CurrentUnitedHealthcarePolicy CS021NM.C

Collagen Crosslinks and Biochemical Markers of Bone Turnover

State-specific (New Mexico) UnitedHealthcare medical policy governing coverage of serum or urine collagen crosslinks and biochemical bone turnover markers for assessing fracture risk, predicting bone loss, and monitoring response to antiresorptive therapy. Includes coverage rationale, applicable CPT code(s), summary of evidence and guideline positions.

Policy Summary

PayerUnitedHealthcare

PolicyCollagen Crosslinks and Biochemical Markers of Bone Turnover

Policy CodePolicy CS021NM.C

Change TypeSupporting information updated

Effective DateFeb 1, 2026

Next Review Date

Key ActionClaims for serum or urine collagen crosslinks or biochemical markers to assess fracture risk, predict bone loss, or assess response to antiresorptive therapy are considered unproven and not medically necessary and may be denied.

POLICY UPDATE CHANGES

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

1Referenced CPT codes

Not coveredCoverage stance summary

MultipleGuideline Statements

No FDA-approved diagnostic useRegulatory Determination

Inconclusive

Fracture Prediction Evidence

Coverage Summary

This is the UnitedHealthcare (New Mexico) medical policy CS021NM.C, effective February 1, 2026 and last reviewed on February 1, 2026. The policy states that serum or urine collagen crosslinks and biochemical bone turnover markers (BTMs) are considered unproven and not medically necessary to assess risk of fracture, predict bone loss, or assess response to antiresorptive therapy.

Key Facts

policy_numberCS021NM.C

subjectCollagen crosslinks and biochemical markers of bone turnover

coverage_stanceNot covered (unproven / not medically necessary for fracture risk assessment, predicting bone loss, or monitoring response to antiresorptive therapy)

referenced_CPT_codes_count1

regulatory_noteNo FDA‑approved diagnostic use identified for BTMs; FDA/CLIA regulate marketed tests and no FDA guidance supports BTMs for diagnosis or therapeutic selection

effective_date/last_reviewEffective: February 1, 2026; Last review: February 1, 2026

Medical Necessity Determinations

Medically Necessary Determination

Policy statement regarding medical necessity

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

General Clinical Conclusions from Guidelines and Societies

Summary of positions from professional societies on the clinical role of BTMs:

ESCEO/IOF/IFCC (2025): Serum PINP and plasma β-CTX-I are reaffirmed as reference BTMs in osteoporosis and are considered useful for monitoring anti-osteoporosis therapy.

ESCEO/IOF/IFCC (2025): BALP and TRACP5b are reference markers for formation and resorption respectively in CKD-associated osteoporosis.

Coding

Applicable CPT Codes (reference only)CPTNot Covered

82523

Collagen cross links, any method

Provider Actions

Denial Risk

Claims for collagen crosslinks/biochemical markers are not medically necessary

Claims for serum or urine collagen crosslinks or biochemical bone turnover markers to assess fracture risk, predict bone loss, or assess response to antiresorptive therapy are considered unproven and not medically necessary and may be denied. Providers should expect denial risk for billing these tests when submitted for those indications.

Affected CPT code: 82523

Documentation Required

Reference and guideline awareness

Providers should be aware of professional society positions that characterize BTMs as having limited, conditional, or evolving clinical utility. Interpret BTM results in the clinical context — alongside bone mineral density (BMD), FRAX and other clinical risk factors, and local guideline recommendations — before making management decisions.

Background and Evidence Summary

Biochemical bone turnover markers (BTMs) are substances measured in serum or urine that reflect bone formation or resorption and are available via commercially marketed tests using methods such as high-performance liquid chromatography or immunoassay. Although BTMs can be useful in research and potentially for monitoring therapy, their clinical use is limited by the complexity of interpreting individual results and by a lack of standardization that has produced unacceptable variation between processing laboratories.

Evidence and Guideline Summary

Overall evidence conclusionClinical validity is unproven; insufficient evidence to support use for diagnosis, fracture risk prediction, or monitoring response to treatment.

Guideline positions summarizedMixed: some societies note potential uses for select markers (PINP, CTX) but emphasize variability and need for more studies; BTMs not included in FRAX.

ESCEO/IOF/IFCC (2025)Reaffirmed serum PINP and plasma β‑CTX‑I as reference BTMs; BALP and TRACP5b recommended in CKD‑associated osteoporosis.

ISCD/IOF (2023)Evidence that BTMs predict fracture risk independent of BMD is inconclusive; BTMs are not included in FRAX.

Revision History

02/01/2026policy_effectiveLatest

Policy effective date set to February 1, 2026 for CS021NM.C.

02/01/2026revision_summaryLatest

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

02/01/2026archived_previous_version

Policy Summary

PayerUnitedHealthcare

PolicyCollagen Crosslinks and Biochemical Markers of Bone Turnover

Policy CodePolicy CS021NM.C

Change TypeSupporting information updated

Effective DateFeb 1, 2026

Next Review Date

On This Page

Endocrine Society: BTMs show promise as independent fracture predictors but further prospective cohort studies (including CKD) are needed before inclusion in risk tools; studies relating BTM changes to fracture risk reduction are needed to guide treatment targets and monitoring.

ISCD (2023): Serial BMD testing combined with clinical assessment, BTMs and other factors can be used to determine treatment initiation in untreated patients according to local guidelines.

ISCD/IOF (2023): Evidence that BTMs predict fracture risk independent of BMD is inconclusive; BTMs are not included in FRAX.

NAMS (2021): BTMs cannot diagnose osteoporosis and have varying ability to predict fracture risk; routine use of BTMs in clinical practice is not recommended.

Osteoporosis Canada (2023): Suggests against monitoring using BTMs for fracture prevention or for deciding resumption of therapy after bisphosphonate drug holiday (conditional; very low-certainty evidence).

Osteoporosis Society of Canada (2002): BTMs should not yet be used for routine clinical management; more studies needed.

FDA / Regulatory Context

FDA regulatory and informational points relevant to BTMs:

FDA regulates marketed tests/test systems and categorizes them by CLIA risk (waived, moderate, high); 510(k) clearance and CLIA databases can be used to identify marketed tests.

Laboratories using internally developed tests are subject to CLIA but not FDA marketing regulations.

No FDA-approved osteoporosis treatments use biochemical markers for diagnosis or selection/dosing/administration per identified information; FDA consumer information does not list BTMs as diagnostic tests.

ESCEO/IOF/IFCC: reaffirm PINP and β-CTX-I as reference BTMs and note usefulness for monitoring (2025)
ISCD: recommend combining serial BMD with clinical assessment and BTMs per local guidelines (2023)
ISCD/IOF: BTMs not included in FRAX; evidence inconclusive for independent fracture prediction (2023)
NAMS: routine use of BTMs not recommended (2021)
Osteoporosis Canada: suggests against monitoring with BTMs for fracture prevention or drug-holiday decisions (2023)
BHOF and Endocrine Society note potential uses but emphasize variability and need for further studies

Documentation Required

Regulatory verification for tests

When using commercially marketed BTM assays or reporting results, verify the regulatory status of the test system using FDA 510(k) and CLIA resources. Laboratories using internally developed tests should confirm CLIA compliance. Documentation of the marketed test's 510(k) clearance or CLIA category can support appropriate test selection and reporting.

Search the FDA 510(k) database by manufacturer or test system name to confirm marketing clearance for commercially marketed assays.
Use the CLIA database to identify the test system or analyte and its CLIA complexity categorization.
Laboratories running their own-developed tests should ensure CLIA compliance and document validation and quality procedures.

ISCD (2023)Serial BMD testing in combination with clinical assessment, BTMs, and other factors can inform treatment decisions per local guidelines.

Osteoporosis Canada (2023)Suggests against monitoring with BTMs for fracture prevention or for deciding resumption of therapy after bisphosphonate holiday (conditional; very low‑certainty).

Endocrine Society / NAMSBTMs show promise as independent fracture predictors but more prospective studies needed; routine use not recommended by NAMS.

FDANo FDA guidance supporting use of BTMs for diagnosis or therapeutic selection identified; FDA/CLIA regulate marketed tests but no approved diagnostic use found.

Bone turnover markers (BTMs) are biochemical markers measured in serum or urine that reflect either bone formation or bone resorption.

Examples of formation markers include P1NP (procollagen type I N propeptide) and bone-specific alkaline phosphatase (BALP), and examples of resorption markers include β-CTX-I (beta crosslaps / CTX), NTx, and pyridinoline/telopeptides.

Other referenced markers include osteocalcin and TRACP5b (tartrate-resistant acid phosphatase 5b) as additional examples used in research and certain clinical contexts.

Archived previous policy version CS021NM.B.

02/01/2026coverage_statementLatest

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

02/01/2026description_of_services_updateLatest

Clarified that commercially marketed tests for BTMs are available in serum/urine, described potential clinical uses (assess rate of bone loss, monitor therapy), and noted interpretation complexity and lack of standardization leading to inter-laboratory variability.

02/01/2026clinical_evidence_updateLatest

Clinical evidence section updated to state that clinical validity is unproven and insufficient evidence exists to support BTMs for diagnosis, fracture risk prediction, or monitoring response to treatment; additional prospective trials are needed.

02/01/2026fda_regulatory_information_updateLatest

FDA/Regulatory context updated: FDA categorizes marketed tests by CLIA risk and 510(k)/CLIA databases can identify marketed assays; no FDA-identified approvals or guidance supporting use of BTMs for osteoporosis diagnosis or therapeutic selection.

02/01/2026timeline_contextLatest

Policy last review and effective date recorded as February 1, 2026.