ModifiedUnitedHealthcarePolicy CS021PA.O

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

This policy governs coverage and medical necessity for serum or urine collagen crosslinks and biochemical markers of bone turnover for patients in Pennsylvania; it addresses use for fracture risk assessment, prediction of bone loss, and monitoring response to antiresorptive therapy.

Policy Summary

PayerUnitedHealthcare

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

Policy CodePolicy CS021PA.O

Change TypeRevised clinical and reference sectionsarchived prior version

Effective DateMar 1, 2026

Next Review Date

Key ActionVerify member benefit and prior authorization requirements with the member's plan before ordering bone turnover marker testing.

SourceLink

POLICY UPDATE CHANGES

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

1CPT code listed in policy

PennsylvaniaState-specific application

UnprovenCoverage stance

PINP, β-CTXReference markers

03/01/2026

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Policy revision date

Coverage Criteria

inv-01: Not medically necessary indications — Not covered for the following purposes

Not covered for the following purposes

Primary not-covered uses: 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.

Pennsylvania-specific policy application.

inv-02: Clinical evidence and guideline positions — Guideline and evidence summary relevant to coverage considerations

Guideline and evidence summary relevant to coverage considerations

Evidence summary: Systematic reviews, health-technology assessments, cohort and randomized studies report mixed results: some analyses find associations between higher baseline BTMs (e.g., PINP, CTX, NTx) and fractures or faster bone loss, and several guideline groups note potential roles for BTMs in monitoring therapy and adherence; however, large prospective studies and ECRI concluded evidence is insufficient to support BTMs for diagnosis, routine fracture-risk prediction, or definitive monitoring because of high biological and assay variability and lack of standardized decision thresholds. Societies differ in recommendations: some (ESCEO/IOF/IFCC, BHOF, AACE/ACE, Endocrine Society, ISCD) recognize potential monitoring uses (noting PINP and β-CTX as reference markers), while others (NAMS, Osteoporosis Canada) do not recommend routine clinical use for fracture prevention.

References include Lorentzon et al. 2019; ECRI 2018; AACE/ACE 2016/2020; BHOF 2022; Endocrine Society 2020; ESCEO/IOF/IFCC 2025; ISCD positions; NAMS 2021; Osteoporosis Canada 2023; Migliorini 2021; Tian 2019; Crandall 2018.

This policy applies only within the state of Pennsylvania. Any requests for serum or urine collagen crosslinks or biochemical markers of bone turnover that fall outside the criteria described here will be evaluated on a case‑by‑case basis under the Pennsylvania Administrative Review process; refer to Pennsylvania Exceptions, Pennsylvania Code, Title 55, Chapter 1101 for procedural details.

Clinical guidance and consensus statements indicate that bone turnover markers (BTMs) cannot be used to diagnose osteoporosis. Several societies note substantial biological and analytical variability in BTMs and do not recommend routine use for fracture prevention or population screening; the routine clinical use of BTMs is therefore discouraged.

This Medical Policy is provided for informational purposes and is intended to assist interpretation of UnitedHealthcare standard benefit plans. Coverage decisions must be made in the context of applicable federal, state, or contractual benefit plan requirements, which govern in the event of a conflict; consult the member’s benefit terms before applying this policy.

Based on the clinical evidence summarized in this policy, serum or urine collagen crosslinks and other biochemical markers of bone turnover are considered unproven and not medically necessary when used to assess fracture risk, predict bone loss, or to monitor response to antiresorptive therapy.

An independent ECRI Health Technology Assessment concluded there is insufficient evidence to determine whether BTMs are useful for diagnosing osteoporosis, monitoring response to osteoporosis treatment, or determining fracture risk; additional research was recommended.

Covered Indications

inv-30: No covered indications provided — clinical validity unproven and prospective trials needed

No covered indications are provided in this policy; clinical validity is unproven and additional prospective trials are needed.

Coverage statement: The clinical validity of collagen crosslinks and bone turnover biomarkers is unproven and additional well‑designed prospective trials are needed to establish their role in managing decreased bone mineral density and improving clinical outcomes.

No covered indications specified in this policy; testing requests should be evaluated per member benefit terms.

inv-31: Assessing therapy response and adherence in treated osteoporosis patients; predicting rapidity of bone loss in certain populations

Potential monitoring roles described by guideline groups and consensus statements

Monitoring and adherence: BTMs may be used to assess treatment response and adherence: repeat measurement at 3 to 6 months after treatment initiation can help identify biochemical response (e.g., serum CTX for antiresorptive therapy; PINP for anabolic therapy).

Not Covered

Use of serum or urine collagen crosslinks or biochemical markers of bone turnover to assess fracture risk, predict bone loss, or monitor response to antiresorptive therapy is considered not medically necessary and is therefore not covered under the criteria set forth in this policy.

Routine use of BTMs for diagnosis of osteoporosis or for population‑level fracture‑risk prediction is not supported by current guideline groups; some organizations explicitly recommend against routine monitoring of BTMs for fracture prevention or bisphosphonate drug‑holiday decisions.

This document does not list explicit test exclusions; actual coverage of BTMs depends on the member’s specific benefit plan and applicable federal, state, or contractual terms. Verify benefit terms when determining coverage applicability.

Coding

Applicable CPT Codes (reference)CPT

82523

Collagen cross links, any method

inv-09: Suggested discriminatory BTM cutoffs from a cited study

Suggested discriminatory cutoffsP1NP < 30 μg/L and CTX < 0.25 μg/L (levels below these yielded the best discrimination for ARD use and prediction of BMD gains in the cited cohort study)

Study contextDerived from a prospective cohort of 228 participants evaluating cutoffs for adherence and prediction of BMD change after fragility fracture

Associated outcomesCutoffs predicted treatment effects on BMD and discriminated participants using versus not using antiresorptive drugs

inv-10: Least significant change for CTX

Least significant change for CTXApproximately a 40% reduction (least significant change cited for serum CTX when characterizing response/adherence)

Guidance context

Provider Actions

Prior Authorization

Verify prior authorization with plan

Verify prior authorization with the member's benefit plan and applicable federal, state, or contractual rules before ordering biochemical markers of bone turnover (BTMs). Prior authorization requirements — including any state-specific programs or plan exclusions — are determined by the member's benefit plan and governing regulations.

Prior auth requirements vary by plan and state (including Pennsylvania-specific PARP rules)
Check member eligibility and benefit terms prior to testing

Note

Regulatory context

FDA clearance or approval of a test does not, by itself, establish that the test is a covered service. The FDA categorizes commercially marketed test systems and provides 510(k) and CLIA information for manufacturers and laboratories; this regulatory status is informational but not determinative for coverage.

FDA approval/clearance is informational only for coverage determinations
CLIA categories (waived/moderate/high) are regulatory descriptors and do not guarantee coverage

Definitions

inv-24: Biochemical markers of bone turnover (BTMs) — definition of bone turnover markers

DefinitionBiochemical markers of bone turnover (BTMs) are measurable substances in serum or urine that reflect bone formation or bone resorption processes.

Measurement methodsCommonly assessed by high-performance liquid chromatography or immunoassay in serum or urine specimens.

Clinical intentStudied to assess rate of bone loss, fracture risk, and response to osteoporosis therapy, though interpretation is complex and affected by assay variability.

inv-25: Common BTMs

Formation markersOsteocalcin, bone-specific alkaline phosphatase (bALP), and P1NP (procollagen type I N-terminal propeptide)

Resorption markersC-terminal cross-linking telopeptide (CTX), pyridinoline, and other telopeptides such as NTx

Frequency Limits

inv-33: Frequency-listed markers — P1NP, CTX

Frequently listed markersP1NP and CTX are reiterated across guidelines and studies as the primary reference BTMs.

RationaleChosen for specificity to bone, study performance, and potential for assay standardization compared with other markers.

Guideline supportMultiple organizations (ESCEO/IOF/IFCC, Lorentzon et al., BHOF) reaffirm PINP and β-CTX as reference markers.

inv-34: Typical monitoring interval for BTMs (CTX for antiresorptive, PINP for anabolic) — 3 to 6 months

Typical monitoring interval3 to 6 months after treatment initiation (CTX for antiresorptive therapy; PINP for anabolic therapy)

Guideline basisEndocrine Society and other guideline documents recommend measuring BTMs at 3–6 months to identify poor response or nonadherence.

Ordering Requirements

Note

No clinician-specific ordering restrictions stated

No specific ordering provider restrictions are stated in this policy.

Note

Policy focuses on clinical context, not who may order tests

Guidance in the policy emphasizes appropriate clinical contexts for testing (e.g., monitoring therapy) rather than restricting which clinicians may order BTMs.

Documentation Required

Verify member benefit terms before ordering

Providers must reference the member's benefit plan when ordering BTMs; the policy does not specify clinician ordering restrictions but requires adherence to the member's contractual and state coverage terms.

Background

Bone remodeling continues after growth with ongoing resorption by osteoclasts and formation by osteoblasts. Biochemical markers of bone turnover (BTMs) — for example, pyridinoline, telopeptides, urinary N‑telopeptide (NTX), CTX, P1NP, osteocalcin, and bone‑specific alkaline phosphatase — are measurable in serum or urine and have been studied as potential tools to assess bone loss, fracture risk, and response to therapy. Interpretation of these markers is complex because of large preanalytical and analytical variability, lack of standardized thresholds, and differences between assays; as a result, clinical validity and utility for routine management remain unproven.

Policy Summary

PayerUnitedHealthcare

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

Policy CodePolicy CS021PA.O

Change TypeRevised clinical and reference sectionsarchived prior version

Effective DateMar 1, 2026

Next Review Date

Key ActionVerify member benefit and prior authorization requirements with the member's plan before ordering bone turnover marker testing.

SourceLink

On This Page

BHOF and Endocrine Society cite 3–6 month monitoring; least significant change for CTX ~40% (BHOF).

Predicting rapid bone loss: BTMs can predict rapidity of bone loss in some untreated postmenopausal women and may predict the magnitude of BMD change with therapy in selected patients.

Described by BHOF and other consensus groups as a potential role, not an established coverage indication.

inv-32: Use of BTMs in diagnosis, assessment, and monitoring as discussed in cited guidelines and studies (specifics deferred to benefit plan)

Use of BTMs in diagnosis, assessment, and monitoring as discussed in cited guidelines and studies (specifics deferred to benefit plan)

Reference markers and assay considerations: Consensus papers and society guidelines reaffirm serum PINP and plasma/serum β‑CTX as reference BTMs and recommend measuring them with standardized assays due to preanalytical and analytical variability.

Lorentzon et al. 2019; ESCEO/IOF/IFCC 2025; Endocrine Society; AACE/ACE.

Diagnostic and monitoring limitations: BTMs cannot be used to diagnose osteoporosis; routine use for population‑level fracture risk prediction or routine monitoring for fracture prevention is not supported by some societies and by health‑technology assessments.

Lorentzon et al. 2019; ECRI 2018; NAMS 2021; Osteoporosis Canada 2023.

Coverage implementation note: Specific covered indications, monitoring frequency, and thresholds for clinical action are determined by the member's benefit plan and clinical judgment; this policy provides summary evidence and guideline positions but does not itself establish benefit plan coverage criteria.

Refer to plan contract and applicable state rules (Pennsylvania).

BHOF notes this threshold when using CTX to characterize adherence or response to antiresorptive therapy

Use implicationA ~40% fall in CTX is considered the minimal change to indicate a true biological response rather than analytical/biological variability

Note

Benefit terms govern

Benefit plan terms and any applicable federal or state laws govern coverage decisions. In the event of a conflict between this Medical Policy and a member's federal, state, or contractual benefit requirements, the federal/state/contractual requirements control.

Reference the member's benefit booklet, state mandates, and contract language
For Pennsylvania members, consider Pennsylvania Exceptions and PARP guidance

Documentation Required

Documentation and benefit verification

Document the clinical indication and medical necessity when ordering BTMs. Include relevant clinical details in the medical record and on the request (e.g., diagnosis, prior treatments, timing relative to therapy initiation, and how results will influence management). Verify and record benefit coverage terms and any prior authorization decision.

Document diagnosis, intended clinical use, and management plan tied to BTM results
Record prior authorization number or benefit determination in the chart and on claims
Inclusion of CPT 82523 in the policy is informational only

Note

Clinical monitoring examples

Clinical studies and guideline statements have explored using BTMs to guide duration of therapy or monitor response (for example, measuring CTX or PINP at 3–6 months after treatment initiation to assess response or adherence). However, evidence is mixed and practice guidelines vary; BTMs are not established as a routine tool for fracture risk prediction or as a sole determinant for changing osteoporosis treatment.

Examples: measuring serum CTX or PINP at 3–6 months after initiation to evaluate biochemical response or adherence (per guideline suggestions)
Research example: perioperative monitoring protocol where alendronate was adjusted based on CTX/PINP (Ma et al., 2021)
Guideline nuance: some societies re-affirm PINP and β-CTX as reference markers but note limitations and variability

Assay considerationsGuidelines recommend using serum PINP and β-CTX as reference markers measured with standardized assays due to variability across methods.

inv-26: Procollagen type I N-terminal propeptide (PINP) — bone formation marker

Marker identityProcollagen type I N-terminal propeptide (PINP) is a bone formation marker reflecting new collagen formation during bone formation.

Clinical roleRecommended as a reference formation marker (serum PINP) for monitoring anabolic therapy and assessing treatment response/adherence.

Assay noteGuideline groups advise measuring PINP in serum using standardized assays due to preanalytical and analytical variability.

inv-27: C-terminal cross-linking telopeptide (CTX) — bone resorption marker

Marker identityC-terminal cross-linking telopeptide (CTX; β-CTX-I) is a bone resorption marker that reflects collagen breakdown during bone resorption.

Clinical roleRecommended as a reference resorption marker (serum CTX) for monitoring antiresorptive therapy and assessing adherence/response.

Preanalytical considerationsCTX exhibits diurnal variation and is influenced by food intake; early-morning samples are often preferred to reduce variability.

inv-28: Urinary NTx and bALP — additional markers evaluated in studies

Urinary NTxUrinary N-telopeptide (NTx) is a resorption marker evaluated in multiple studies but may have higher variability than serum markers.

bALPBone-specific alkaline phosphatase (bALP) is a formation marker that has been evaluated in trials and systematic reviews for associations with BMD and outcomes.

Study useBoth urinary NTx and bALP were included in RCTs and meta-analyses assessing BTMs as monitoring tools and predictors of outcomes.

inv-29: BTMs — examples including CTX, PINP, osteocalcin, bone-specific alkaline phosphatase

Examples of BTMsCTX (C-telopeptide), PINP (procollagen type I N-terminal propeptide), osteocalcin, bone-specific alkaline phosphatase (bALP)

Usage contextsThese markers are used in clinical trials, cohort studies, and some clinical evaluations to assess bone resorption and formation.

LimitationsInterpretation is limited by biological and analytical variability and lack of universally standardized thresholds.

Clinical useInterval allows assessment of early biochemical response that may precede detectable BMD changes.

inv-35: (blank frequency-limits key_value placeholder)

Frequency limits placeholderNo specific frequency limit provided in this policy segment; refer to benefit plan language and clinical guidance.

Policy noteFrequency rules may be determined by the member's benefit plan; clinical guidelines suggest clinical monitoring intervals where applicable.

Actionable stepVerify plan-specific frequency limits and document clinical indication when ordering BTMs.