CAM 20415

Bone Turnover Markers for Diagnosis and Management of Osteoporosis and Diseases Associated with High Bone Turnover

Category:Laboratory   Last Reviewed:October 2018
Department(s):Medical Affairs   Next Review:October 2019
Original Date:July 1999    

Description:
Bone turnover markers are biochemical markers of either bone formation or bone resorption. Commercially available tests are available to assess some of these markers in urine and/or serum by high performance liquid chromatography or immunoassay. Assessment of bone turnover markers is proposed to supplement bone mineral density measurement in the diagnosis of osteoporosis and to aid in treatment decisions. Bone turnover markers could also potentially be used to evaluate treatment effectiveness before changes in bone mineral density can be observed.

For individuals with osteoporosis or risk factors for age-related osteoporosis who are tested with measurement of bone turnover markers, the evidence includes observational studies on the association between markers and osteoporosis and fracture risk and systematic reviews of those studies. Relevant outcomes are test accuracy, test validity, and morbid events. Studies have suggested that bone turnover marker levels may be independently associated with osteoporosis and fracture risk in some groups, but there is insufficient evidence reporting an association with any specific marker. Questions remain whether bone turnover markers are sufficiently sensitive to reliably determine individual treatment responses. In addition, controlled studies do not provide sufficient evidence that bone turnover marker measurement improves adherence to treatment, impacts management decisions, or improves health outcomes (e.g., reducing fracture rates). The evidence is insufficient to determine the effects of the technology on health outcomes. 

For individuals with conditions associated with high rates of bone turnover other than age-related osteoporosis (e.g., primary hyperparathyroidism, Paget disease, renal osteodystrophy) who are tested with measurement of bone turnover markers, the evidence includes observational studies on the association between markers and disease activity and systematic reviews of those studies. Relevant outcomes are test accuracy, test validity, and morbid events. The largest amount of evidence has been published on Paget disease; a systematic review found correlations between several bone turnover markers and disease activity prior to and/or after bisphosphonate treatment. There is a lack of evidence on how measurement of bone turnover markers can change patient management or improve health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background 
After cessation of growth, bone is in a constant state of remodeling (or turnover), with initial absorption of bone by osteoclasts followed by deposition of new bone matrix by osteoblasts. This constant bone turnover is critical to the overall health of the bone, by repairing microfractures and remodeling the bony architecture in response to stress. Normally, the action of osteoclasts and osteoblasts is balanced, but bone loss occurs if the 2 processes become uncoupled. Bone turnover markers can be categorized as bone formation markers or bone resorption markers, and can be identified in serum and/or urine. Table 1 summarizes the various bone turnover markers. 

Table 1. Bone Turnover Markers

Formation Markers 

Resorption Markers 
Serum osteocalcin    Serum and urinary hydroxyproline
Serum total alkaline phosphatase    Urinary total pyridinoline   
Serum bone-specific alkaline phosphatase Urinary total deoxypyridinoline
Serum procollagen I carboxyterminal propeptide   Urinary-free pyridinoline (also known as Pyrilinks)  
Serum procollagen type 1 N-terminal propeptide Urinary-free deoxypyridinoline (also known as Pyrilinks-D)  
Bone sialoprotein   Serum and urinary collagen type I cross-linked N-telopeptide (also referred to as Osteomark)  
  Serum and urinary collagen type I cross-linked C-telopeptide (also referred to as CrossLaps)  
  Serum carboxyterminal telopeptide of type I collagen  
  Tartrate-resistant acid phosphatase   

There is interest in the use of bone turnover markers to evaluate age-related osteoporosis, a condition characterized by slow, prolonged bone loss, resulting in an increased risk of fractures at the hip, spine, or wrist. Currently, fracture risk is primarily based on measurements of bone mineral density (BMD) in conjunction with other genetic and environmental factors, such as family history of osteoporosis, history of smoking, and weight. It is thought that the level of bone turnover markers may also predict fracture risk, possibly through a different mechanism than that associated with BMD. However, it must be emphasized that the presence of bone turnover markers in the serum or urine is not necessarily related to bone loss. For example, even if bone turnover is high, if resorption is balanced with formation, there will be no net bone loss. Bone loss will only occur if resorption exceeds formation. Therefore, bone turnover markers have been primarily studied as an adjunct, not an alternative, to measurements of BMD to estimate fracture risk and document the need for preventive or therapeutic strategies for osteoporosis.

In addition, bone turnover markers might provide a more immediate assessment of treatment response and predict change in BMD in response to treatment. Treatment-related changes in BMD occur very slowly. This fact, coupled with the precision of BMD technologies, has suggested that clinically significant changes in BMD could not be reliably detected until at least 2 years. In contrast, changes in bone turnover markers could be anticipated after 3 months of therapy.

Bone turnover markers have also been researched as markers of diseases associated with markedly high levels of bone turnover, such as Paget disease, primary hyperparathyroidism, and renal osteodystrophy.

Regulatory Status
Several tests for bone turnover markers have been cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k). Examples are listed in Table 2.   

Table 2. Approved Tests for Bone Turnover Markers

Test Manufacturer Year Indication
Pyrilinks® Metra Biosystems 1995 Collagen type 1 cross-link, pyridinium
Osteomark® Ostex International 1996 Cross-linked N-telopeptides of type 1 collagen
Serum Crosslaps® ELISA Immunodiagnostic Systems 1999 Hydroxyproline
Ostase® Beckman Coulter 2000 Bone-specific alkaline phosphatase
N-MID Osteocalcin One-Step ELISA Osteometer Bio Tech 2001 Osteocalcin

ELISA: enzyme-linked immunosorbent assay.

Related Policies
60101 Bone Mineral Density Studies
60144 Vertebral Fracture Assessment With Densitometry

Policy:
Measurement of bone turnover markers is considered INVESTIGATIONAL in the diagnosis and management of osteoporosis.

Measurement of bone turnover markers is considered INVESTIGATIONAL in the management of patients with conditions associated with high rates of bone turnover, including, but not limited to, Paget's disease, primary hyperparathyroidism and renal osteodystrophy.

Policy Guidelines
CPT code 82523 describes collagen cross-links, any method. CPT code 83937 describes osteocalcin testing. There is no specific CPT code for bone-specific alkaline phosphatase (ALK), but several laboratories’ websites identify CPT 84080 (phosphatase, alkaline; isoenzymes) as being used for the Ostase test.

Benefit Application:
BlueCard®/National Account Issues
State or federal mandates (e.g., FEP) may dictate that laboratory tests approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational, and, thus, these devices may be assessed only on the basis of their medical necessity.

Rationale
This evidence review was originally created in July 1999 and has been updated regularly with literature reviews of the MEDLINE database. Most recently, the literature was searched through November 7, 2016.

For the markers to be considered clinically useful, studies need to demonstrate that tests for bone turnover markers are accurate and reliable, and that their use can improve health outcomes. For example, to evaluate their utility for diagnosing osteoporosis as an adjunct to bone mineral density (BMD) measurements using dual-energy X-ray absorptiometry, studies would also need to show that bone turnover markers independently predict fracture risk beyond BMD and that the additional information provided by information on bone turnover has the potential to influence treatment decisions and clinical outcomes. Similarly, to be considered useful for monitoring osteoporosis treatment beyond follow-up BMD measurements, bone turnover test results would have to impact the decision to continue or change treatment in a way that improves patient outcomes. Following is a summary of key literature.

ANALYTIC VALIDITY
The analytic methods used to measure bone turnover markers vary and are not discussed in depth in this review. For a number of the markers, commercially available immunoassay kits have been developed, which have improved standardization of measurement.

DIAGNOSIS AND MANAGEMENT OF OSTEOPOROSIS
Clinical Validity of Bone Turnover Markers and Future Fracture Risk
Few studies have directly addressed whether any bone turnover markers beyond BMD measurements are independent predictors of fracture risk. One study conducted in men and another conducted in women are described next.

A 2013 analysis of the Japanese Population-based Osteoporosis (JPOS) study data included postmenopausal women and adjusted for BMD.1 The study involved baseline surveys, bone turnover marker assessment and BMD measurements, and 3 follow-ups over 10 years. At baseline, 851 women who participated were ages 50 years or older and eligible for vertebral fracture assessment. Of these, 730 women had BMD measurements taken at the initial examination and at 1 or more follow-ups. Women with early menopause (i.e., <40 years old), with a history of illness or medication known to affect bone metabolism, and with incomplete data were excluded. After exclusions, 522 women were included in the analysis.

Over a median follow-up period of 10 years, 81 (15.5%) of 522 women were found on imaging to have an incident vertebral fracture. Seventy-eight of the 81 women with radiographically detected vertebral fractures were more than 5 years from menopause at baseline. Risk of incident vertebral fractures adjusted for BMD T-scores was significantly associated with several bone turnover markers, specifically alkaline phosphatase (ALP), urinary total deoxypyridinoline (tDPD), and urinary free deoxypyridinoline (fDPD). For example, in a multivariate model adjusting for a variety of covariates including femoral neck BMD, the risk of developing a fracture per standard deviation of change in ALP was increased by 33% (relative risk, 1.33; 95% confidence interval [CI], 1.06 to 1.66). Risk of incident vertebral fracture was not significantly associated with other bone turnover markers including osteocalcin (OC) and cross-linked C-telopeptide (CTX). It is not clear how generalizable findings from this study are, given the association between subsequent fracture risk and certain bone turnover markers, and the lack of association between fracture risk and other bone turnover markers. Study analysis also excluded a large number of women due to incomplete data. 

In men, a subanalysis of prospectively collected data from the Osteoporotic Fractures in Men (MrOS) study also included adjustment of BMD.2 Baseline levels of bone turnover markers were compared in 384 men, ages 65 years or older, with nonspine fractures over an average follow-up of 5 years, to 885 men without nonspine fracture. A second analysis compared 72 hip fracture cases and 993 controls without hip fracture. After adjusting for age and recruitment site, the association between nonspine fracture and quartile of the bone turnover marker procollagen type 1 N-terminal propeptide (PINP) was statistically significant (for each analysis, p<0.05 was used). The associations between nonspine fracture and quartiles of the 2 other bone turnover markers, beta C-terminal cross-linked telopeptide of type 1 collagen (b-CTX) and tartrate-resistant acid phosphatase 5b (TRACP5b) were not statistically significant. Moreover, in the analysis adjusting only for age and recruitment site, when the highest quartile of bone turnover markers was compared with the lower 3 quartiles, the risk of nonspine and hip fractures was significantly increased for PINP and b-CTX, but not TRACP5b. After additional adjustment for baseline BMD, or baseline BMD and other potential confounders, there were no statistically significant relations between any bone turnover marker and fracture risk. Authors concluded that their results did not support the routine use of bone turnover markers to assess fracture risk in older men when measuring hip BMD was an option. 

Systematic reviews have examined the association between bone turnover markers and fracture risk, but have not included analyses of the additional predictive value beyond BMD. For example, a 2014 meta-analysis by Johansson et al. focused on PINP and CTX markers and examined their ability to predict future fracture risk.3 Reviewers included 10 prospective cohort studies in which bone turnover markers were measured at baseline and incident fractures were recorded. Pooled analyses were performed on a subset of these studies. Meta-analysis of 3 studies found a statistically significant association between baseline PINP and subsequent fracture risk (hazard ratio [HR], 1.23; 95% CI, 1.09 to 1.39). Similarly, a meta-analysis of 6 studies found an association between CTX and fracture risk (HR=1.18; 95% 1.09 to 1.29). None of the individual studies adjusted for BMD and, consequently, the pooled analyses do not reflect the ability of bone turnover markers to predict fracture risk beyond BMD.

A 2012 systematic review by Biver et al. did not find a statistically significant association between OC (another bone turnover marker) and fracture risk.4 When findings from 3 studies were pooled, the mean difference in OC levels in patients with and without vertebral fractures was 1.61 ng/mL (95% CI, -0.59 to 3.81 ng/mL). Both systematic reviews noted a high degree of heterogeneity among the published studies identified.

Section Summary: Clinical Validity of Bone Turnover Markers and Future Fracture Risk
Some studies have found statistically significant associations between bone turnover markers and fracture risk, but there is insufficient literature on any specific marker. For example, an analysis of MrOS data found a significant association between PINP and risk of nonspine fracture in men, and the JPOS study from Japan found a significant association between ALP, tDPD, and fDPD and risk of incident vertebral fracture in women. Overall, the evidence does not suggest that any bone turnover marker is an independent predictor of fracture risk, beyond BMD.

Clinical Validity of Bone Turnover Markers and Response to Osteoporosis Treatment
Studies have examined the ability of bone turnover markers to evaluate response to osteoporosis treatment. For example, a subanalysis of the randomized Fracture Intervention Trial (FIT; N=6184) by Bauer et al. (2006) found that pretreatment levels of the bone turnover marker PINP significantly predicted the antifracture efficacy of alendronate.5 Over a mean follow-up of 3.2 years, there were 492 nonspine and 294 vertebral fractures. Compared with those in the placebo group, the efficacy of alendronate for reducing nonspine fractures was significantly greater in women who were in the highest tercile of PINP (>56.8 ng/mL) than in those in the lowest tercile (<41.6 ng/mL). Baseline bone turnover rates were not associated with alendronate efficacy in reducing vertebral fractures. Authors indicated that this result needed confirmation in additional studies, and, even if verified, the impact on treatment recommendations was unclear. A 2008 randomized trial of an osteoporosis treatment (N=43) found that urinary cross-linked N-terminal telopeptides provided a more sensitive measure of treatment response than serum levels.6 Another small randomized trial from Japan measured OC levels in response to osteoporosis treatment in 109 postmenopausal women.7 Authors found that undercarboxylated OC levels in serum were significantly lower at 1 month in the group receiving active treatment for osteoporosis compared with the control intervention; the implication for fracture prevention was not studied.

A 2011 systematic review by Funck-Brentano et al. assessed whether early changes in serum biochemical bone turnover markers predict the efficacy of osteoporosis therapy.8 Reviewers included 24 studies that presented correlations between bone turnover markers and the outcomes of fracture risk reduction or change in BMD. Five studies (including the Bauer study, previously described) reported on fracture risk, and 20 studies reported on BMD changes. Reviewers discussed study findings qualitatively but did not pool study results. The evidence did not support a correlation between short-term changes in bone turnover markers and fracture risk reduction. In addition, few studies were available on this topic, leading to the conclusion that bone turnover markers "have shown limited value" as a technique to monitor osteoporosis therapy. An additional study on this topic was published by Baxter et al. in 2013.9 This retrospective review evaluated 200 patients commencing treatment with bisphosphonates for osteoporosis or osteopenia requiring treatment. Investigators found a statistically significant inverse correlation between change in urine N-terminal telopeptide (NTX) at 4 months and change in spine BMD at 18 months (r=0.33, p<0.001). There was no significant association between change in urine NTX and hip BMD.

Section Summary: Clinical Validity of Bone Turnover Markers and Response to Osteoporosis Treatment
The available evidence on the association between any specific bone turnover marker and response to osteoporosis treatment is limited in quantity and quality. While some individual studies have reported positive correlations for markers (e.g., PINP in the FIT), a body of evidence in support of any specific marker is lacking. As a result, the evidence does not permit conclusions about whether bone turnover markers are an independent predictor of treatment response.

Clinical Utility of Diagnosis and Management of Osteoporosis
To provide clinical utility, bone turnover markers would have to provide information beyond that offered by BMD measurements, that has an impact on treatment decisions and/or leads to improved health outcomes. Bone turnover markers can be measured more frequently than BMD and thus could provide information with clinical utility. For example, the 2013 guidelines from the National Osteoporosis Foundation stated that biochemical markers of bone turnover can be used to predict the extent of fracture risk reduction when measured 3 to 6 months after starting FDA-approved osteoporosis treatments.10

Several randomized controlled trials (RCTs) have addressed whether measurement of bone turnover markers can improve adherence to oral bisphosphonate treatment. A 2014 systematic review identified 5 RCTs and did not find significant differences in compliance rates between groups that did and did not receive feedback on bone turnover marker test results.11 Study data were not pooled. Reviewers noted a high baseline compliance rate that limited the studies’ ability to detect an impact of feedback. As an example, a 2012 industry-sponsored study by Roux et al. from France randomized physicians to manage patients on oral monthly ibandronate with a collagen cross-links test or usual care.12 In the collagen cross-links group, bone marker assessment was done at baseline and week 5 for the week 6 visit. A standardized message was delivered to patients regarding change in CTX since baseline. If the decrease in CTX was more than 30% of the baseline value, they were told that the treatment effect was optimal. If not, they were told that the treatment effect was suboptimal and given additional advice. Patients told they had a suboptimal response were retested with CTX at week 13 for the week 14 visit. The primary outcome was the proportion of patients who were adherent at 1 year. After 1 year, rates of adherence to ibandronate were 74.8% in the collagen cross-links group and 75.1% in the usual care group; the difference between groups was not statistically significant (p=0.93). There was also no statistically significant difference in the proportion of patients having taken at least 10 of 12 pills (82.4% in the collagen cross-links group vs 80.0% in the usual care group). In this study, monitoring bone markers and providing this information to patients did not improve adherence to oral osteoporosis medication.

Section Summary: Clinical Utility of Diagnosis and Management of Osteoporosis
There is a limited amount of evidence on the impact of bone turnover markers on management of osteoporosis. Individual RCTs and a meta-analysis of these RCTs have not found that feedback on bone turnover marker results improves adherence rates. No studies were identified that evaluated whether the use of bone turnover markers leads to management changes that are expected to improve outcomes.

MANAGEMENT OF OTHER CONDITIONS ASSOCIATED WITH HIGH RATES OF BONE TURNOVER
There is little published literature on use of bone turnover markers in the management of conditions associated with high rates of bone turnover (e.g., primary hyperparathyroidism, Paget disease), and many available studies were published 10 or more years ago.

Hyperparathyroidism
One 2012 study by Rianon et al. reported on 198 patients with primary hyperparathyroidism who underwent parathyroidectomy.13 They found a statistically significant association (p<0.05) between preoperative serum OC levels and persistent postoperative elevation of parathyroid hormone 6 months after the surgery.

Paget Disease
A 2015 systematic review and meta-analysis by Al Nofal et al. reviewed the literature on bone turnover markers in Paget disease.14 Reviewers focused on the correlation between bone markers and disease activity before and after treatment with bisphosphonates. All study design types were included in the review and bone scintigraphy was used as the reference standard. Reviewers identified 18 studies. Seven assessed bone markers in patients with Paget disease before treatment, 6 considered both the pre- and post-treatment associations, and 5 included only the post-treatment period. Only 1 study was an RCT; the rest were prospective cohort studies. There was a moderate-to-strong correlation between several bone turnover markers (bone ALP, total ALP, PINP, NTX) and pretreatment disease activity. In a pooled analysis of available data, there was a statistically significant correlation between levels of bone turnover marker and disease activity after treatment with bisphosphonates (p=0.019). Reviewers did not address the potential impact on bone turnover measurement on patient management or health outcomes.

SUMMARY OF EVIDENCE
For individuals with osteoporosis or risk factors for age-related osteoporosis who are tested with measurement of bone turnover markers, the evidence includes observational studies on the association between markers and osteoporosis and fracture risk and systematic reviews of those studies. Relevant outcomes are test accuracy, test validity, and morbid events. Studies have suggested that bone turnover marker levels may be independently associated with osteoporosis and fracture risk in some groups, but there is insufficient evidence reporting an association with any specific marker. Questions remain whether bone turnover markers are sufficiently sensitive to reliably determine individual treatment responses. In addition, controlled studies do not provide sufficient evidence that bone turnover marker measurement improves adherence to treatment, impacts management decisions, or improves health outcomes (e.g., reducing fracture rates). The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with conditions associated with high rates of bone turnover other than age-related osteoporosis (e.g., primary hyperparathyroidism, Paget disease, renal osteodystrophy) who are tested with measurement of bone turnover markers, the evidence includes observational studies on the association between markers and disease activity and systematic reviews of those studies. Relevant outcomes are test accuracy, test validity, and morbid events. The largest amount of evidence has been published on Paget disease; a systematic review found correlations between several bone turnover markers and disease activity prior to and/or after bisphosphonate treatment. There is a lack of evidence on how measurement of bone turnover markers can change patient management or improve health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes 

National Osteoporosis Foundation
In 2014, the National Osteoporosis Foundation updated its guideline on prevention and treatment of osteoporosis.15 Regarding biochemical markers of bone turnover, the guidelines stated:

"Biochemical markers of bone turnover may: 

  • Predict risk of fracture independently of bone density in untreated patients
  • Predict rapidity of bone loss in untreated patients
  • Predict extent of fracture risk reduction when repeated after 3-6 months of treatment with FDA [Food and Drug Administration]-approved therapies
  • Predict magnitude of BMD [bone mineral density] increases with FDA-approved therapies
  • Help determine adequacy of patient compliance and persistence with osteoporosis therapy
  • Help determine duration of ‘drug holiday’ and when and if medication should be restarted (Data are quite limited to support this use, but studies are underway.)" 

North American Menopause Society
In 2010, the North American Menopause Society updated its position statement on management of osteoporosis in postmenopausal women. The statement included the recommendation that "the routine use of biochemical markers of bone turnover in clinical practice is not generally recommended."16 

International Osteoporosis Foundation et al.
In 2011, the International Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) published a position statement by a joint IOF-IFCC working group.17 The group’s aim was to evaluate evidence on using bone turnover markers for fracture risk assessment and monitoring of treatment. The overall conclusion was: "In summary, the available studies relating bone turnover marker changes to fracture risk reduction with osteoporosis treatments are promising. Further studies are needed that take care of sample handling, ensure that bone turnover markers are measured in all available patients, and use the appropriate statistical methods, including an assessment of whether the final bone turnover marker level is a guide to fracture risk."

International Society for Clinical Densitometry and International Osteoporosis Foundation
In 2011, a joint statement by the International Society for Clinical Densitometry and IOF on the Fracture Risk Assessment Model (FRAX) fracture risk prediction algorithms stated18: "Evidence that bone turnover markers predict fracture risk independent of BMD is inconclusive. Therefore, bone turnover markers are not included as risk factors in FRAX."

U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
As of November 2016, the U.S. Preventive Services Task Force (USPSTF) recommendations on osteoporosis screening are in the process of being updated. The 2011 USPSF recommendations on osteoporosis screening address dual-energy x-ray absorptiometry testing but do not mention bone turnover markers.19  

ONGOING AND UNPUBLISHED CLINICAL TRIALS
A search of ClinicalTrials.gov in November 2016 did not identify any ongoing or unpublished trials that would likely influence this review.

References: 

  1. Tamaki J, Iki M, Kadowaki E, et al. Biochemical markers for bone turnover predict risk of vertebral fractures in postmenopausal women over 10 years: the Japanese Population-based Osteoporosis (JPOS) Cohort Study. Osteoporos Int. Mar 2013;24(3):887-897. PMID 22885773
  2. Bauer DC, Garnero P, Harrison SL, et al. Biochemical markers of bone turnover, hip bone loss, and fracture in older men: the MrOS study. J Bone Miner Res. Dec 2009;24(12):2032-2038. PMID 19453262
  3. Johansson H, Oden A, Kanis JA, et al. A meta-analysis of reference markers of bone turnover for prediction of fracture. Calcif Tissue Int. May 2014;94(5):560-567. PMID 24590144
  4. Biver E, Chopin F, Coiffier G, et al. Bone turnover markers for osteoporotic status assessment? A systematic review of their diagnosis value at baseline in osteoporosis. Joint Bone Spine. Jan 2012;79(1):20-25. PMID 21724445
  5. Bauer DC, Garnero P, Hochberg MC, et al. Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the fracture intervention trial. J Bone Miner Res. Feb 2006;21(2):292-299. PMID 16418785
  6. Abe Y, Ishikawa H, Fukao A. Higher efficacy of urinary bone resorption marker measurements in assessing response to treatment for osteoporosis in postmenopausal women. Tohoku J Exp Med. Jan 2008;214(1):51-59. PMID 18212487 
  7. Shiraki M, Itabashi A. Short-term menatetrenone therapy increases gamma-carboxylation of osteocalcin with a moderate increase of bone turnover in postmenopausal osteoporosis: a randomized prospective study. J Bone Miner Metab. 2009;27(3):333-340. PMID 19172219
  8. Funck-Brentano T, Biver E, Chopin F, et al. Clinical utility of serum bone turnover markers in postmenopausal osteoporosis therapy monitoring: a systematic review. Semin Arthritis Rheum. Oct 2011;41(2):157-169. PMID 21507464
  9. Baxter I, Rogers A, Eastell R, et al. Evaluation of urinary N-telopeptide of type I collagen measurements in the management of osteoporosis in clinical practice. Osteoporos Int. Mar 2013;24(3):941-947. PMID 22872068
  10. National Osteoporosis Foundation. 2014 Clinician's guide to prevention and treatment of osteoporosis. http://nof.org/files/nof/public/content/file/344/upload/159.pdf. Accessed July 9, 2015.
  11. Burch J, Rice S, Yang H, et al. Systematic review of the use of bone turnover markers for monitoring the response to osteoporosis treatment: the secondary prevention of fractures, and primary prevention of fractures in high-risk groups. Health Technol Assess. Feb 2014;18(11):1-180. PMID 24534414
  12. Roux C, Giraudeau B, Rouanet S, et al. Monitoring of bone turnover markers does not improve persistence with ibandronate treatment. Joint Bone Spine. Jul 2012;79(4):389-392. PMID 21703900
  13. Rianon N, Alex G, Callender G, et al. Preoperative serum osteocalcin may predict postoperative elevated parathyroid hormone in patients with primary hyperparathyroidism. World J Surg. Jun 2012;36(6):1320-1326. PMID 22278606
  14. Al Nofal AA, Altayar O, BenKhadra K, et al. Bone turnover markers in Paget's disease of the bone: a systematic review and meta-analysis. Osteoporos Int. Jul 2015;26(7):1875-1891. PMID 26037791
  15. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician's guide to prevention and treatment of osteoporosis. Osteoporos Int. Oct 2014;25(10):2359-2381. PMID 25182228
  16. North American Menopause Society. Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause. Jan-Feb 2010;17(1):25-54; quiz 55-26. PMID 20061894
  17. Vasikaran S, Cooper C, Eastell R, et al. International Osteoporosis Foundation and International Federation of Clinical Chemistry and Laboratory Medicine position on bone marker standards in osteoporosis. Clin Chem Lab Med. Aug 2011;49(8):1271-1274. PMID 21605012
  18. McCloskey EV, Vasikaran S, Cooper C. Official Positions for FRAX(R) clinical regarding biochemical markers from Joint Official Positions Development Conference of the International Society for Clinical Densitometry and International Osteoporosis Foundation on FRAX(R). J Clin Densitom. Jul-Sep 2011;14(3):220-222. PMID 21810528
  19. U.S. Preventive Services Task Force (USPSTF). Screening for Osteoporosis. 2011; http://www.uspreventiveservicestaskforce.org/uspstf10/osteoporosis/osteosum.htm. Accessed November 26, 2016.
  20. CMS National Coverage Determinations. 190.19 Collagen Crosslinks, Any Method. 2009; http://www.cms.hhs.gov/CoverageGenInfo/Downloads/manual200907.pdf. Accessed November 26, 2016.
  21. Rules and Regulations: Medicare National Coverage Decision for Collagen Crosslinks, Any Method Other Names/Abbreviations. Federal Register. 2001;66(226):58843-58844.

Coding Section

Codes Number Description
CPT 82523 Collagen cross-links, any method
  83937 Osteocalcin (bone g1a protein)
  84080 Phosphatase, alkaline; isoenzymes
ICD-9 Diagnosis   Investigational for all relevant diagnoses
  733 Osteoporosis
HCPCS    
ICD-10-CM (effective 10/01/15)   Investigational for all relevant diagnoses
  M81.0-M81.8 Osteoporosis without current pathological fracture code range (includes osteoporosis NOS)
  Z13.820 Encounter for screening for osteoporosis
  Z82.62 Family history of osteoporosis
ICD-10-PCS (effective 10/01/15)   Not applicable. No ICD procedure codes for laboratory tests.
Type of Service Pathology/Laboratory  
Place of Service Outpatient  

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

10/29/2018 

Annual review, no change to policy intent. 

11/06/2017 

Annual review, no change to policy intent. Updating background, description, regulatory status, rationale and references. 

04/25/2017 

Updated category to Laboratory. No other changes. 

07/05/2016 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

07/20/2015 

Annual review, no change to policy intent. Updated background, description, rationale and references. Added guidelines and coding. 

07/10/2014

Annual review. Added regulatory status and related policies. Updated rationale and references. No change to policy intent.


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