fluctuations and is less sensitive to food. However, this doesn't mean it can be tested any way you like: for accurate comparisons, it's still advisable to use the same laboratory and the same methodology, as some analyzers measure the overall form, while others measure the intact form. This is especially important in patients with chronic kidney disease. [27]

The outcome is also influenced by factors that are not always readily controllable. Reviews and recommendations list age, gender, menopausal status, pregnancy, body mass index, recent immobilization, comorbidities, medications, and a recent fracture. After a fracture, bone turnover markers can remain altered for weeks, and sometimes longer, so it is advisable to set a baseline for monitoring outside the acute healing phase. [28]

Interlaboratory comparability also poses a significant challenge. The same test name does not always imply an identical measurement method. This is why international consensus constantly returns to the topic of standardization and harmonization of tests: without uniform approaches, differences between laboratories can be almost as significant as differences between patients. In practice, this means a simple rule: it is better to have control tests performed in the same laboratory. [29]

Finally, any repeat measurement should be assessed not based on the principle of "slightly higher or slightly lower," but rather taking into account real clinically significant dynamics. The 2025 consensus reminds that, to be confident, the change must exceed intra-individual variability and analytical error. Therefore, minor fluctuations without a change in the clinical situation should often not become a reason for hasty changes in treatment. [30]

Table 5. What most often distorts the results

Factor	Which markers are affected more?	Practical significance
The sample should not be taken in the morning or on an empty stomach.	First of all, on the β-isomerized C-terminal telopeptide of type I collagen	May create false dynamics
Different laboratories and methods	For all markers	Impairs the comparability of results
Recent turning point	On markers of formation and resorption	Temporarily increases metabolism
Chronic kidney disease	On the general form of the N-terminal propeptide of procollagen type I, β-isomerized C-terminal telopeptide of collagen type I, osteocalcin	May give a false increase
Medicines and immobilization	Different markers respond differently	Require clinical context
Re-analysis under different conditions	For all markers	Makes the dynamics unreliable

The data are summarized according to preanalytical guidelines and international consensuses. [31]

How to interpret marker changes during treatment and in special clinical situations

With antiresorptive therapy, a reduction in bone resorption markers is considered an expected sign of response. The American Association of Clinical Endocrinology guidelines explicitly state that a significant reduction in bone turnover markers is characteristic of antiresorptive drugs and is associated with treatment effectiveness. Typically, bone resorption declines first, followed by a decrease in bone formation markers over time, reflecting a general slowdown in bone remodeling. [32]

With anabolic therapy, on the other hand, the physician expects an increase in bone formation markers. This is especially important because densitometry reveals an increase in mineral density later, while laboratory changes appear earlier. Therefore, markers can confirm that the drug is indeed stimulating bone formation even before this is visible on densitometry. [33]

A special scenario involves discontinuing denosumab treatment. After its discontinuation, bone resorption can sharply increase, and the risk of vertebral fractures increases. The UK National Osteoporosis Group guidelines recommend monitoring serum β-isomerized C-terminal telopeptide of type I collagen after switching to zoledronic acid to guide the timing of further therapy. This is one of the most practical examples where a marker influences real-world clinical decisions. [34]

In chronic kidney disease, the interpretation changes fundamentally. The total form of N-terminal propeptide of type I collagen, β-isomerized C-terminal telopeptide of type I collagen, and osteocalcin may be elevated due to renal retention, and not just due to actual acceleration of remodeling. Therefore, in this group of patients, international consensus suggests focusing primarily on bone alkaline phosphatase and tartrate-resistant acid phosphatase 5b, as well as on the intact form of N-terminal propeptide of type I collagen. It is emphasized that parathyroid hormone alone is insufficient for a complete assessment of bone metabolism. [35]

The most important practical conclusion is that bone turnover markers are useful not as a "magic number," but as a tool for consistent monitoring. They are most valuable when the reason for their use, the specific marker chosen, the conditions under which it was performed, and the physician's expectations for treatment are known. With this approach, they truly aid in the management of osteoporosis and complex metabolic bone diseases. When used out of context, they, on the contrary, often become a source of unnecessary anxiety and diagnostic confusion. [36]

Table 6. How markers typically change in different clinical situations

Situation	What usually happens with markers	How is this interpreted?
Initiation of antiresorptive therapy	Resorption markers decrease, then formation markers	Expected response to treatment
Initiation of anabolic therapy	Education markers are rising	Sign of stimulation of bone formation
Denosumab discontinuation	Resorption markers are rising rapidly	Risk of rebound resorption and fractures
Recent turning point	Remodeling markers are temporarily elevated	Not the best point for basic control
Chronic kidney disease	Some markers accumulate independently of remodeling	A different set of indicators is needed
Lack of expected dynamics during therapy	Markers change little or not where expected	It is necessary to check the adherence, technique of administration, diagnosis and delivery conditions.

The table is based on consensus documents and clinical guidelines.[37]

Result

Bone formation and resorption markers are not a replacement for densitometry or a standalone test for osteoporosis. Their main strength lies elsewhere: they indicate the rate of bone remodeling and allow for an earlier detection of treatment response than is evident in bone mineral density. In routine practice, the primary reference markers remain the N-terminal propeptide of procollagen type I and the β-isomerized C-terminal telopeptide of collagen type I. In chronic kidney disease, the emphasis shifts to bone alkaline phosphatase, intact N-terminal propeptide of procollagen type I, and tartrate-resistant acid phosphatase 5b. [38]

These tests are most useful for monitoring therapy, assessing adherence, monitoring after denosumab discontinuation, and in a number of complex metabolic situations. However, their results are only meaningful when the correct conditions are met and the physician takes into account the clinical context, kidney function, recent fractures, and medications used. It is in this form that bone turnover markers truly help make more accurate and timely decisions. [39]