ModifiedUnitedHealthcarePolicy CS021TN.O

Collagen Crosslinks and Biochemical Markers of Bone Turnover (for Tennessee Only)

Policy governing use of serum or urine collagen crosslinks and biochemical markers of bone turnover for Medicaid and CoverKids members in Tennessee; addresses medical necessity for assessment of fracture risk, bone loss prediction, and monitoring response to antiresorptive therapy.

Policy Summary

PayerUnitedHealthcare

PolicyCollagen Crosslinks and Biochemical Markers of Bone Turnover (for Tennessee Only)

Policy CodePolicy CS021TN.O

Change TypeMaterial revisionarchived prior version

Effective DateFeb 1, 2026

Next Review Date

Key ActionDo not submit claims for collagen crosslinks or biochemical bone turnover marker testing for fracture risk, bone loss prediction, or monitoring antiresorptive therapy without meeting policy criteria; such claims may be denied as not medically necessary.

SourceLink

POLICY UPDATE CHANGES

Updated Description of Services, Clinical Evidence, FDA, and References sections to reflect the most current information.

Tennessee Medicaid & CoverKidsprograms governed

1 CPTprocedure codes referenced

ECRI: insufficienttechnology assessment

PINP & β-CTXrecommended reference markers

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Coverage Criteria for Bone Turnover Marker Testing

Overall coverage stance

Covered when ALL of the following are met

Central policy stance: 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 applies to Tennessee Medicaid and CoverKids.

Coverage-related clinical criteria

Summary of evidence and guideline positions regarding clinical use of BTMs

General evidence summary: Evidence is heterogeneous: systematic reviews, HTAs, and cohort studies show mixed results — some associations between baseline BTMs and outcomes are reported, but major assessments (ECRI) concluded evidence is insufficient to establish clinical utility; large prospective studies found no association with hip fracture.

Supported by ECRI 2018, Lorentzon 2019, Crandall 2018 and other systematic reviews.

Guideline consensus on diagnostic use: Multiple professional societies state BTMs cannot be used alone to diagnose osteoporosis and are not included in FRAX due to inconclusive evidence; routine use in clinical practice is not universally recommended.

ISCD/IOF, NAMS, Osteoporosis Canada positions.

Monitoring and adherence potential: Some guidelines and consensus groups endorse use of reference markers (serum PINP and plasma β-CTX-I) for monitoring therapy response and assessing adherence, with recommendations to measure at 3–6 months after treatment initiation; a ~40% reduction in CTX has been cited as a least significant change for antiresorptive therapy adherence assessment.3-6 months; ~40% CTX reduction

Statements from AACE/ACE, BHOF, Endocrine Society, ESCEO/IOF/IFCC.

Use in specific clinical protocols: BTM-guided treatment protocols and small RCTs have shown potential short-term benefits in selected perioperative or monitoring protocols, but larger confirmatory studies are needed before routine adoption for coverage decisions.

Example: Ma et al. 2021 RCT and other small trials referenced in evidence summaries.

Serum or urine collagen crosslinks and other biochemical bone turnover markers (BTMs) are considered unproven and not medically necessary for the purposes of assessing fracture risk, predicting bone loss, or monitoring response to antiresorptive therapy for Tennessee Medicaid and CoverKids members.

BTMs should not be used to diagnose osteoporosis. Multiple professional societies and guideline groups note that evidence is inconclusive for using BTMs alone to establish a diagnosis, and routine use in clinical practice is not universally recommended. The ISCD/IOF position states BTMs do not predict fracture risk independent of BMD and are not included in FRAX; NAMS and Osteoporosis Canada advise against routine clinical use or monitoring with BTMs given limited and low‑certainty evidence.

FDA information is provided for context only. The FDA regulates commercially marketed bone marker test systems and categorizes them under CLIA regulatory levels, but FDA consumer information on osteoporosis does not list biochemical markers as diagnostic tests, and no FDA materials were identified supporting use of BTMs for diagnosis or drug selection/dosing.

Claims for serum or urine collagen crosslinks or other biochemical BTMs to assess fracture risk, predict bone loss, or monitor response to antiresorptive therapy are considered not medically necessary and may be denied.

The available evidence is insufficient to support routine use of BTMs for diagnosis of osteoporosis, for monitoring treatment response as a basis for coverage decisions, or for determining fracture risk. A technology assessment (ECRI) concluded there is insufficient evidence of clinical utility, and no FDA information was identified that endorses BTMs for diagnostic or drug‑selection purposes.

Because no FDA consumer or regulatory materials were identified that support using biochemical markers for the diagnosis of osteoporosis or for selecting/dosing osteoporosis drugs, the policy infers a limited role for BTMs in these clinical decisions and treats any FDA clearance as informational rather than determinative for coverage.

Coding and Test Identifiers

Applicable CPT Codes (reference)CPT

82523

Collagen cross links, any method

No specific CPT/HCPCS/ICD codes listed in this document portionmixed

No codes listed

P1NP and CTX discrimination thresholds

P1NP discrimination thresholdP1NP < 30 (units as reported in study) best discriminated participants using vs not using antiresorptive drugs and predicted BMD gains after 2 years

CTX discrimination thresholdCTX < 0.25 μg/L best discriminated participants using vs not using antiresorptive drugs and predicted BMD gains after 2 years

Study contextThresholds reported from Borgen et al. (prospective cohort, n=228) assessing adherence, BMD change, and fracture prediction with 1- and 2-year BTM measures

Least significant change

Least significant change for CTXApproximately 40% reduction in serum CTX characterizes adherence/persistence for antiresorptive therapy

Marker application

Provider Actions, Prior Authorization & Billing Guidance

Prior Authorization

Prior Authorization & Coverage Stance

Prior authorization and coverage stance: This policy governs use of serum or urine collagen crosslinks/biochemical bone turnover marker (BTM) testing for Tennessee Medicaid and CoverKids. Serum or urine collagen crosslinks or biochemical markers are considered unproven and not medically necessary to assess fracture risk, predict bone loss, or assess response to antiresorptive therapy; coverage determinations should follow applicable federal, state, or contractual benefit plan requirements.

Applies to Tennessee Medicaid & CoverKids
Not medically necessary for fracture risk assessment, predicting bone loss, or therapy response

Prior Authorization

Check Plan-Level Prior Authorization

Check plan-level prior authorization: This Medical Policy is informational and reflects UnitedHealthcare standard benefit plan interpretation. Providers must check the member’s specific federal, state, or contractual benefit plan for any plan-level prior authorization or coverage requirements before providing or billing services.

Verify member-specific benefits and any plan or state prior authorization requirements before ordering or billing tests

Background and Scope

Bone is continuously remodeled by osteoclast‑mediated resorption and osteoblast‑mediated formation. Biochemical markers measured in serum or urine — including collagen crosslinks such as N‑ and C‑telopeptides and markers of formation such as P1NP, osteocalcin, and bone alkaline phosphatase — reflect aspects of bone resorption and formation and have been used in research and some clinical settings to estimate turnover, predict bone loss, and monitor therapy. However, interpretation is complex because of substantial preanalytical and analytical variability (for example, diurnal variation, feeding status, age, sex, and assay differences), and lack of standardization limits their routine clinical application.

Definitions and Reference Markers

Bone turnover markers (BTMs)

Examples — formation markersP1NP, osteocalcin, bone alkaline phosphatase (bALP)

Examples — resorption markersCTX (C-terminal telopeptide), NTx (N-telopeptide), pyridinoline/deoxypyridinoline

Clinical role summaryBTMs reflect bone formation or resorption and have been proposed for fracture risk assessment, predicting bone loss, and monitoring therapy, though clinical use is limited by variability and lack of standardization

Collagen crosslinks

Urinary crosslinks examplesUrinary cross-linked N-telopeptide of type I collagen (NTx), pyridinoline, deoxypyridinoline

Serum/Plasma telopeptidesSerum C-terminal telopeptide (CTX), serum N-telopeptide (NTx) measured in some assays

Policy Revision History

2026-02-01archived_previous_version

Archived previous policy version CS021TN.N and updated Description of Services, Clinical Evidence, FDA, and References sections to reflect current information.

2026-02-01policy_effectiveLatest

Policy CS021TN.O effective; material changes include updates to Description of Services, Clinical Evidence, FDA, and References sections and archival of prior version CS021TN.N.

Policy Summary

PayerUnitedHealthcare

PolicyCollagen Crosslinks and Biochemical Markers of Bone Turnover (for Tennessee Only)

Policy CodePolicy CS021TN.O

Change TypeMaterial revisionarchived prior version

Effective DateFeb 1, 2026

Next Review Date

SourceLink

On This Page

Reduction in CTX used to assess response to antiresorptive medications and to characterize persistence during treatment or bisphosphonate holidays

Guidance sourceStatement from BHOF consensus (LeBoff et al., 2022) describing least significant change for CTX

In case of conflict, federal/state/contractual requirements govern

Billing Rule

Procedural/Billing Authorization (Not Specified)

No explicit procedural or billing authorization specified in this policy excerpt: The policy does not define a specific procedural prior authorization workflow or billing preauthorization process. Providers should follow applicable plan or state processes if required.

No procedural prior authorization workflow described in this document portion
Follow plan-specific billing or authorization processes if applicable

Denial Risk

FDA Approval Is Not Sufficient for Coverage

FDA approval not sufficient for coverage: FDA approval, clearance, or marketing is informational only and alone is not a basis for coverage under this policy.

Coverage decisions require clinical evidence beyond FDA marketing status
Presence of FDA 510(k) clearance for a marketed test does not mandate coverage

Billing Rule

Coding / Reference Note

Coding/reference note: The following CPT code is provided for reference purposes only and may not be all-inclusive. Inclusion does not imply coverage or reimbursement rights. Providers should reference the applicable benefit plan when submitting claims.

CPT 82523 — Collagen cross links, any method (informational)
Listing of a code does not guarantee coverage or payment

Note

FDA / CLIA Regulatory Context (Informational)

FDA/CLIA regulatory context: The FDA regulates commercially marketed bone marker test systems and categorizes them under CLIA risk categories (waived, moderate, high). Laboratories using in-house tests (LDTs) are subject to CLIA standards but are not subject to FDA marketing regulations. Information regarding FDA-approved osteoporosis treatments and routine use of biochemical markers in diagnosis or treatment selection was not identified.

Commercially marketed tests may have 510(k) marketing clearance — searchable via FDA or CLIA databases
Laboratory-developed tests (LDTs) are regulated under CLIA, not FDA marketing rules

Documentation Required

Reference Plan-Specific Requirements

Reference plan-specific requirements: Before relying on this policy for coverage decisions, providers must reference the member’s federal, state, or contractual benefit plan because those terms may differ from the standard benefit plan. In the event of conflict, the federal, state, or contractual requirements govern.

Check federal, state, and contractual plan documents for definitive coverage rules
This policy is informational and does not supersede contractual or statutory obligations

Step Therapy

Step Therapy — Not Specified

No step therapy requirements described: The policy excerpt does not specify any step therapy or prior-treatment failure requirements for BTM testing. Note that some clinical studies described BTM-guided monitoring protocols, but these do not establish plan-level step therapy rules.

No step therapy mandates in this policy excerpt
Clinical trials may use BTM-guided protocols, but these are not step therapy requirements for coverage

Clinical interpretation noteThese collagen breakdown products indicate bone resorption but are affected by preanalytical and analytical variability

Reference BTMs

Reference formation markerSerum PINP recommended as the reference bone formation marker by IOF/IFCC/ESCEO

Reference resorption markerPlasma β-CTX-I recommended as the reference bone resorption marker by IOF/IFCC/ESCEO

Recommendation contextChosen for specificity to bone, analytical performance, availability, and potential for standardization

BTMs discussed

Commonly discussed markersPINP, CTX (serum and urinary), NTx

Additional markersBone alkaline phosphatase (bALP), TRACP5b

Use in research vs practiceThese markers have been widely used in clinical trials and studies, but routine clinical interpretation is limited by variability and method differences

FDA/CLIA categorization

Regulatory oversight — commercial testsCommercially marketed bone marker tests and test systems are regulated by the FDA and categorized into CLIA categories (waived, moderate, high)

510(k) clearanceCommercial test systems with 510(k) marketing clearance can be found via the FDA 510(k) database or CLIA database

Laboratory-developed tests (LDTs)Laboratories using in-house tests that are not marketed remain subject to CLIA standards but not FDA marketing regulations