2.1 Biochemical Markers of Bone Turnover
Key Takeaways
For osteoporosis with normal renal function, the 2025 consensus reaffirms total PINP and β-CTX-I and prefers EDTA plasma for β-CTX-I.
Use standardized morning fasting β-CTX-I collection and compare like specimens and methods. Recent fracture and renal function affect interpretation.
The consensus recommends BALP and TRACP5b in CKD-associated osteoporosis. Neither establishes turnover or drug suitability by itself.
A laboratory reference change value can be direction-specific. A change beyond it does not prove treatment benefit or adherence.
Know what the specimen measures
Bone turnover markers reflect products of matrix synthesis or breakdown and enzymes associated with bone cells. They provide a systemic measure related to remodeling. DXA instead estimates mineral per projected area at an imaged site. Neither measurement establishes the cause of an individual fracture.
| Marker | Source and interpretation |
|---|---|
| β-CTX-I | A β-isomerized C-terminal fragment of type I collagen released during matrix degradation. It is a reference resorption marker in osteoporosis with normal renal function. Kidney impairment can increase measured levels independently of turnover. |
| Total PINP | The N-terminal propeptide released in type I collagen formation. A total assay detects intact and smaller forms. With reduced renal function, retained smaller forms can contribute to the result. |
| Bone-specific alkaline phosphatase (BALP) | A formation-related enzyme associated with osteoblasts and mineralization. It can be useful in CKD. Consider method and clinical context, including potential interference from other ALP isoforms. |
| TRACP5b | An osteoclast-derived enzyme associated with the number of osteoclasts. It is less affected by reduced renal clearance than collagen telopeptides. |
| Other markers | NTX and collagen cross-links such as deoxypyridinoline reflect matrix degradation. Osteocalcin is produced by osteoblasts and its circulating forms and renal handling complicate interpretation. |
Control collection and interpretation conditions
The 2025 ESCEO/IOF/IFCC consensus reaffirms total PINP and β-CTX-I as the reference formation and resorption markers in osteoporosis with normal renal function. It prefers EDTA plasma for β-CTX-I because of analyte stability. Follow the local laboratory's validated specimen and processing instructions. For serial β-CTX-I, use consistent morning fasting collections, because food intake and time of day can alter concentrations. The consensus recommends collection between 7:30 and 10:00 a.m. after an overnight fast for bone resorption markers. Use the same matrix and assay when possible. PINP is generally less affected by meals and time of day. Assays, units and reference intervals can differ.
A β-CTX-I sample drawn after lunch cannot be compared straightforwardly with a morning fasting baseline. The afternoon and postmeal conditions can lower the value independently of treatment. Document collection and obtain a comparable specimen if the result would guide a decision. Recent fracture healing can alter marker levels, as can age and growth, menopause, immobilization and kidney function. Consider timing in the specific clinical context.
In advanced CKD, total PINP and β-CTX-I can accumulate. Distinguish intact from total PINP. The consensus recommends BALP and TRACP5b as reference markers in CKD-associated osteoporosis. KDIGO supports PTH or bone-specific ALP, with markedly high or low values helping predict turnover. One marker is insufficient to establish the underlying bone disorder or select a drug. A specialist may consider other tests or bone biopsy when the result would change management.
Compare the change with the right reference
The reference change value (RCV) reflects within-person biological and analytical variation under specified conditions. It can be different for increases and decreases. A population reference interval describes between-person distributions and answers a different question from serial change in one patient. As an illustration, EuBIVAS-derived estimates for β-CTX-I reported in the 2025 consensus are approximately −30.8% and +44.5%. With a comparable baseline of 500 ng/L and follow-up of 330 ng/L, the measured change is −34%. That exceeds the example decrease threshold in magnitude. Applying a symmetric 44.5% threshold would give the wrong conclusion for the supplied model. Use the laboratory's applicable procedure or the specified study method for real decisions. A biomarker RCV is separate from a facility DXA least significant change.
Connect the result to the clinical question
Resorption markers generally fall on antiresorptive therapy, and formation markers can rise early with PTH analogs. Romosozumab initially raises formation and suppresses resorption. The size and timing vary by drug, individual and collection. When using oral bisphosphonates, one named baseline-to-three-month strategy can screen for poor adherence. A result can support reviewing medication administration and specimen comparability. It does not confirm a specific cause, establish that a person has remained adherent, or prove fracture protection.
Higher levels have been associated with fracture risk in some cohorts. Such findings do not make markers stand-alone tools for diagnosing osteoporosis or measuring BMD. Use a marker when it can answer a defined question alongside the clinical assessment, DXA and other findings.
2025 ESCEO/IOF/IFCC consensus · EuBIVAS · KDIGO CKD-MBD · IOF/ECTS oral adherence position · Evenity label
A patient with advanced CKD is being assessed for mineral and bone disorder. Which formation marker is recommended in the 2025 CKD-associated osteoporosis consensus?
Bone-specific alkaline phosphatase.
β-CTX-I.
Urinary NTX.
Total PINP without considering renal retention.
A patient has follow-up β-CTX-I sampled at 14:30 after lunch, while the baseline sample was fasting in the morning. What is the most appropriate interpretation?
Both specimens are directly comparable because the assay name is unchanged.
The afternoon and meal may lower the result. Review collection and obtain a comparable specimen if needed for the decision.
The afternoon and meal necessarily raise β-CTX-I enough to diagnose poor adherence.
An afternoon sample can be adjusted using a fixed correction factor.
A problem supplies the EuBIVAS-derived β-CTX-I change boundaries of −30.8% for decreases and +44.5% for increases. Comparable measurements fall from 600 to 390 ng/L. Which interpretation follows?
The decrease is 35%, but it must exceed 44.5% to be considered significant.
The decrease is 54% and proves the patient’s fracture risk has fallen by 54%.
The decrease is 35% and exceeds the specified decrease boundary in magnitude. It does not prove clinical efficacy.
The difference of 210 ng/L is a DXA least significant change.
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