ModifiedUnitedHealthcarePolicy CS021LA.N

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

Policy governing use of serum or urine collagen crosslinks and biochemical bone turnover markers to assess fracture risk, predict bone loss, or monitor response to antiresorptive therapy for members in Louisiana.

Policy Summary

PayerUnitedHealthcare

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

Policy CodePolicy CS021LA.N

Change TypeRevised (archived prior version)

Effective DateMar 1, 2026

Next Review Date

Key ActionDo not submit claims for BTMs to assess fracture risk, predict bone loss, or monitor antiresorptive response because they are considered unproven and not medically necessary.

SourceLink

POLICY UPDATE CHANGES

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

03/01/2026policy revision date

not medically necessarycoverage stance

82523referenced CPT

LAstate-specific

very low

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certainty level (OC)

Coverage Criteria — Summary and Rationale

Not medically necessary

Covered when ALL of the following are met

Primary coverage 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 statement — not covered for these indications.

Evidence and guideline context (informational)

Clinical evidence and guideline positions relevant to utility of BTMs

Evidence summary: Studies report that CTX and PINP change during fracture healing and with osteoporosis therapy, but associations with radiographic or functional healing, BMD changes, adverse events, and fracture risk are inconsistent across trials, cohorts, and meta-analyses; systematic reviews and health-technology assessments have concluded that evidence is mixed or insufficient and further well-designed studies are needed.

RCTs, prospective cohorts, systematic reviews, and meta-analyses cited noting limitations (sample size, variability, follow-up).

Guideline positions: Professional society recommendations vary: some organizations (AACE/ACE, BHOF, Endocrine Society, ESCEO/IOF/IFCC, ISCD) endorse using serum PINP and CTX as reference markers to monitor therapy, assess adherence, or predict aspects of treatment response; others (NAMS, Osteoporosis Canada) advise against routine clinical use for diagnosis, fracture prevention monitoring, or decisions about bisphosphonate holidays due to low certainty or inconclusive predictive value.

Guidance ranges from supporting BTMs as adjuncts for monitoring to recommending against routine clinical use for certain decisions.

This policy applies to measurement of serum or urine collagen crosslinks and biochemical bone turnover markers (BTMs) when ordered to assess fracture risk, predict bone loss, or assess response to antiresorptive therapy for members in Louisiana; such uses are considered unproven and not medically necessary.

BTMs cannot be used alone to diagnose osteoporosis. Professional society guidance notes that while BTMs can provide dynamic information about skeletal activity, several organizations advise against routine use of BTMs for diagnosis or for making definitive therapy decisions in isolation.

Osteoporosis Canada suggests against using BTMs for routine monitoring aimed at fracture prevention or to guide resumption of bisphosphonate therapy during a drug holiday (conditional recommendation; very low‑certainty evidence).

Serum or urine collagen crosslinks and other BTMs are considered unproven and not medically necessary for the purposes of assessing fracture risk, predicting bone loss, or assessing response to antiresorptive therapy.

The ECRI Health Technology Assessment concluded there is insufficient evidence to determine whether BTMs have clinical utility for diagnosing osteoporosis, monitoring treatment response, or predicting fracture risk; additional research is needed.

Historical guidance from Osteoporosis Canada previously stated that BTMs should not be used for routine clinical management pending further studies; routine clinical management using BTMs is not supported by these prior recommendations.

Covered Indications and Clinical Uses

No covered indications provided

No covered indications provided: No covered indications for serum or urine collagen crosslinks or biochemical bone turnover markers are specified in the provided excerpts; the policy concludes these tests are unproven for fracture risk assessment, prediction of bone loss, or monitoring response to antiresorptive therapy.

Refer to full policy for any narrowly defined covered indications (none present in these sections).

Monitoring response to osteoporosis therapy and assessing adherence/persistence

Clinical uses cited: Monitoring response to osteoporosis therapy and assessing treatment adherence/persistence: serum CTX is cited for monitoring response to antiresorptive therapy and P1NP (PINP) for anabolic therapy; BTMs may be repeated after 3–6 months to assess response or adherence.Repeat after 3-6 months for treatment monitoring

Guidelines (BHOF, Endocrine Society, ISCD) propose these roles as adjuncts to BMD and clinical assessment.

Not Covered — Explicit Exclusions

Serum or urine collagen crosslinks and biochemical markers of bone turnover are not covered for use to assess fracture risk, predict bone loss, or assess response to antiresorptive therapy.

Use of BTMs for the routine diagnosis of osteoporosis or for guiding the resumption of bisphosphonate therapy during a drug holiday is not covered, reflecting society positions that BTMs alone should not determine diagnosis or such treatment decisions.

Routine monitoring with BTMs to prevent fractures or to decide whether to resume bisphosphonate therapy after a drug holiday is not covered, consistent with Osteoporosis Canada’s 2023 suggestion against this practice (conditional; very low‑certainty evidence).

Coding — Referenced Procedure Codes and Test Thresholds

Applicable CPT CodesCPT

82523

Collagen cross links, any method

P1NP and CTX discrimination thresholds reported in a cohort

P1NP thresholdP1NP < 30 (units as reported in cohort)

CTX thresholdCTX < 0.25 μg/L

Cohort contextThresholds derived from a prospective cohort (Borgen et al. 2022) assessing discrimination of ARD use and prediction of BMD gains

Provider Actions, Billing and Regulatory Considerations

Prior Authorization

Prior Authorization — Check Plan

Check plan-specific prior authorization requirements before ordering testing. This policy is informational and does not replace federal, state, or contractual benefit plan rules that may require prior authorization for laboratory testing or related services.

Verify member benefits and any plan prior authorization requirements with UnitedHealthcare or the applicable plan administrator prior to testing.
CPT 82523 (Collagen cross links, any method) is listed for reference; inclusion does not imply coverage or authorization.
When in doubt, obtain prior authorization per the member's benefit plan.

Denial Risk

Denial Risk for Testing

There are no explicit denial triggers stated in this policy excerpt; however, claims for collagen crosslink or other biochemical bone marker testing to assess fracture risk, predict bone loss, or assess response to antiresorptive therapy are identified in the Coverage Rationale as unproven and not medically necessary and therefore may be at risk for denial under applicable benefit terms.

Definitions and Biomarker Glossary

Bone turnover markers (BTMs) — definition and examples

DefinitionBiochemical markers of bone formation or bone resorption measured in serum or urine

Examples — resorption markersPyridinoline, telopeptides, urinary cross-linked N-telopeptide of type I collagen (NTX)

Examples — formation markersOsteocalcin, bone alkaline phosphatase, P1NP (procollagen type I N-terminal propeptide)

Measurement methodsMeasured in urine and/or serum by high-performance liquid chromatography or immunoassay

CTX — definition and role

Full nameC-terminal telopeptide of type I collagen (CTX)

Frequency Limits and Monitoring Intervals

Frequency limits — placeholder

PlaceholderNo frequency-limit label or summary was provided in the inventory; block retained for completeness

BTM (CTX or PINP) — recommended repeat interval for monitoring

Test(s)BTM (serum CTX or PINP)

Recommended repeat intervalRepeat after 3 to 6 months for treatment monitoring

Use caseMonitoring response to osteoporosis therapy and assessing adherence or persistence

Frequency limits — placeholder (empty summary)

Ordering Requirements and Provider Eligibility

Note

No ordering-provider restrictions specified

No specific ordering provider restrictions are stated in the provided portions of the policy.

Note

No explicit ordering clinician restrictions; follow clinical guidelines

The excerpts do not specify ordering-provider limits; guideline recommendations apply to clinicians who manage osteoporosis when considering testing.

Guidelines reference clinicians monitoring osteoporosis (e.g., endocrinologists, primary care).

Documentation Required

Follow CLIA and plan-specific laboratory/coverage rules for ordering

Follow CLIA requirements and any plan-specific laboratory/coverage rules when ordering or performing BTMs; no ordering clinician restrictions are specified in these excerpts.

Background — Bone Remodeling and Marker Biology

After skeletal maturity, bone remodeling continues via osteoclastic resorption and osteoblastic formation. Biochemical markers reflect these processes and include pyridinoline, telopeptides (e.g., CTX), urinary NTx, osteocalcin, and bone alkaline phosphatase; these analytes are measurable in serum or urine and have been studied as indicators of bone resorption or formation.

Revision History and Policy Changes

2026-03-01revisedLatest

Archived previous policy version CS021LA.M and updated Description of Services, Clinical Evidence, FDA, and References sections to reflect the most current information.

Policy Summary

PayerUnitedHealthcare

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

Policy CodePolicy CS021LA.N

Change TypeRevised (archived prior version)

Effective DateMar 1, 2026

Next Review Date

Key ActionDo not submit claims for BTMs to assess fracture risk, predict bone loss, or monitor antiresorptive response because they are considered unproven and not medically necessary.

SourceLink

On This Page

No specific covered indications defined; guidance advises against routine use for fracture prevention or drug-holiday decisions

Guidance caution: No specific covered indications are defined in the provided sections; several guideline statements and assessments advise against routine use of BTMs for fracture prevention or for making bisphosphonate 'holiday' resumption decisions due to very low to low certainty or inconclusive evidence.

Osteoporosis Canada (2023) suggests against monitoring with BTMs for fracture prevention or to guide bisphosphonate resumption (conditional; very low-certainty). ECRI concluded insufficient evidence to determine clinical utility.

Coverage Rationale indicates these tests are unproven and not medically necessary for fracture risk assessment, prediction of bone loss, or response assessment to antiresorptive therapy.
Denial decisions will be made based on federal, state, or contractual benefit plan language and applicable medical necessity criteria.

Note

FDA / Regulatory Considerations

FDA clearance or approval of a commercially marketed test is informational only and is not by itself a basis for coverage. CLIA certification and laboratory validation requirements apply to labs performing these tests.

FDA 510(k) clearance status can be checked via the FDA 510(k) database; CLIA database may be searched by manufacturer/test/analyte.
Laboratories using laboratory-developed tests must meet CLIA standards even if the test is not marketed.
FDA informational resources do not list biochemical markers as diagnostic tests for osteoporosis.

Documentation Required

Coding and Documentation Note

Coding and documentation: CPT 82523 (Collagen cross links, any method) is provided for reference only. Inclusion of a code in this policy does not imply coverage or guarantee payment; submitters must follow benefit plan documentation and coding requirements.

CPT 82523 listed for reference; verify correct coding and billing guidance with the member's plan.
Maintain clinical documentation demonstrating medical necessity consistent with federal, state, and contractual requirements.

Note

Clinical Study Methods and Evidence — Informational

This section contains excerpts from clinical studies and trial methods that describe sampling timing and assay details (e.g., CTX, P1NP measurements at baseline, 6 and 12 weeks) and study limitations; these research details do not establish provider documentation mandates for coverage decisions.

Clinical evidence summarizes RCTs and observational studies assessing BTMs (CTX, P1NP, periostin) with timing and assay notes; limitations include small samples, variability in sampling (e.g., fasting status), and short follow-up.
Study methods are informational and do not replace plan-specific medical necessity documentation requirements.

Documentation Required

Plan Documentation Requirements

When deciding coverage, always reference and follow the applicable federal, state, or contractual benefit plan requirements; this Medical Policy is informational and may differ from plan-specific coverage rules.

In the event of conflict, federal, state, or contractual benefit plan language governs coverage determinations.
UnitedHealthcare may use third-party tools (e.g., InterQual) to assist in benefit administration; providers should confirm plan-specific documentation expectations prior to submission.

Note

Unlabeled Provider Action (Source Mapping)

Preserve source mapping: this callout acknowledges an unlabeled provider action entry in the inventory and is retained for traceability; no additional provider action is specified.

Step Therapy

Step Therapy — None Specified

Step therapy: no step therapy requirements are specified in the provided policy excerpts.

No step therapy or prior trial requirements are detailed for biochemical bone marker testing in the available excerpts.

RoleA bone resorption marker measured in serum or urine

Clinical use notedRecommended as a reference resorption marker in guideline statements (e.g., ESCEO/IOF/IFCC) and used to monitor antiresorptive therapy or adherence

PINP — definition and role

Full nameProcollagen type I N-terminal propeptide (PINP)

RoleA bone formation marker used to assess anabolic bone activity

Clinical use notedRecommended as a reference formation marker in guideline statements and used to monitor response to anabolic therapy or treatment adherence

Periostin — proposed marker and study finding

AnalytePeriostin (serum periostin)

Study populationEvaluated in Chinese postmenopausal women in a cross-sectional study (Li et al. 2021)

Key findingNo correlation between serum periostin and traditional BTMs or BMD in that cohort

BTMs — regulatory and specimen notes

Specimen typesBTMs are measured in blood (serum or plasma) or urine

Regulatory frameworkTest systems are regulated under Clinical Laboratory Improvement Amendments (CLIA) as laboratory test systems

FDA clearance noteSome commercially marketed BTM systems may have FDA 510(k) marketing clearance; laboratories using in-house tests remain under CLIA rather than FDA marketing regulations

Inventory item contained no summary text; included for completeness

Laboratories that use their own tests are regulated under CLIA, and plan terms govern coverage.