ModifiedUnitedHealthcarePolicy CSO21.P

Collagen Crosslinks and Biochemical Markers of Bone Turnover

This policy governs the medical necessity and coverage stance for serum or urine collagen crosslinks and biochemical bone turnover marker tests for assessment of fracture risk, prediction of bone loss, and monitoring response to antiresorptive therapy for UnitedHealthcare members.

Policy Summary

PayerUnitedHealthcare

PolicyCollagen Crosslinks and Biochemical Markers of Bone Turnover

Policy CodePolicy CSO21.P

Change TypeState application addedevidence/references updated

Effective DateFeb 1, 2025

Next Review Date

Key ActionVerify plan-specific prior authorization and state-specific policy applicability before submitting claims or requests for BTM testing.

SourceLink

POLICY UPDATE CHANGES

Added language that this Medical Policy does not apply to the states of Idaho and Kansas and to refer to state-specific policy versions.

Updated Clinical Evidence and References sections to reflect the most current information.

Not medically necessaryCoverage stance

2State exceptions added

35RCTs in review

36,706Total patients

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Coverage Criteria — Bone Turnover Marker Testing

Not medically necessary

Not covered — the following tests are considered not medically necessary for the listed uses.

Primary coverage determination: 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 stance based on insufficient clinical standardization and lack of demonstrated improvement in patient outcomes.

Coverage: Clinical utility and limitations

Coverage stance and clinical contexts where testing may have limited or adjunctive roles, and the evidence-based limitations:

Adjunctive monitoring use (suggested but not definitive): BTMs may be used to assess treatment adherence or biochemical response to osteoporosis therapy (for example, reductions in resorption markers with antiresorptives or increases in formation markers with anabolic therapy).

Supported by AACE/ACE and Endocrine Society guidance that BTMs can reflect therapy-related changes but are limited by assay and pre-analytical variability.

Not established for diagnosis or routine fracture risk prediction: BTMs cannot be used alone to diagnose osteoporosis and evidence is inconclusive that BTMs predict fracture risk independently of bone mineral density.

Multiple society positions and an ECRI assessment indicate insufficient or mixed evidence to support routine diagnostic or fracture-prediction use.

Recommendation for cautious use: If BTMs are measured, use standardized assays (serum PINP and serum CTX recommended as reference markers), control pre-analytical variables (timing of sample, fasting status, sample handling), and interpret results alongside BMD and clinical risk factors.

ISCD/IOF and guideline working groups recommend standardized measurement and careful interpretation due to variability.

This Medical Policy does not apply in every jurisdiction. For states listed in the Application section, providers must refer to the applicable state-specific policy or guideline rather than this national policy. See the Application section for state-specific directions and confirm any state or plan-level exceptions before submitting claims or authorization requests.

Providers should also verify benefit-specific prior authorization and coding rules because inclusion of a procedure or diagnosis code in this policy is for reference only and does not guarantee coverage or payment.

The routine use of biochemical bone turnover markers (BTMs) measured in serum or urine is not recommended as the sole basis to diagnose osteoporosis. Systematic reviews and guideline statements note that BTMs have been used extensively in research and clinical trials but their value for diagnosing osteoporosis in individual patients is limited by biological and analytical variability and lack of standardization.

BTMs may provide adjunctive information in some clinical contexts, but they should not be used alone to establish a diagnosis of osteoporosis; diagnosis should be made using established clinical risk assessment and bone mineral density (BMD) testing as appropriate.

Operational note: This Medical Policy expressly does not apply to certain states listed in the Application section. Most recently, language was added to indicate that providers in Idaho and Kansas must consult the state-specific policy versions referenced in the Application section rather than this national policy.

When providing care for members in these states, follow the named state policy/guideline and confirm any state-mandated coverage or documentation requirements prior to requesting authorization or submitting claims.

Serum or urine collagen crosslinks and other biochemical markers of bone turnover are considered unproven and not medically necessary to assess fracture risk, predict bone loss, or to assess response to antiresorptive therapy for the purposes of coverage.

Health technology assessments and primary studies have found mixed results and methodological limitations; consequently, these tests lack sufficient evidence of clinical utility to support routine coverage for fracture risk prediction, diagnosis, or monitoring of therapy.

Use of BTMs as standalone diagnostic tests for osteoporosis or as sole predictors of fracture risk is not supported by sufficient evidence and therefore is not medically necessary. International working groups and professional societies have concluded that BTMs cannot be used alone to diagnose osteoporosis.

When BTMs are measured, guideline groups recommend standardized assays (for example, serum PINP and serum CTX as reference markers), control of pre-analytical variables, and interpretation of results alongside BMD and clinical risk factors rather than relying on BTMs in isolation.

Coding and Test Identifiers

Commercial Policy descriptorsmixed

Collagen cross links, any method

Commercial Policy - Collagen Crosslinks and Biochemical Markers of Bone Turnover

PINP and CTX discrimination thresholds

PINP discrimination thresholdPINP < 30 (units as reported by study) — best discrimination for patients using vs not using antiresorptive drugs and predicted BMD gains after 2 years

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

Source study contextProspective cohort (Borgen et al. 2022) of 228 patients with 1–2 year BTM measurements reporting these cut points for adherence and BMD response

Provider Actions, Prior Authorization & Documentation

Prior Authorization

Prior authorization and code listing

Prior authorization and code listing — Procedure and diagnosis codes are provided for reference and to help confirm benefit‑specific prior authorization requirements. Inclusion of a code in this policy does not imply coverage or guarantee payment; confirm member benefits and any federal, state, or contractual requirements before submitting authorization requests.

Verify plan-specific prior authorization requirements before ordering testing.
Listing of a code does not imply the service is covered or reimbursable.

Prior Authorization

Prior authorization for routine BTM testing

Prior authorization may be required for routine or repeated biochemical marker of bone turnover (BTM) testing because guidelines and evidence do not consistently support routine serial testing for diagnosis or monitoring. Submit prior authorization when repeating tests for longitudinal monitoring or routine surveillance.

Consider prior authorization for repeated/routine BTM testing.
Support requests with clinical rationale given guideline uncertainty.

Clinical Background

Background: Bone is in continuous remodeling through osteoclast-mediated resorption and osteoblast-mediated formation. Biochemical markers measured in serum or urine—such as telopeptides (including CTX), procollagen type I N-terminal propeptide (PINP), osteocalcin, and bone-specific alkaline phosphatase—reflect aspects of bone resorption or formation.

Although these biochemical markers can indicate dynamic changes in bone turnover and have been useful in research and clinical trials, their interpretation in individual patients is limited by considerable biological and analytical variability, differences in assay standardization, and sensitivity to pre-analytical factors (for example, timing and fasting). As a result, BTMs are generally considered adjunctive to BMD and clinical risk assessment rather than standalone diagnostic tests.

Key Definitions and Marker Glossary

Bone turnover markers — formation vs resorption

Formation markers (examples)Procollagen type I N‑terminal propeptide (PINP); bone alkaline phosphatase (bALP); osteocalcin

Resorption markers (examples)C‑terminal telopeptide of type I collagen (CTX); N‑telopeptide (NTx); pyridinoline and telopeptides

Specimen types and assaysMeasured in serum or urine using HPLC or immunoassay methods; standardized serum PINP and CTX are recommended as reference markers

CTX (C‑terminal telopeptide of type I collagen)

DefinitionC‑terminal telopeptide of type I collagen (CTX) — a biochemical marker of bone resorption measured in serum or urine

Clinical useUsed in research and as an adjunctive marker to assess resorption changes with antiresorptive therapy; variability and standardization issues limit routine diagnostic use

Policy Summary

PayerUnitedHealthcare

PolicyCollagen Crosslinks and Biochemical Markers of Bone Turnover

Policy CodePolicy CSO21.P

Change TypeState application addedevidence/references updated

Effective DateFeb 1, 2025

Next Review Date

Key ActionVerify plan-specific prior authorization and state-specific policy applicability before submitting claims or requests for BTM testing.

SourceLink

On This Page

Prior Authorization

Prior authorization and decision tools

Prior authorization decision tools — Verify whether plan-specific prior authorization tools (including third‑party tools such as InterQual) are required for authorization determinations.

Check plan portals or authorization instructions for required decision‑support tools.
If a third‑party tool is used, follow its documentation requirements when submitting requests.

Documentation Required

Required documentation for BTM interpretation

Provider action — When submitting for review, include documentation needed to interpret BTM results: assay type/name, timing of sample collection (eg, fasting morning sample or second‑void urine), and the clinical context (indication, treatment being monitored, baseline values).

Include assay name/method and reference range.
Document timing of specimen (eg, 2nd void urine, fasting morning serum) and relation to therapy initiation or change.
Provide baseline and prior results if available and specific clinical question (adherence, biochemical response, suspected nonresponse).

Note

BTMs as adjunctive monitoring

BTMs should be used primarily as adjunctive monitoring (eg, to assess adherence or biochemical response to therapy), not as a standalone first‑line diagnostic test for osteoporosis or fracture risk prediction.

Use BTMs to supplement clinical assessment and BMD measurements, not as the sole basis for treatment decisions.

Denial Risk

Denial for tests judged not medically necessary

Denial risk — Claims for serum or urine collagen crosslinks or BTMs used for fracture risk prediction, diagnosis of osteoporosis, or routine monitoring without adequate clinical justification may be denied as not medically necessary.

Tests ordered solely for fracture prediction, general osteoporosis diagnosis, or routine surveillance without documentation of clinical indication are at risk for denial.
Provide specific therapeutic context and rationale when requesting testing to reduce denial risk.

Step Therapy

Step therapy

Provider action — No step therapy requirements are specified in this policy excerpt. Check benefit terms for any plan‑specific step therapy or other utilization management rules that might apply.

Confirm there are no applicable step therapy protocols in the member's specific benefit plan prior to ordering.
If step therapy is present in the plan, follow those requirements for medication management; this policy does not specify step therapy for testing.

Billing Rule

Coding/documentation note

Coding/documentation note — The presence of a code in the policy does not imply coverage or guarantee payment. Always confirm coverage under the member's specific benefit plan and include required documentation when requesting authorization or submitting claims.

Include clinical rationale and required specimen/timing details to support medical necessity.
Verify federal, state, and contractual coverage rules that may modify standard policy application.

Note

Verify plan-specific requirements

Verify plan‑specific requirements — Coverage decisions are governed by federal, state, or contractual benefit terms which may differ from this standard policy. Check for any local regulatory or contract variations before applying this policy to a member.

Confirm state‑mandated coverage rules or plan contract language that could affect coverage determinations.
When in doubt, contact the plan's medical policy or provider relations representative for guidance.

Reference marker recommendationInternational working groups recommend serum CTX as a reference resorption marker when using standardized assays

PINP (Procollagen type I N‑terminal propeptide)

DefinitionProcollagen type I N‑terminal propeptide (PINP) — a biochemical marker of bone formation measured in serum

Clinical usePINP levels have been evaluated to predict treatment effects (BMD gains) and may help monitor anabolic response; interpretation requires standardized assays

Discrimination threshold reportedPINP < 30 was reported in a prospective cohort (Borgen et al. 2022) as a cut point discriminating ARD use and predicting BMD response

bALP (Bone‑specific alkaline phosphatase)

DefinitionBone‑specific alkaline phosphatase (bALP) — an enzyme isoform measured in serum that reflects osteoblastic bone formation activity

Clinical associationsGreater bALP has been associated with lower femoral BMD in pooled analyses; used in therapy monitoring studies

Measurement considerationsAssessed in serum; variability across assays and pre‑analytical factors limits standalone diagnostic use

Biochemical markers of bone turnover — definition and examples

General definitionBiochemical markers of bone turnover are laboratory measurements in serum or urine that reflect bone formation (e.g., PINP, bALP, osteocalcin) or bone resorption (e.g., CTX, NTx, pyridinoline) and are used to estimate bone remodeling dynamics

Common examplesFormation: PINP, bone alkaline phosphatase (bALP), osteocalcin; Resorption: CTX, NTx, pyridinoline, other telopeptides

Clinical considerationsMarkers are used in research and as adjunctive tools to monitor therapy or adherence but have limitations due to pre‑analytical variability and lack of standardization; guidelines recommend standardized assays and interpretation alongside BMD and risk factors