Coverage Policy Manual
Policy #: 1997186
Category: Laboratory
Initiated: January 1997
Last Review: February 2024
  Bone Markers (Collagen Crosslinks as Biological Markers of Bone Turnover)

Description:
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 (Kim, 2020). 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 osteoblasts and osteoclasts is balanced, but bone loss occurs if the 2 processes become uncoupled. Bone-turnover markers can be categorized as bone-formation markers that are measured in the serum or bone-resorption markers that are measured in the urine (Greenblatt, 2017). 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. Measurement of bone turnover markers may aid in the diagnosis (by determining fracture risk) and therapeutic monitoring (by determining response to treatment) of osteoporosis. Bone turnover markers may also be used for the management of other diseases associated with high bone turnover (e.g., primary hyperparathyroidism, Paget disease, renal osteodystrophy). Below is a summary of the various bone turnover markers (Shetty, 2016).
 
Markers of bone turnover developed in the past few years appear to have advantages over those used previously. Markers of bone formation include:
    • Serum osteocalcin (OC)*  
    • Serum total alkaline phosphatase (ALP)*  
    • Serum bone specific alkaline phosphatase (BSAP)*  
    • Serum procollagen I carboxyterminal propeptide (PICP)
    • Serum procollagen type 1 N-terminal propeptide (PINP)
    • Bone sialoprotein*   
 
Markers of bone resorption include:
    • Serum and urinary hydroxyproline (Hyp)  
    • Urinary total pyridinoline (Pyr)  
    • Urinary total deoxypyridinoline (dPyr)  
    • Urinary-free pyridinoline (f-Pyr, also known as Pyrilinks®)  
    • Urinary-free deoxypyridinoline (f-dPyr, also known as Pyrilinks-D®)  
    • Serum and urinary collagen type I cross-linked N-telopeptide (NTx, also referred to as Osteomark)
    • Serum and urinary collagen type I cross-linked C-telopeptide (CTx, also referred to as Cross Laps)
    • Serum carboxyterminal telopeptide of type I collagen (ITCP)
    • Tartrate-resistant acid phosphatase*
 
Regulatory Status
Several tests for bone turnover markers have been cleared for marketing by the U.S. Food and Drug Administration through the 510(k).
 
FDA-Cleared Tests for Bone Turnover Markers
    • Pyrilinks®, manufactured by Metra Biosystems, received clearance in 1995 for Collagen type 1 cross-link, pyridinium
    • Osteomark®, manufactured by Ostex International, received clearance in 1996 for Cross-linked N-telopeptides of type 1 collagen
    • Serum CrossLaps® ELISA, manufactured by Immunodiagnostic Systems, received clearance in 1999 for Hydroxyproline
    • Ostase®, manufactured by Beckman Coulter, received clearance in 2000 for Bone-specific alkaline phosphatase
    • N-MID Osteocalcin One-Step ELISA, manufactured by Osteometer BioTech, received clearance in 2001 for Osteocalcin
    • Elecsys® N-MID Osteocalcin, manufactured by Roche Diagnostics, received clearance in 2005 for Osteocalcin
    • IDS-iSYS Ostase® BAP, manufactured by Immunodiagnostic Systems, received clearance in 2020 for Bone-specific alkaline phosphatase
 
 
Coding
Biological markers of bone turnover performed to serve as indices of bone formation may be billed with CPT codes 83519, 83937, 84075 and/or 84080; bone resorption may be billed with 82523 and/or 82570. However, these codes may also be used to billed for these tests for other indications.

Policy/
Coverage:
Effective, October 2010
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Biological Markers of Bone Turnover meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when:
 
        • Performed to serve as indices of bone formation and resorption in patients with metabolic bone disease. These tests are useful in the selection of therapy and in monitoring the affects of anti-resorptive treatment of osteoporosis;
        • The patient's medical record documents the medical necessity for the use of the Biological Markers of Bone Turnover and the patient's response to the treatment. The records must clearly show the tests usefulness in the management of the patient's metabolic bone disease;
        • One bone formation and one bone resorption test are provided on the same date up to a maximum of three times per year.
 
Coverage is limited to three sets of tests per year.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Biological Markers of Bone Turnover does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in any of the following circumstances:
 
        • To diagnose osteoporosis;
        • For screening purposes;
        • More than three times per year;
        • More than one type of bone formation or one type of bone resorption test performed on the same date;
        • In any circumstance not noted above as meeting primary coverage criteria.
 
For members with contracts without primary coverage criteria, Biological Markers of Bone Turnover are considered investigational in any of the following circumstances:
 
        • To diagnose osteoporosis;
        • For screening purposes;
        • More than three times per year;
        • More than one type of bone formation or one type of bone resorption test performed on the same date;
        • In any circumstance not noted above as meeting primary coverage criteria.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Note: Screening tests are exclusions in most member benefit certificates of coverage except for coverage based on the Patient Protection and Affordable Care Act (PPACA) screening recommendations for non-grandfathered plans and those contracts with wellness benefits (which like PPACA, covers specific screening procedures). (Effective, August 2011)
 
Effective January 1997 - September 2010
Biological Markers of Bone Turnover meet primary coverage criteria for effectiveness and are covered when:
    • Performed to serve as indices of bone formation and resorption in patients with metabolic bone disease. These tests are useful in the selection of therapy and in monitoring the affects of anti-resorptive treatment of osteoporosis;
    • The patient's medical record documents the medical necessity for the use of the Biological Markers of Bone Turnover and the patient's response to the treatment. The records must clearly show the tests usefulness in the management of the patient's metabolic bone disease;
    • One bone formation and one bone resorption test are provided on the same date up to a maximum of three times per year. It is not medically necessary to measure all of the markers to monitor response to therapy.
 
Coverage is limited to three sets of tests per year.
 
Biological Markers of Bone Turnover:
    • To diagnose osteoporosis;
    • For screening purposes;
    • More than three times per year;
    • More than one type of bone formation or one type of bone resorption test performed on the same date;
    • In any circumstance not noted above;
are not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For contracts without primary coverage criteria, Biological Markers of Bone Turnover:
    • To diagnose osteoporosis;
    • For screening purposes;
    • More than three times per year;
    • More than one type of bone formation or one type of bone resorption test performed on the same date;
    • In any circumstance not noted above;
are considered either not medically necessary, screening or investigational.  Medically unnecessary, screening and investigational services are exclusions in the member certificate of coverage.

Rationale:
The following clinical applications of bone-turnover markers have been investigated.
 
Bone turnover markers in conjunction with measurements of bone mineral densitometry have been investigated as a technique to identify those patients at highest risk of osteoporosis-related fractures.  Bone turnover markers may reflect fracture risk through a different mechanism than that associated with BMD. Therefore, markers have been investigated as an adjunct to BMD to increase the prediction assessment for fracture risk compared to the use of BMD alone. For example, a prospective cohort study of 7,500 women over 75 years old reported that the overall relative risk of hip fracture among patients with osteoporosis is 2.7 but rises to as high as 4.8 if markers of bone turnover are elevated.
 
However, it is not clear how this information may be used in the clinical management of the patient. Presumably, all patients with osteoporosis, as identified by measurement of BMD, would be considered candidates for drug therapy, typically the use of hormone replacement therapy, bisphosphonates, or calcitonin. It is not clear how therapy should be adjusted according to the level of fracture risk or whether the use of bone-turnover markers can predict response to therapy. For example, studies have shown that bone-turnover markers are only weakly correlated to magnitude of treatment response, a finding that questions their role in treatment decisions. Specifically, bone-turnover markers were assessed as part of the postmenopausal estrogen/progestin intervention (PEPI) trial, which randomized women to receive placebo or hormone replacement therapy. The changes in these turnover markers correlated poorly with treatment-related changes in BMD. Bone-turnover markers were also measured in the fracture intervention trial, which randomized participants to receive either bisphosphonates or placebo. Changes in bone-turnover markers were measured in a subset of 390 patients. While the authors found that higher baseline levels of bone-turnover markers were associated with greater increases in spine BMD (but not hip BMD), the authors concluded that association between markers and BMD may not be sufficient to predict response to bisphosphonate therapy.
 
Bone markers can be used to provide a more immediate assessment of treatment response and can be used to 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, suggests that clinically significant changes in BMD cannot be reliably detected until at least 2 years. In contrast, changes in bone-turnover markers can be anticipated after 3 months of therapy. Therefore, bone-turnover markers may be assessed at diagnosis to provide a baseline, followed by repeat assay at 3 months to determine the response to therapy. Studies have reported an inconsistent relationship between the change in bone-turnover markers in response to therapy and the magnitude of subsequent change in BMD. While bone-turnover markers have been included in the recent large scale clinical trials addressing the use of hormone replacement therapy and bisphosphonates (i.e., alendronate), their role in the trials was as a validating intermediate outcome; that is, a reduction in bone-turnover markers was consistent with the anti-bone-resorptive effect of therapy. Levels of bone-turnover markers were not used to guide adjustment of dosage or prompt discontinuation of therapy. In addition, changes in bone- turnover markers among treated patients who nonetheless lost bone mass is not known, nor is the converse known (i.e., the likelihood of increases in BMD in subjects who exhibit no change in bone-turnover markers with treatment).
 
Both bisphosphonates and intranasal calcitonin represent new treatment options for osteoporosis. However, long-term experience with these agents is limited, and some physicians may feel uncomfortable in committing a patient to long-term therapy without prompt evidence that the intervention is working. Nonetheless, this specific role of bone-turnover markers has not been formally studied in controlled trials. The limitations discussed above, i.e., the poor correlation between bone-turnover markers and treatment effects are applicable here. In addition, there is marked diurnal variation in bone-turnover markers in individual patients, and results of markers measured in the urine must be correlated to the serum creatinine, all of which complicate the interpretation of serial studies.  Finally, validated cut-offs for response vs. non-response have not been established, although many authors define elevated levels as those that are greater than 1 SD above the premenopausal mean.
 
It has also been hypothesized that serial measurement of bone-turnover markers may be used to increase compliance with therapy by demonstrating a prompt treatment response. Osteoporosis is a chronic, silent disease, and thus much like treatment of hypertension or hypercholesterolemia, long-term patient compliance may be poor, particularly if a beneficial treatment effect cannot be measured by BMD until after several years of therapy.
 
Patients may be initially screened for osteoporosis using a peripheral measurement of BMD, i.e., at the heel or wrist.  For unknown reasons, serial BMD testing of peripheral sites does not reflect treatment response. Therefore, if a patient has been initially diagnosed with osteoporosis using a peripheral BMD measurement, some physicians may recommend an additional BMD of the more clinically relevant central sites, i.e., the hip and spine, to serve as a baseline for future serial measurements of BMD. This strategy thus requires 2 BMD measurements in patients with osteoporosis. In this setting, bone-turnover markers have been proposed as an alternative to an additional central measurement. For example, Miller and colleagues state that patients with a 50% reduction in baseline of bone-turnover markers after 3 months of therapy may not require a central measurement to monitor therapy.
 
This testing strategy has never been formally examined in controlled trials. In addition, the need for serial BMD testing to monitor treatment response is controversial and is not specifically recommended by the recent practice guidelines of the National Osteoporosis Foundation.
 
Bone-turnover markers have also been studied in diseases associated with high bone-turnover rates, such as glucocorticoid-induced osteoporosis, hyperparathyroidism, or renal osteodystrophy.  Similar to the discussion here regarding age-related osteoporosis, it is unclear how levels of collagen cross links as a marker of bone turnover might be used in the management of the patient. In 1996, the American College of Rheumatology issued practice guidelines regarding the management of glucocorticoid-induced osteoporosis.  Bone-turnover markers were not recommended as part of the workup or management of patients. In patients with renal disease, measurement of urinary levels of collagen cross links cannot be used. In patients with primary hyperparathyroidism, levels of collagen cross links have been used as a research tool to monitor bone turnover after parathyroidectomy, but again, it is unclear how these markers may be used in the management of the patient.
 
2002–2004 Update
A literature search of the MEDLINE database between the period of 1999 and July 2004 did not identify any published articles that would change the above conclusions; thus, the policy statement remains unchanged. While markers of bone turnover have emerged as a useful research tool, and there are several articles discussing the potential value of bone-turnover markers, no outcomes studies were identified in which patient management was based on the results of bone-turnover markers. For example, while it is agreed that the results of BMD testing are the single best predictor of fracture risk, advocates of bone-turnover markers point out that determinations of bone turnover may be capable of independently predicting fracture risk. However, it is unclear how that knowledge would change patient management, and whether such treatment decisions would ultimately result in a reduction in the fracture risk in individual patients. It is clear that changes in serum levels of bone turnover markers continue to be included as intermediate outcomes in trials examining drug therapy for osteoporosis.
 
While the original National Osteoporosis Foundation guidelines for the treatment of osteoporosis did not comment on the use of biochemical markers, a report subtitled, “A Report from the Ad Hoc Committee on Bone Turnover Markers of the National Osteoporosis Foundation” was subsequently published.  This report points out that there have been few studies that have been specifically designed to examine the use of markers in the care of individual patients with osteoporosis, ranging from elderly women to younger postmenopausal women. This review offered the following conclusions regarding the following potential applications of bone-turnover markers:
 
Evaluating Risk for Osteoporosis and Fracture
Although the combination of bone-turnover markers and BMD is appealing from a theoretical standpoint, currently few published data have appropriately analyzed such combinations. Until additional studies are published and verified, the routine use of combinations of marker and BMD for the prediction of fracture is not justified.
 
Biochemical Markers for the Prediction of Fractures in Individuals
Data are encouraging to suggest that elevated markers of bone resorption in older women are associated with an increased risk of hip and non-spine fractures. If additional studies confirm that resorption markers provide information about fracture risk, clinicians might consider measurement of markers in older women when BMD measurements are not available. Clinicians will need further guidance regarding treatment thresholds to judge whether the modest information about fracture risk provided by markers is clinically useful.
 
Ability of Baseline Markers to Predict BMD Changes
Among untreated patients, the published data do not support the ability of bone markers to predict the magnitude of changes in axial BMD from baseline.  None of the reported studies show a strong relationship between baseline marker and magnitude of change in BMD in response to alendronate or hormone replacement therapy.
 
Ability of Change in Marker to Predict Change in BMD in Response to Treatment
Published data are inconsistent regarding the ability of change in a bone marker to predict magnitude of change in BMD from baseline in postmenopausal women treated with either alendronate or hormone replacement therapy.  Interpretation of change in marker levels in individuals is complicated by large within-person variability.  The review by Looker et. al. concluded by stating, “markers have potential in the clinical management of the patient with osteoporosis, but, based on presently available information, recommendations for or against the use of current markers in this regard are not warranted.”
 
2007-2008 Update
A search of the MEDLINE database was performed for the period of August 2006 through March 2008. Biochemical markers of bone turnover continue to be used primarily to test the efficacy of new pharmaceutical agents. (Valimaki, 2007)  No new studies were identified to indicate that the results from markers of bone turnover alter clinical decision making. One small 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. (Abe, 2008)  In another report, 432 untreated elderly Japanese women were followed for 5 years; this observational study found that a urinary test of glycoxidative (nonenzymatic) collagen cross-links was a significant predictor (hazard ratio of 1.33) of incident vertebral fracture after adjustment for other traditional risk factors. (Shiraki, 2008)  Further study of the predictive ability of this advanced glycation end product is needed.
 
Updated guidelines from the National Osteoporosis Foundation (2008) state that osteoporosis (defined by BMD at the hip or spine of less than or equal to 2.5 standard deviations below the young normal mean reference population) “is an intermediate outcome for fractures and is a risk factor for fracture, just as hypertension is for stroke. The majority of fractures, however, occur in patients with low bone mass rather than osteoporosis.”  This indicates a need to better assess bone strength using non-invasive technologies. The guidelines also indicate that although biochemical markers of bone turnover may be predictive of greater mean BMD responses when evaluating large groups of patients in clinical trials, the “precision error” of the specific biochemical marker, along with daily and seasonal variability in bone turnover, must be taken into account when evaluating individuals. Thus, “because of the high degree of biological and analytical variability in measurement of biochemical markers, changes in individuals must be large in order to be clinically meaningful.”
 
Current literature indicates that alternative measures of bone strength have the potential to assess individual responses to treatment or identify individuals at high risk of future fracture, thereby potentially altering clinical management.  However, current methods for measuring collagen cross links are not sufficiently sensitive (the least significant change) to reliably determine individual treatment responses, and other types of assays appear to be at an early stage of development.
 
2010 Update
A literature search was conducted through September 2010.  There were no studies identified that would prompt a change in the coverage statement.  
 
In 2009, a study evaluating the association between bone turnover markers and fracture risk in men has been published (Bauer, 2009). This was a sub-analysis of prospectively-collected data from the Osteoporotic Fractures in Men (MrOS) study. Baseline levels of bone turnover markers were compared in 384 men age 65 or older who had non-spine fractures over an average follow-up of 5 years to 885 men without non-spine 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 non-spine fracture and quartile of the bone turnover marker procollagen type 1 N-terminal propeptide (PINP) was statistically significant (for a each analysis, p<0.05 was used). The associations between non-spine fracture and quartiles of the two 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, the associations between risk of hip fracture and quartiles of bone turnover markers were not statistically significant. However, in the analysis adjusting only for age and recruitment site, when the highest quartile of bone turnover markers was compared to the lower 3 quartiles, the risk of non-spine and hip fractures was significantly increased for PINP and b-CTX but not TRACTP5b. After additional adjustment for baseline BMD, or baseline BMD and other potential confounders, there were no statistically significant relationships between any bone turnover marker and fracture risk. The authors concluded that their results do not support the routine use of bone turnover markers to assess fracture risk in older men when there is the option of measuring hip BMD.
 
In 2010, the North American Menopause Society issued an updated position statement on management of osteoporosis in postmenopausal women. The statement included the recommendation, “the routine use of biochemical markers of bone turnover in clinical practice is not generally recommended.”
 
2012 Update
A literature search conducted through September 2012 did not identify any new information that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
 
A 2011 systematic review by Funck-Brentano and colleagues addressed the issue of whether early changes in serum biochemical bone turnover markers predict the efficacy of osteoporosis therapy (Funck-Brentano, 2011). Their review 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, described above) reported on fracture risk and 20 studies reported on BMD changes. The review authors 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.
 
Several randomized controlled trials (RCTs) have addressed the issue of whether measurement of bone turnover markers can improve adherence to oral bisphosphonate treatment. In 2012, Silverman and colleagues randomized 239 women with BMD at least 2 standard deviations (SD) below normal and a new prescription for alendronate to 1 of 4 treatment groups (Silverman, 2012). The first group received educational materials each month, the second received results of bone turnover markers at baseline and 3 and 12 months, the third group received both bone marker and educational information, and the fourth group, received usual care. Overall, 130 of 240 (54%) patients adhered to medication through the 12-month follow-up. According to survival analysis, there was no significant difference among groups in adherence rates. For example, the relative risk of non-adherence between group 2 (received results of bone turnover marker tests) and the control group was 0.95 (95% CI: 0.72 to 1.26, p>0.91). Exact rates of adherence by group were not reported.
 
There is little published literature on use of bone turnover markers in the management of conditions associated with high rates of bone turnover, such as Paget’s disease, primary hyperparathyroidism, and renal osteodystrophy. Moreover, very few studies on this topic have been published since 2000. One recent study, by Rainon and colleagues, reported on 198 patients with primary hyperparathyroidism who underwent parathyroidectomy (Rianon, 2012). The authors found a statistically significant association (p<0.05) between pre-operative serum osteocalcin levels and persistent postoperative elevation of parathyroid hormone 6 months after the surgery. In addition, several studies were identified that tested bone turnover levels in patients with Paget’s disease before and after treatment with bisphosphonates. (Woitge, 2000; Reid, 2004; Alvarez, 2001) For example, Alvarez and colleagues found that the mean values of bone markers decreased significantly after bisphosphonate treatment in 31 of 38 patients who completed a 3-month course of oral bisphosphonates. Bone markers measured in the Alvarez study included serum total alkaline phosphatase (ALP), serum bone-specific alkaline phosphatase (B-ALP), and PINP and urinary hydroxyproline (Hyp), CTx and NTx. No studies were identified that addressed whether bone turnover markers for these conditions associated with high bone turnover resulted in improved patient management decisions or health outcomes.
 
In 2011, the Joint Official Positions Development Conference of the International Society for Clinical Densitometry and the IOF on the FRAX® fracture risk prediction algorithms published the following statement (McCloskey, 2011):
“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.”
 
The coverage statement is unchanged.  
 
2014 Update
A literature search conducted through February 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In 2013, Tamaki and colleagues in Japan published an analysis of data from the Japanese Population-based Osteoporosis (JPOS) study that focused on the ability of bone turnover markers to predict vertebral fracture risk in postmenopausal women (Tamaki, 2013). The authors adjusted for BMD in their analyses. 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 aged 50 years or older and were 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., younger than 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 of 522 women (15.5%) 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 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 (SD) of change in ALP was increased by 33% (Risk ratio 1.33, 95% CI: 1.06-1.66). Risk of incident vertebral fracture was not significantly associated with other bone turnover markers including OC and CTx. It is not clear how generalizable findings from this study are; that is, the association between subsequent fracture risk and certain bone turnover markers, and the lack of association between fracture risk and other bone turnover markers. This study is also limited by the large number of women excluded from analysis due to incomplete data.
 
A 2011 systematic review by Funck-Brentano and colleagues addressed the issue of whether early changes in serum biochemical bone turnover markers predict the efficacy of osteoporosis therapy. Their review 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, described above) reported on fracture risk and 20 studies reported on BMD changes. The review authors 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 and colleagues in 2013 (Baxter, 2013). This was a retrospective review of data on 200 patients commencing treatment with bisphosphonates for osteoporosis or osteopenia requiring treatment. The investigators found statistically significant inverse correlation between change in urine NTx at 4 months and change in spine BMD at 18 months (Pearson’s correlation [r]: 0.33, p<0.0001). There was not a significant association between change in urine NTx and hip BMD.
 
Practice Guidelines and Position Statements
In 2013, the National Osteoporosis Foundation updated their guideline for prevention and treatment of osteoporosis (NOF, 2013). Regarding biochemical markers of bone turnover, the guideline states:
Biochemical markers of bone turnover may:
  • Predict risk of fracture independently of bone density
  • Predict extent of fracture risk reduction when repeated after 3-6 months of treatment with FDA-approved therapies.
  • Predict magnitude of BMD increases with FDA-approved therapies.
  • Predict rapidity of bone loss.
  • 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).
 
2015 Update
Paget Disease
A literature search conducted through July 2015 did not reveal any new information that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
A 2015 systematic review and meta-analysis by Al Nofal et al. reviewed the literature on bone turnover markers in Paget disease (Al Nofal, 2015).  The authors focused on the correlation between bone markers and disease activity before and after treatment with bisphosphonates. All study designs were included in the review and bone scintigraphy was used as the reference standard. The authors identified a total of 18 studies. Seven studies assessed bone markers in patients with Paget disease before treatment, 6 considered both the pre- and posttreatment associations and five included only the posttreatment period. Only 1 of the studies was an RCT and the rest were prospective cohort studies. There was a moderate to strong correlation between several bone turnover markers (bone ALP, total ALP, PINP and 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). The systematic review did not address the potential impact on bone turnover measurement on patient management or health outcomes.
 
2017 Update
A literature search conducted through August 2017 did not reveal any new information that would prompt a change in the coverage statement.  
 
2018 Update
A literature search was conducted through August 2018.  There was no new information identified that would prompt a change in the coverage statement.  
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Zhang et al studied the use of multiple bone turnover markers for diagnosis of osteoporosis in a prospective study of 9053 Chinese post-menopausal women (2464 with osteoporosis and 6589 without osteoporosis) (Zhang, 2018). The markers were bone-specific alkaline phosphatase, bone sialoprotein, CTX, osteoprotegerin, OC, and soluble receptor activator of nuclear factor kappa-B ligand. When compared to BMD measured by DXA, no individual marker had sufficient diagnostic accuracy. However, a model using all 6 markers was found to have a sensitivity of 0.99, a specificity of 0.99, and an agreement of 0.978 compared to BMD. Several advantages of using serum BTMs compared to DXA were discussed. The study was funded by the National Natural Science Foundation of China, and there is currently no commercially available panel that includes all 6 markers.
 
Studies have also reported that bone turnover markers might be used along with other factors to determine who is likely to develop osteoporosis, with the goal of beginning treatment before skeletal deterioration (Gutierrez-Buey, 2019; Shieh, 2019). For example, a study by Shieh et al found that baseline urinary N-telopeptide in combination with age, race/ethnicity, and body mass index was found to predict a significant bone loss in perimenopausal women (Shieh, 2019). No evidence was identified that has evaluated whether earlier treatment reduces fracture risk.
 
2019 guidelines from the Endocrine Society recommend that in postmenopausal women with a low BMD and at high-risk of fractures who are being treated for osteoporosis, monitoring should be conducted by dual-energy X-ray absorptiometry at the spine and hip every 1 to 3 years (Eastell, 2019). The Society considers measuring bone turnover markers (serum CTX for antiresorptive therapy or P1NP for bone anabolic therapy) as an alternative way of monitoring for poor response or nonadherence to therapy. The society notes that there is uncertainty over what constitutes an optimal response to treatment, but some experts suggest that a meaningful change is approximately 40% when compared from before to 3 to 6 months after starting treatment.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
The 2020 guidelines from the American Association of Clinical Endocrinologists and the American College of Endocrinology (AACE/ACE) gave a Grade B recommendation to consider using bone turnover markers for assessing patient compliance and therapy efficacy (Camacho, 2020). AACE/ACE reviewed evidence that markers respond quickly to therapeutic intervention, and changes in markers have been associated with bone response to therapy and fracture risk reduction.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A meta-analysis by Tian et al examined whether bone turnover markers, specifically procollagen type 1 N-terminal propeptide (PINP) and cross-linked C-telopeptide (CTX), are associated with fractures (Tian, 2019). A total of 11,572 patients from 9 prospective cohort studies were included in the analysis. The crude and adjusted gradient of risk (GR) for PINP were extracted from 2 and 5 studies, respectively, while the crude and adjusted GR for CTX were extracted from 4 and 6 studies, respectively. PINP was not associated with fracture without adjusting covariates (crude GR, 1.03; 95% confidence interval [CI], 0.91 to 1.17). After adjusting for potential confounders (including age, body mass index, mobility score, past fractures, and hip BMD), PINP demonstrated a significant positive association with fracture (adjusted GR, 1.28; 95% CI, 1.15 to 1.42). For CTX, both the crude GR (1.16; 95% CI, 1.04 to 1.20) and adjusted GR (1.20; 95% CI, 1.05 to 1.37) showed a significant positive association with fractures. A subgroup analysis (performed based on gender, age, and site of fracture) found significant associations in elderly (age >65 years), female, and hip fracture patients. A sensitivity analysis that excluded 1 study per iteration confirmed the stability of the findings. Limitations of this meta-analysis include the use of GR as the metric of predictive power to create a common approximation of risk. The included studies also had different settings for adjustment and various fracture endpoints.
 
In 2021, the North American Menopause Society (NAMS) issued a position statement on the management of osteoporosis in postmenopausal women (McClung, 2021). Per the NAMS:
 
    • “Bone turnover markers cannot diagnose osteoporosis and have varying ability to predict fracture risk in clinical trials. Bone turnover markers have been used primarily in clinical trials to demonstrate group responses to treatment. Although used by some osteoporosis specialists, the routine use of bone turnover markers in the evaluation of patients with osteoporosis is not recommended.”
    • “Although changes in bone turnover markers are used by some specialists to assess adherence and effectiveness of therapy, routine use of bone markers is not recommended.”
 
In 2019, guidelines from the Endocrine Society recommended that in postmenopausal women with a low BMD and at high-risk of fractures who are being treated for osteoporosis, monitoring should be conducted by dual-energy X-ray absorptiometry (DXA) at the spine and hip every 1 to 3 years (Eastell, 2019). The Society considers measuring bone turnover markers (serum C-telopeptide [CTX] for antiresorptive therapy or procollagen type 1 N-terminal propeptide [PINP] for bone anabolic therapy) as an alternative way of monitoring for poor response or nonadherence to therapy. The Society notes that there is uncertainty over what constitutes an optimal response to treatment, but some experts suggest that a meaningful change is approximately 40% when compared from before to 3 to 6 months after starting treatment. A guideline update was published in 2020, in which the statements concerning measurement of bone turnover markers remained unchanged (Shoback, 2020).
,
The Endocrine Society also published guidelines regarding the management of Paget disease in 2014 (Singer, 2014). The guideline states:
    • “We recommend measurement of serum total alkaline phosphatase or, when warranted, a more specific marker of bone formation or bone resorption to assess the response to treatment or evolution of the disease in untreated patients.”
    • “In patients with monostotic disease who have a normal serum total alkaline phosphatase, we suggest that a specific marker of bone formation and bone resorption be measured, although these may still be normal. Serial radionuclide bone scans may determine the response to treatment if the markers are normal.”
    • "In assessing the response to treatment: “For most patients, measurement of total ALP [alkaline phosphatase] or other baseline disease activity markers at 6 to 12 weeks, when bone turnover will have shown a substantial decline, is an acceptable and cost-effective option.”
 
In the 2019 ISCD position statement on repeating measurement of BMD when monitoring with DXA, there is a comment on bone turnover markers: “Serial BMD testing in combination with clinical assessment of fracture risk, bone turnover markers, and other factors…can be used to determine whether treatment should be initiated in untreated patients, according to locally applicable guidelines” (Kendler, 2019).
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2024. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Kashii et al reported a prospective review of 63 treatment-naive patients with postmenopausal osteoporosis commencing 12 months of treatment with romosozumab (Kashii, 2023). Multiple regression analysis revealed that PINP value was significantly and independently associated with at least a 3% increase in BMD in both total hip and femoral neck (p=.019). The optimal PINP cutoff was 53.7 mcg/L, with 54.3% sensitivity and 92.3% specificity.
 
A study by Martli et al reported on 55 patients with primary hyperparathyroidism who underwent parathyroidectomy (Marli, 2023). The investigators sought to determine the relationship between preoperative P1NP and CTx levels and the risk of postoperative hypocalcemia. Results demonstrated that a CTx value exceeding 2.665 pg/dL was an independent risk factor for postoperative hypocalcemia (p=.036).
 
In 2022, the Bone Health and Osteoporosis Foundation (formerly the National Osteoporosis Foundation) published updated guidelines on the prevention and treatment of osteoporosis to prevent fractures. Regarding biochemical markers of bone turnover, the guidelines stated: "Biochemical bone turnover markers can play a role in assessing fracture risk in appropriate individuals". (LeBoff, 2022)
 
Furthermore, biochemical markers of bone turnover may
    • Predict rapidity of bone loss in untreated postmenopausal women
    • 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 using a serum CTX for an antiresorptive medication and P1NP for an anabolic therapy (least significant change [LSC] is approximately a 40% reduction in CTX)
    • 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.)

CPT/HCPCS:
82523Collagen cross links, any method
82570Creatinine; other source
83519Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, by radioimmunoassay (eg, RIA)
83937Osteocalcin (bone g1a protein)
84075Phosphatase, alkaline;
84080Phosphatase, alkaline; isoenzymes

References: Abe Y, Ishikawa H, Fukao A.(2008) Higher efficacy of urinary bone resorption marker measurements in assessing response to treatment for osteoporosis in postmenopausal women. Tohoku J Exp Med 2008; 214(1):51-9.

Al Nofal AA, Altayar O, BenKhadra K, et al.(2015) 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.

Alvarez L, Guanabens N, Peris P et al.(2001) Usefulness of biochemical markers of bone turnover in assessing response to the treatment of Paget's disease. Bone 2001; 29(5):447-52.

American College of Rheumatology Task Force on Osteoporosis Guidelines.(1996) Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheum 1996; 39(11):1791-801.

Bauer DC, Black DM, Ott SM et al.(1997) Biochemical markers predict spine but not hip BMD response to bisphosphonates: the Fracture Intervention Trial (FIT). J Bone Miner Res 1997; 12(suppl 1):S150.

Bauer DC, Garnero P, Harrison SL et al.(2009) Biochemical markers of bone turnover, hip bone loss and fracture in older men: the MrOS Study. J Bone Mineral Res 2009; 24(12):2032-8.

Baxter I, Rogers A, Eastell R et al.(2013) Evaluation of urinary N-telopeptide of type I collagen measurements in the management of osteoporosis in clinical practice. Osteoporos Int 2013; 24(3):941-7.

Bell Meade, NJ.(1998) National Osteoporosis Foundation. Physician’s Guide to Diagnosis and Management of Osteoporosis. Excerpta Medica 1998.

Black DM, Greenspan SL, Ensrud KE et al.(2003) The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. NEJM 2003; 349(13):1207-15.

Blumsohn A, Eastell R.(1997) The performance and utility of biochemical markers of bone turnover: do we know enough to use them in clinical practice. Ann Clin Biochem 1997; 34(pt 5):449-59.

Bone HG, Downs RW, Tucci JR et al.(1997) Dose-response relationships for alendronate treatment in osteoporotic elderly women. J Clin Endocrine Metab 1997; 82(1):265-74.

Camacho PM, Petak SM, Binkley N, et al.(2020) AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS/AMERICAN COLLEGE OF ENDOCRINOLOGY CLINICAL PRACTICE GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS-2020 UPDATE. Endocr Pract. May 2020; 26(Suppl 1): 1-46. PMID 32427503

de Vernejoul MC.(1998) Markers of bone remodeling in metabolic bone disease. Drugs Aging 1998; 12 (suppl 1):9-14.

Eastell R, Rosen CJ, Black DM et al.(2019) Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society* Clinical Practice Guideline. J. Clin. Endocrinol. Metab., 2019 Mar 26;104(5). PMID 30907953

Funck-Brentano T, Biver E, Chopin F et al.(2011) Clinical utility of serum bone turnover markers in postmenopausal osteoporosis therapy monitoring: a systematic review. Semin Arthritis Rheum 2011; 41(2):157-69.

Garnero P, et al.(1996) Bone resorption markers predict hip fracture risk in women. The EPIDOS prospective study. J Bone Min Res 1996; 11:1531-38.

Garnero P, Hausherr E, Chapuy MC, et al.(1996) Markers of bone resorption predict hip fracture in elderly women: the EPIDOS prospective study. J Bone Miner Res 1996; 11(10):1531-8.

Gutierrez-Buey G, Restituto P, Botella S et al.(2019) Trabecular bone score and bone remodelling markers identify perimenopausal women at high risk of bone loss. Clin. Endocrinol. (Oxf), 2019 May 30;91(3). PMID 31141196

Kashii M, Kamatani T, Nagayama Y, et al.(2023) Baseline serum PINP level is associated with the increase in hip bone mineral density seen with Romosozumab treatment in previously untreated women with osteoporosis. Osteoporos Int. Mar 2023; 34(3): 563-572. PMID 36585509

LeBoff MS, Greenspan SL, Insogna KL, et al.(2022) The clinician's guide to prevention and treatment of osteoporosis. Osteoporos Int. Oct 2022; 33(10): 2049-2102. PMID 35478046

Lindsay R.(1999) Clinical utility of biochemical markers. Osteoporos Int 1999; 9 (suppl 2):S29-32.

Looker AC, Bauer DC, Chestnut CH, et al.(2000) Clinical use of biochemical markers of bone remodeling: current status and future directions. Osteoporosis Int 2000; 11(6):467-80.

Management of osteoporosis in postmenopausal women: 2010 position statement of the North American Menopause Society. Available online at www.guideline.gov. Last accessed August 23 2010.

Marcus R, Holloway L, Wells B.(1997) Turnover markers only weakly predict bone response to estrogen: the Postmenopausal Estrogen/Progestin Interventions Trial (PEPI). J Bone Miner Res 1997; 12 (suppl 1):S103.

Martli HF, Saylam B, Er S, et al.(2023) Evaluation of preoperative procollagen type 1 N-terminal peptide and collagen type 1 C-telopeptide levels in the prediction of postoperative hypocalcemia in patients undergoing parathyroidectomy due to primary hyperparathyroidism. Langenbecks Arch Surg. Jan 31 2023; 408(1): 71. PMID 36720758

McCloskey EV, Vasikaran S, Cooper C.(2011) 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 2011; 14(3):220-2.

Meunier PJ, Roux C, Seeman E et al.(2004) The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. NEJM 2004; 350(5):459-68.

Miller PD, Baran DT, Bilezikian JP et al.(1999) Practical clinical application of biochemical markers of bone turnover. Consensus of an expert panel. J Clin Densitom 1999; 2(3):323-42.

Miller PD, Bonnick SL, Johnston CC, et al.(1998) The challenges of peripheral bone density testing: which patients need additional central density skeletal measurements. J Clin Densitom 1998; 1(3):211-8.

Miller PD, Zapalowski C, Kulak CA, et al.(1999) Bone densitometry: the best way to detect osteoporosis and to monitor therapy. J Clin Endocrinol Metab 1999; 84(6):1867-71.

National Osteoporosis Foundation.(2008) Clinician's guide to prevention and treatment of osteoporosis. http://www.nof.org/professionals/NOF_Clinicians_Guide.pdf (last viewed April 2008).

National Osteoporosis Foundation.(2013) 2013 Clinician's guide to prevention and treatment of osteoporosis. Available online at: http://www.nof.org/professionals/clinical-guidelines. Last accessed September, 2013.

No. 226/November 23.(2001) Federal Register, Vol. 66. Rules and Regulations Federal Register, Vol. 66, 2001.

Reid IR, Davidson JS, Wattie D et al.(2004) Comparative responses of bone turnover markers to bisphosphonate therapy in Paget's disease of bone. Bone 2004; 35(1):224-30.

Rianon N, Alex G, Callender G et al.(2012) Preoperative serum osteocalcin may predict postoperative elevated parathyroid hormone in patients with primary hyperparathyroidism. World J Surg 2012; 36(6):1320-6.

Salamone LM, Pressman AR, Seeley DG et al.(1996) Estrogen replacement therapy. A survey of older women’s attitudes. Arch Intern Med 1996; 156(12):1293-7.

Sambrook PN, Geusens P, Ribot C, et al.(2004) Alendronate produces greater effects than raloxifene on bone density and bone turnover in postmenopausal women with low bone density: results of EFFECT (Efficacy of FOSAMAX versus EVISTA Comparison Trial) International. J Intern Med 2004; 255(4):503-11.

Shieh A, Greendale GA, Cauley JA et al.(2019) Urinary N-Telopeptide as Predictor of Onset of Menopause-Related Bone Loss in Pre- and Perimenopausal Women. JBMR Plus, 2019 May 3;3(4). PMID 31044185

Shiraki M, Kuroda T, Tanaka S, et al.(2008) Nonenzymatic collagen cross-links induced by glycoxidation (pentosidine) predicts vertebral fractures. J Bone Miner Metab 2008; 26(1):93-100.

Silverman SL, Nasser K, Nattrass S et al.(2012) Impact of bone turnover markers and/or educational information on persistence to oral bisphosphonate therapy: a community setting-based trial. Osteoporos Int 2012; 23(3):1069-74.

Tamaki J, Iki M, Kadowaki E et al.(2013) 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 2013; 24(3):887-97.

Tanaka Y, Funahashi H, Imai T, et al.(1997) Parathyroid function and bone metabolic markers in primary and secondary hyperparathyroidism. Semin Surg Oncol 1997; 13(2):125-33.

Välimäki MJ, Farrerons-Minguella J, Halse J et al.(2007) Effects of risedronate 5 mg/d on bone mineral density and bone turnover markers in late-postmenopausal women with osteopenia: a multinational, 24-month, randomized, double-blind, placebo-controlled, parallel-group, phase III trial. Clin Ther 2007; 29(9):1937-49.

Woitge HW, Oberwittler H, Heichel S et al.(2000) Short- and long-term effects of ibandronate treatment on bone turnover in Paget disease of bone. Clin Chem 2000; 46(5):684-90.

Zhang T, Liu P, Zhang Y et al.(2018) Combining information from multiple bone turnover markers as diagnostic indices for osteoporosis using support vector machines. Biomarkers, 2018 Nov 18;24(2). PMID 30442069


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