Currentsierra health and lifePolicy 2026T0419Z

Collagen Crosslinks and Biochemical Markers of Bone Turnover

Defines UnitedHealthcare policy on use of serum or urine collagen crosslinks and biochemical bone turnover markers for assessing fracture risk, predicting bone loss, or monitoring response to antiresorptive therapy for Commercial and Individual Exchange plans.

Policy Summary

Payersierra health and life

PolicyCollagen Crosslinks and Biochemical Markers of Bone Turnover

Policy CodePolicy 2026T0419Z

Change TypeTemplate update and content refresh (non‑material)

Effective DateJanuary 1, 2026

Next Review DateN/A

Key ActionWhen BTMs are requested, document the clinical indication, marker type, timing (baseline and 3–6 months as appropriate), and intended use for monitoring or treatment decisions.

SourceLink

POLICY UPDATE CHANGES

Updated Clinical Evidence, FDA, and References sections to reflect the most current information and created a shared policy version to support application to Oxford plan membership.

2026-01-01Effective date

Not medically necessaryCoverage stance

Commercial & ExchangePlans applicable

1CPT codes listed

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Policy revision date

Coverage Criteria and Clinical Position

General coverage stance

Covered when ALL of the following are met

Not applicable: Serum or urine collagen crosslinks or biochemical markers are considered unproven and not medically necessary to assess risk of fracture, predict bone loss, or assess response to antiresorptive therapy.

Policy does not list any coverage criteria permitting use; requests for CPT 82523 should be denied absent documented justification.

Coverage-relevant clinical positions — guideline and evidence summaries

Coverage stance informed by guideline and evidence summaries in the document:

Reference-marker monitoring: Serum PINP and serum CTX are identified as reference markers and may be useful for monitoring treatment effect or adherence when measured with standardized assays and appropriate timing (baseline and ~3–6 months).3-6 months; ~40% reduction in CTX cited as least significant change

Supported by AACE/ACE, BHOF, ESCEO/IOF/IFCC, and Endocrine Society guidance; however, assay variability and limited predictive ability in individuals are noted.

Adjunct, not diagnostic alone: BTMs should not be used alone to diagnose osteoporosis and are adjunctive to BMD and clinical assessment.

AACE/ACE and NAMS state BTMs cannot be used alone for diagnosis; insufficient evidence for diagnostic use.

Fracture risk prediction—limited/inconclusive: Although some analyses find associations between BTMs and fracture risk or rate of bone loss, evidence is inconsistent and BTMs are not included in FRAX; routine use for fracture risk estimation is inconclusive.

ISCD/IOF and guideline reviews conclude evidence that BTMs predict fracture independent of BMD is inconclusive.

Guideline recommendations

Stance from clinical guideline bodies regarding use of BTMs

Guideline consensus: Major guideline bodies have the following positions: ISCD/IOF (2023) — evidence is inconclusive that BTMs predict fracture risk independent of BMD and BTMs are not included in FRAX; NAMS (2021) — BTMs cannot diagnose osteoporosis and routine use is not recommended; Osteoporosis Canada (2023) — suggests against monitoring with BTMs for fracture prevention or for deciding on resumption of therapy during bisphosphonate holidays (conditional, very low–certainty); AACE/ACE, BHOF, ES, and ESCEO/IOF/IFCC recognize potential roles for BTMs in monitoring therapy effect or adherence but note assay variability and limited individual predictive power.

References: ISCD/IOF 2023; NAMS 2021; OC 2023; AACE/ACE 2016/2020; BHOF 2022; ES 2020; ESCEO/IOF/IFCC consensus.

Use of serum or urine collagen crosslinks or other biochemical bone turnover markers (BTMs) to assess fracture risk, predict bone loss, or assess response to antiresorptive therapy is addressed in this policy. The policy states that these tests are unproven and not medically necessary for those purposes and therefore are not covered for routine clinical use to estimate fracture risk, forecast bone loss, or monitor therapeutic response.

BTMs should not be used as a standalone diagnostic test for osteoporosis or as the sole determinant in fracture risk assessment (including incorporation into FRAX). International working groups and technology assessments conclude that BTMs cannot diagnose osteoporosis and that evidence is insufficient to support their solitary use for fracture risk prediction.

FDA clearance or marketing authorization of commercially marketed bone marker test systems does not by itself establish coverage. The FDA regulates these tests and maintains 510(k) and CLIA databases, but no FDA-recognized role was identified for BTMs in the diagnosis of osteoporosis or in selecting, dosing, or administrating osteoporosis drugs; therefore FDA approval alone is not a basis for coverage.

Based on current evidence, serum or urine collagen crosslinks and other biochemical BTMs are considered unproven for routine clinical applications described above and are therefore deemed not medically necessary when used to assess fracture risk, predict bone loss, or evaluate response to antiresorptive therapy.

Routine, unconditional ordering of BTMs for general screening or diagnosis in asymptomatic individuals is not supported by the evidence and would be considered not medically necessary without a documented clinical rationale. Technology assessments and professional society statements advise against routine BTM testing in asymptomatic population screening.

Routine use of BTMs for diagnosis of osteoporosis, routine clinical management, monitoring for fracture prevention, or for deciding on resumption of therapy after bisphosphonate drug holidays is not supported by guideline bodies. Positions from ISCD/IOF, NAMS, and Osteoporosis Canada conclude that evidence is insufficient to recommend BTMs for these routine purposes.

Coding and Test Codes

Applicable CPT CodesCPT

82523

Collagen cross links, any method

BTM cutoff values discussed

Study discriminatorsP1NP < 30 μg/L and CTX < 0.25 μg/L were identified as cutoff values that best discriminated participants using or not using antiresorptive drugs and predicted BMD gains after 2 years in a prospective cohort study.

Study populationProspective cohort of 228 participants (82.2% women) followed for a mean of 4.6 years with BTM measured at 1- and 2-year follow-up.

Drugs evaluatedParticipants started alendronate, denosumab, or zoledronic acid as antiresorptive therapy in the study that reported these cutoffs.

Provider Actions, Prior Authorization, and Documentation

Prior Authorization

Prior Authorization and Member Plan Reference

Prior authorization and coverage requirements for biochemical markers of bone turnover (BTMs) and collagen crosslinks are governed by the member-specific benefit plan. Providers must check the member's benefit document and any applicable federal or state mandates to determine whether prior authorization is required. In the event of a conflict between this policy guidance and the member-specific benefit plan, the member-specific plan governs.

Prior authorization governed by member plan — verify member-specific benefit document before ordering
FDA approval alone is not a basis for coverage; check applicable mandates and plan terms (chunk 39)

Denial Risk

Evidence Limitations — Hip Fracture Prediction

BTMs (including serum CTX and PINP) have limited predictive utility for hip fracture risk in postmenopausal women aged 50–79 based on a prospective case-control study (Crandall et al., 2018) which found no significant association between serum CTX or PINP and hip fracture. This evidence supports caution in using BTMs alone to predict hip fracture for coverage or clinical decision-making.

Background and Rationale

Bone is continually remodeled by osteoclast-mediated resorption and osteoblast-mediated formation. Biochemical markers measurable in serum or urine reflect these processes and include markers of formation (for example, P1NP, osteocalcin, bone alkaline phosphatase) and resorption (for example, pyridinoline, telopeptides, CTX). Although these markers have been widely used in research and in some clinical settings, interpretation is complex due to substantial preanalytic and analytic variability, lack of standardized assays across laboratories, and factors such as diurnal variation, feeding, age, sex, and menopausal status that affect levels.

Definitions and Reference Terms

Bone turnover markers (BTMs)

DefinitionBiochemical markers measurable in serum or urine that reflect bone formation or bone resorption, assessed by immunoassay or chromatography.

Formation marker examplesOsteocalcin; bone alkaline phosphatase (BALP); procollagen type I N-terminal propeptide (P1NP).

Resorption marker examplesPyridinoline; telopeptides (NTx/CTx); beta-C-terminal telopeptide of type I collagen (β-CTX).

Collagen crosslinks

ExamplesPyridinoline and telopeptides (including urinary cross-linked N-telopeptide of type I collagen) are biochemical measures indicating collagen breakdown associated with bone resorption.

Sample typesOften measured in urine or serum depending on the specific crosslink assay.

Policy Revision History

2026-01-01template_updateLatest

Template update; updated Clinical Evidence, FDA, and References sections and archived previous policy version 2025T0419Y; created a shared policy version to support application to Oxford plan membership.

Policy Summary

Payersierra health and life

PolicyCollagen Crosslinks and Biochemical Markers of Bone Turnover

Policy CodePolicy 2026T0419Z

Change TypeTemplate update and content refresh (non‑material)

Effective DateJanuary 1, 2026

Next Review DateN/A

Key ActionWhen BTMs are requested, document the clinical indication, marker type, timing (baseline and 3–6 months as appropriate), and intended use for monitoring or treatment decisions.

SourceLink

On This Page

Lack of predictive utility for hip fracture in women 50–79 — CTX and PINP not significantly associated with hip fracture risk (chunk 30)

Documentation Required

Documentation Requirements

When BTMs are considered for use, document the clinical indication, the specific marker(s) ordered, timing of sample collection relative to treatment or circadian influences, and the rationale for testing. Routine or non-indicated use is not supported by current evidence.

Document marker type (e.g., CTX, PINP), timing (fasting morning sample when appropriate), and rationale for use
Routine use not supported; require clinical indication when used

Step Therapy

Step Therapy and Sequencing

Step therapy or sequencing requirements are not specified in this policy. Evidence is insufficient to support replacing standard diagnostics or mandating BTMs before initiation of osteoporosis therapies. If a plan elects to apply step therapy, consider linking BTM testing to the intent to use an FDA-approved osteoporosis therapy and to a defined monitoring interval (for example, repeat testing at 3–6 months to assess response when used).

No plan-level step therapy specified — check member-specific plan for any sequencing rules
Consider requiring demonstration of intent to start FDA-approved osteoporosis therapy and a planned monitoring interval (e.g., 3–6 months) if BTM testing is used to monitor response (chunk 32)

Denial Risk

Coverage Stance and Coding Reference

Collagen crosslinks and BTMs (CPT 82523 and related markers) are considered unproven and not medically necessary for assessing fracture risk, predicting bone loss, or monitoring response to antiresorptive therapy in routine clinical practice. Inclusion of CPT 82523 in code lists is for reference only and does not imply coverage; verify coverage via the member-specific benefit plan.

CPT 82523 — Collagen cross links, any method (reference only; inclusion does not imply coverage) (chunk 5)
BTMs considered unproven and not medically necessary for listed uses — potential denial trigger (chunk 4)

Clinical relevanceUsed in research and sometimes clinical evaluation to reflect collagen degradation during bone resorption, though interpretation is limited by variability and lack of standardization.

Reference BTMs

Reference markers recommendedSerum P1NP (formation) and serum β-CTX-I (resorption) are recommended as reference BTMs by international groups for standardized measurement.

Rationale for selectionChosen for adequate characterization, bone specificity, performance in clinical studies, biological and analytical variability, availability, and potential for standardization.

UseConsidered useful for monitoring anti-osteoporosis therapy when measured with standardized assays and appropriate timing.

Least significant change

Least significant change (BHOF)BHOF states that an approximate 40% reduction in CTX is the least significant change to assess response to antiresorptive therapy.

Monitoring intervalBHOF suggests repeating BTMs 3–6 months after treatment initiation to assess response or adherence.

ContextLeast significant change threshold is intended to distinguish true biological change from assay variability when using CTX to monitor antiresorptive therapy.

FRAX (Fracture Risk Assessment Tool)

FRAX roleFRAX is a clinical fracture risk algorithm; ISCD/IOF states evidence is inconclusive that BTMs predict fracture risk independent of BMD, and therefore BTMs are not included as risk factors in FRAX.

Guideline contextMultiple guideline groups note that BTMs are not part of routine FRAX-based fracture risk estimation due to inconclusive independent predictive value.

ImplicationBTMs should not be used as standalone inputs to FRAX or as sole determinants of fracture risk estimation.

FDA/CLIA regulated tests

Regulatory oversightCommercially marketed bone marker test systems are regulated by the FDA and categorized under CLIA risk levels (waived, moderate, high) based on potential public health risk.

510(k) clearance and databasesTests with 510(k) marketing clearance can be found in the FDA 510(k) database; marketed analytes and systems can be searched in the CLIA database.

Laboratory-developed testsLaboratories that use their own (non-marketed) tests are subject to CLIA standards but not FDA marketing regulations.