CurrentBlue Cross Blue Shield - South DakotaPolicy N/A

Bone Turnover Markers for Diagnosis and Management of Osteoporosis and Other Conditions

Defines Wellmark/Blue Cross Blue Shield - South Dakota's coverage position on biochemical bone turnover marker (BTM) testing for diagnosis, fracture risk assessment, monitoring response to therapy, and management of other high bone-turnover conditions; affects clinicians ordering BTM tests and reimbursement determinations.

Policy Summary

PayerBlue Cross Blue Shield - South Dakota

PolicyBone Turnover Markers for Diagnosis and Management of Osteoporosis and Other Conditions

Policy CodePolicy N/A

Change TypePolicy renewed (annual review)

Effective DateN/A

Next Review DateN/A

Key ActionWhen ordering bone turnover markers to assess response to osteoporosis therapy, document that results will inform a management decision (start/continue/modify/discontinue therapy).

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

InvestigationalBTM testing for fracture risk in osteoporosis

InvestigationalBTM testing to determine response or duration of osteoporosis therapy

No RCTsRandomized controlled trials

UncertainClinical utility

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Last evidence update

RenewedMost recent policy action

Coverage Criteria for Bone Turnover Marker Testing

Osteoporosis Fracture Risk

Osteoporosis fracture risk: Measurement of bone turnover markers (BTMs) to determine fracture risk in individuals with osteoporosis or age-related risk factors is considered investigational

Evidence insufficient to determine effects on health outcomes (see source).

Osteoporosis Therapy

Osteoporosis therapy monitoring: Measurement of bone turnover markers (BTMs) to determine response to therapy or duration of therapy in individuals being treated for osteoporosis is considered investigational

Evidence insufficient to determine effects on health outcomes (see source).

Conditions Associated with High Rates of Bone Turnover

Conditions associated with high bone turnover: Measurement of bone turnover markers is considered investigational for management of conditions associated with high rates of bone turnover (including but not limited to: diabetes; oncologic indications including monitoring of metastatic disease; Paget disease; primary hyperparathyroidism; renal osteodystrophy; rheumatologic conditions; vitamin D deficiency)

Observational correlations exist for some conditions but clinical utility for management is unproven.

Coverage with criteria: Adjunctive monitoring of osteoporosis therapy

Covered when BTMs are used as adjuncts to DXA to inform management decisions about osteoporosis therapy and when results are expected to change treatment within a clinically actionable timeframe:

Adjunctive use to DXA: BTMs must be used in addition to, not instead of, bone mineral density measured by DXA to inform treatment decisions

DXA remains the primary comparator; BTMs are adjunctive information.

Timing for expected change: BTMs are ordered when the clinician intends to assess biochemical response within 3 to 6 months of therapy initiation or change3-6 months

BTMs typically change more rapidly than BMD (3–6 months vs years).

Intended management impact: There must be a documented plan that BTM results will inform a management decision (start, continue, modify, or discontinue therapy)

Clinical utility depends on whether results change management and improve outcomes; document intended action when ordering.

Clinical utility requirement

Coverage contingent on evidence of clinical utility and validity

General requirement: There must be sufficient evidence that a specific BTM result changes management and improves net health outcomes; absent such evidence, coverage is not supported.

Current evidence is insufficient to support that BTM results affect patient management or outcomes.

Study-level performance criteria

When used for clinical validity assessment in studies

Study eligibility and reporting: Test performance studies should report the marketed assay version, include a suitable reference standard, and describe patient/sample clinical characteristics and selection criteria

These elements are required to evaluate clinical validity and applicability.

Paget disease

Condition-specific evidence summary

Paget disease evidence: Systematic review found moderate-to-strong correlations between several BTMs (eg, bone ALP, total ALP, PINP, N-terminal telopeptide) and disease activity before and after bisphosphonate treatment; reviewers did not assess impact on management or outcomes

Evidence base: 18 studies; most nonrandomized.

Observational evidence

Observational findings (not sufficient for coverage decisions alone)

Markers predicting response or complications: Some observational studies report associations (eg, FIT subgroup: higher baseline PINP predicted greater alendronate efficacy for nonspine fractures; Kashii 2023: PINP associated with BMD increase with romosozumab with optimal cutoff ~53.7 mcg/L; Martli 2023: CTx >2.665 pg/dL associated with postoperative hypocalcemia), but quantity and quality of evidence are limited and do not establish management guidance

Associations do not establish that testing changes clinical outcomes.

Evidence-based coverage summary

Overall coverage stance from evidence review

Evidence requirements: No randomized controlled trials identified that demonstrate BTM-guided management improves health outcomes; indirect and observational evidence is insufficient to conclude that BTM testing changes patient management or improves outcomes; therefore clinical utility is unproven and coverage is not supported

Direct evidence (RCTs) is lacking; chain-of-evidence does not support clinical utility.

Conditional guideline-supported indications

Guideline-based conditional uses (supplemental information)

Guideline-endorsed uses: Professional societies note possible conditional uses: monitoring treatment response or adherence (serum CTX for antiresorptives; PINP for anabolic therapy), predicting rapid bone loss or treatment-associated BMD change when measured 3–6 months after therapy initiation, and assessing disease activity in Paget disease or follow-up in hyperparathyroidism; recommendations are variable and routine use is not universally endorsed

Guidelines cite ~40% as an approximate meaningful change for CTX/PINP measured 3–6 months after treatment initiation.

The policy lists specific clinical situations in which measurement of bone turnover markers (BTMs) is considered investigational. These investigational indications include: fracture risk assessment in individuals with osteoporosis or age-related risk factors, monitoring response to or duration of osteoporosis therapy, and management of disorders associated with high rates of bone turnover (examples include diabetes, oncologic monitoring of metastatic disease, Paget disease, primary hyperparathyroidism, renal osteodystrophy, rheumatologic conditions, and vitamin D deficiency). Because the evidence is insufficient to determine effects on health outcomes, requests for testing in these situations may be denied.

BTMs are not a replacement for bone mineral density testing by DXA. The evidence does not support using BTMs as a standalone test to predict future fracture risk or to substitute for DXA when making treatment decisions; DXA remains the primary comparator for diagnosis and management of osteoporosis.

There are no randomized controlled trials demonstrating that management strategies guided by bone turnover marker results improve patient health outcomes. Direct evidence of clinical utility would require RCTs comparing outcomes for patients managed with and without BTM-guided decisions; such trials have not been identified.

Overall, the chain of evidence is incomplete: although observational studies show associations between BTMs and disease activity or fracture risk, the current evidence is insufficient to conclude that measuring BTMs changes clinical management or improves outcomes for conditions with high bone turnover.

A Medicare National Coverage Determination exists for collagen crosslinks (NCD 190.19). This federal NCD may affect coverage determinations for collagen crosslink testing and should be considered when evaluating requests for CPT 82523.

In summary, investigational indications include: (1) use of BTMs to predict fracture risk—some meta-analyses report modest associations for markers such as PINP and CTX but clinical usefulness beyond BMD is unproven; (2) use of BTMs to monitor response to or determine duration of osteoporosis therapy—evidence does not show that BTM-based monitoring improves adherence or outcomes; and (3) use of BTMs in other high bone-turnover conditions—observational correlations exist (for example, Paget disease and selected surgical series) but evidence that testing changes management or outcomes is lacking.

Routine or population-level screening with BTMs to predict future fracture risk or to replace DXA is not medically necessary. The available literature does not demonstrate independent predictive value sufficient to support screening in asymptomatic populations.

Using BTM results to direct patient management (for example, to start, stop, or change osteoporosis therapy) is not supported by the current evidence base. Because clinical validity and the impact of test-directed management on outcomes are not established, routine use of BTMs to guide therapy is considered unsupported.

Ordering BTMs solely with the expectation of improving clinical outcomes is considered unproven/uncertain. No randomized trials have shown that testing changes net health outcomes, and indirect evidence is insufficient to infer clinical benefit.

Coding and Billing for Bone Turnover Marker Tests

Codes table referenced in policymixed

No codes listed

Listed CPT CodesCPT

82523	Collagen cross links, any method
83937	Osteocalcin (bone g1a protein)

Example biomarker thresholds reported in studies

PINP cutoff (example)PINP 53.7 mcg/L (optimal cutoff in Kashii et al. 2023) — sensitivity 54.3%, specificity 92.3%

CTX threshold (example)CTX > 2.665 pg/dL associated with increased risk of postoperative hypocalcemia (Martli et al. 2023)

PINP — associated outcomePINP level independently associated with ≥3% increase in BMD with romosozumab treatment (Kashii et al. 2023)

Least significant change (LSC) for CTX

Least significant change (LSC) for CTXApproximately a 40% reduction from baseline (LSC cited by Bone Health & Osteoporosis Foundation guidance)

Purpose of LSC

Provider Actions, Documentation, and Denial Risk

Prior Authorization

Prior Approval

Prior approval is not applicable for measurement of bone turnover markers (BTMs). However, verify member benefits and any contract limitations prior to ordering; benefit determinations depend on the member's specific plan and contract language.

Verify member benefits and coverage before ordering — benefits may vary by contract.
Prior approval: Not applicable (no prior approval required).

Prior Authorization

Prior Authorization Guidance

Prior authorization guidance: although explicit payer PA codes are not listed in this policy, providers should follow the payer's prior authorization process when required by the member's benefit plan. If uncertain, contact provider services to determine whether prior authorization is needed for laboratory services related to BTMs.

No specific PA codes stated in this policy.
If the member's contract requires prior authorization for laboratory services, submit supporting clinical documentation per the payer's PA requirements.

Background and Rationale

Bone turnover markers (BTMs) are biochemical markers of bone formation or resorption measured in serum or urine (examples include osteocalcin, bone-specific alkaline phosphatase, PINP, CTX, and telopeptides). They have been proposed as adjuncts to BMD for assessing osteoporosis risk, for monitoring biochemical response to therapy (which can occur within months), and for assessing disease activity in conditions with high bone turnover. However, while BTMs reflect metabolic activity and correlate with some clinical measures in observational studies, their role in improving patient management or outcomes remains unproven.

Definitions and Test Descriptions

Bone turnover markers (BTMs) — examples and specimen types

Examples of BTMsOsteocalcin, bone-specific alkaline phosphatase (formation markers); PINP (formation); CTX, N-telopeptides, pyridinoline, deoxypyridinoline (resorption)

Specimen typesSerum and/or urine measurements depending on the marker and assay (commercial HPLC or immunoassay methods)

Common assay methodsHigh-performance liquid chromatography (HPLC) or immunoassay for serum/urine BTMs

Clinical utility (as referenced)

Policy definition of clinical utilityTest use that provides information leading to treatment decisions that improve net health outcomes (i.e., changes in management that improve benefits vs harms)

Evidence requirementStudies must show tests are accurate, reliable, and that use of results improves patient outcomes to establish clinical utility

Policy Summary

PayerBlue Cross Blue Shield - South Dakota

PolicyBone Turnover Markers for Diagnosis and Management of Osteoporosis and Other Conditions

Policy CodePolicy N/A

Change TypePolicy renewed (annual review)

Effective DateN/A

Next Review DateN/A

Key ActionWhen ordering bone turnover markers to assess response to osteoporosis therapy, document that results will inform a management decision (start/continue/modify/discontinue therapy).

SourceLink

On This Page

Used to interpret biochemical response to antiresorptive therapy (serum CTX) and assess adherence/response

Clinical contextGuidelines reference LSC when assessing change after 3–6 months of therapy initiation

Meaningful change timeframe

Typical timeframe for meaningful changeChange in bone turnover markers observed approximately 3–6 months after starting treatment

Relation to BMD changesBTM changes precede measurable BMD changes; BMD impact may be observed over 2–5 years

Guideline noteProfessional societies recommend assessing markers at ~3 months and up to 6 months to predict treatment effect or adherence

Billing Rule

Reporting Requirement for Listed CPT Codes

Report tests using the appropriate CPT codes and document the place of service. Claims for collagen crosslinks (CPT 82523) or osteocalcin (CPT 83937) must follow ICD-10 and CPT coding rules. Use the Codes table and the member's contract to determine correct billing.

Report CPT 82523 (Collagen cross links, any method) when applicable.
Report CPT 83937 (Osteocalcin) when applicable.
Document place of service (eg, outpatient) and use appropriate ICD-10 diagnosis codes.

Denial Risk

Investigational Indications — Potential for Denial

Measurement of BTMs for fracture risk assessment, to determine response or duration of osteoporosis therapy, or for management of conditions with high bone turnover (eg, Paget disease, primary hyperparathyroidism, renal osteodystrophy, oncologic indications, rheumatologic conditions, diabetes, vitamin D deficiency) is considered investigational. Coverage could be denied when testing is requested for these indications because the evidence is insufficient to demonstrate an effect on health outcomes.

Fracture risk assessment using BTMs — investigational.
Monitoring therapy response or duration using BTMs — investigational.
Management of high bone turnover conditions using BTMs — investigational; includes but is not limited to: Diabetes; Oncologic indications (including monitoring metastatic disease); Paget disease; Primary hyperparathyroidism; Renal osteodystrophy; Rheumatologic conditions; Vitamin D deficiency.

Denial Risk

Lack of Demonstrated Clinical Utility

Evidence is insufficient to demonstrate clinical utility of BTMs for changing patient management or improving health outcomes. No randomized controlled trials were identified that show measurement of BTMs leads to improved outcomes, and indirect evidence is limited by insufficient clinical validity.

No RCTs demonstrating that BTMs-guided management improves health outcomes.
Systematic reviews and RCTs have not shown improved adherence or management changes that affect outcomes.
If test results are unlikely to affect management, coverage may be denied.

Documentation Required

Verify Member Benefits and Use Codes Table

Verify member benefits and use the Codes table to select appropriate CPT/HCPCS and diagnosis codes for claims. Benefit determinations depend on contract language and applicable exclusions or limitations.

Check member's contract for exclusions/limitations before ordering.
Refer to the Codes section for CPT codes (eg, 82523, 83937) and place of service guidance.

Documentation Required

Study-Level Documentation Standards

Study-level documentation standards: when submitting clinical information to support medical necessity or prior authorization (if required by the member's benefit), include study-level details consistent with the policy's study selection criteria — describe patient/sample characteristics, selection criteria, the marketed version of the test, and the reference standard used.

Include patient/sample clinical characteristics and selection criteria.
Report the marketed version of the technology and any algorithms used.
Document the reference standard and study accuracy if providing supporting literature.

Note

Recommended Marker Selection and Interpretation Notes

Recommended marker selection and interpretation notes: when BTMs are used adjunctively to DXA (DXA remains the standard), consider markers recommended by specialty societies — serum CTX for antiresorptive therapy, PINP for anabolic therapy, and total or specific alkaline phosphatase for Paget disease. Interpret changes after 3–6 months; some experts suggest a meaningful change is ~40% (least significant change for CTX ~40%).

Use BTMs adjunctively to DXA; DXA remains the primary monitoring tool.
Preferred markers: serum CTX for antiresorptives; PINP for anabolic agents; total ALP or specific formation/resorption markers for Paget disease.
Expect treatment-related marker changes within 3–6 months; meaningful change often cited as ~40%.

Billing Rule

Required Coding and Service Documentation

Required coding and service documentation: code laboratory services accurately (eg, CPT 82523, 83937) and document diagnosis codes that justify testing. Place of service and pathology/laboratory service type should be recorded. Misaligned coding or lack of supporting clinical documentation may result in claim denial.

Use CPT 82523 for collagen crosslinks and CPT 83937 for osteocalcin where applicable.
Document the pathology/laboratory service and place of service (eg, Outpatient).
Ensure ICD-10 diagnosis codes support medical necessity; claims not aligning with ICD/CPT rules risk denial.

Step Therapy

Step Therapy and Monitoring

Step therapy and monitoring: there are no specific payer step therapy requirements for BTMs in this policy. Societal guidance supports monitoring with DXA at recommended intervals; societies note BTMs may be used to monitor therapy response or adherence but do not replace DXA. If a member's plan includes step edits or monitoring requirements, follow those contract-specific rules.

No step therapy requirements specified in this policy.
Follow society recommendations for monitoring (eg, DXA every 1–3 years; BTMs may be adjunctive).
If plan-level step therapy edits exist, comply with the member's contract and prior authorization processes.

Coverage implicationCoverage contingent on sufficient evidence that specific BTM results change management and improve net health outcomes

PINP, CTX — commonly studied serum BTMs

PINPProcollagen type 1 N-terminal propeptide — serum formation marker commonly studied for predicting treatment response and BMD increases

CTXC-terminal telopeptide of type I collagen — serum resorption marker commonly studied for monitoring antiresorptive therapy and adherence

Evidence examplesMeta-analyses report associations of PINP and CTX with fracture risk; observational studies link PINP to BMD response and CTX to clinical outcomes in select cohorts

Sources of BTM variability

Preanalytic factorsSample handling, assay method, and postprandial status affect BTM levels

Physiologic and patient factorsDiurnal variation, menopausal status, recent exercise or fracture, alcohol use, medications, and comorbid health conditions can alter marker levels

Implication for interpretationSources of variability necessitate standardized collection and clinical context when interpreting results

Bone turnover markers (BTMs) — short definition

Short definitionBiochemical tests measuring markers of bone formation or resorption used to assess bone metabolic activity and potentially guide management in high-turnover conditions

Intended usesProposed as adjuncts to BMD for fracture risk assessment, monitoring therapy response, and evaluating diseases with high bone turnover

Specimen typesMarkers measured in serum and/or urine depending on the analyte and assay

CTX — definition and monitoring role

Definition of CTXC-telopeptide of type I collagen — a serum marker of bone resorption used to monitor response to antiresorptive therapy and assess adherence

Guideline roleRecommended by some societies (eg, Endocrine Society) as an alternative monitoring tool to DXA to detect poor response or nonadherence

Interpretation noteMeaningful decreases (eg, ~40% LSC) may be expected within 3–6 months after treatment initiation

PINP — definition and monitoring role

Definition of PINPProcollagen type 1 N-terminal propeptide — a serum marker of bone formation used to monitor anabolic therapy and predict BMD response

Clinical applicationUsed to assess magnitude of BMD increase with therapies and as an alternative marker for monitoring when evaluating anabolic agents

Example thresholdPINP 53.7 mcg/L identified as optimal cutoff in a prospective romosozumab study (sensitivity 54.3%, specificity 92.3%)

Total alkaline phosphatase (ALP) — role in Paget disease monitoring

Total alkaline phosphatase (ALP)Serum total ALP used to assess response or disease activity in Paget disease; a more specific formation or resorption marker may be used when warranted

Guideline recommendationEndocrine Society recommends measuring total ALP or a specific marker to assess treatment response in Paget disease, often at 6–12 weeks

Clinical roleTotal ALP serves as the primary biochemical monitor of disease activity in Paget disease when markedly elevated

collagen crosslinks — code reference

Collagen crosslinks CPT codeCollagen crosslinks — CPT 82523

Use noteCPT 82523 corresponds to assays reporting collagen crosslinks by any method; claims must be reported with appropriate coding per policy

osteocalcin — code reference

Osteocalcin CPT codeOsteocalcin (bone G1A protein) — CPT 83937

Use noteCPT 83937 corresponds to osteocalcin assays; report with appropriate CPT/ICD coding consistent with payer rules