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MP 2.04.15 Bone Turnover Markers for the Diagnosis and Management of Osteoporosis and Diseases Associated with High Bone Turnover

Medical Policy    
Original Policy Date
Last Review Status/Date
Reviewed with literature search/9:2014
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Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.


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 (HPLC) or immunoassay. Assessment of bone turnover markers is proposed to supplement bone mineral density (BMD) 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 BMD can be observed.


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. The table summarizes the various bone-turnover markers.

Formation Markers

Resorption Markers 
Serum osteocalcin (OC)   Serum and urinary hydroxyproline (Hyp)  
Serum total alkaline phosphatase (ALP)   Urinary total pyridinoline (Pyr)  
Serum bone specific alkaline phosphatase (B-ALP)   Urinary total deoxypyridinoline (d-Pyr)  
Serum procollagen I carboxyterminal propeptide (PICP)   Urinary-free pyridinoline (f-Pyr, also known as Pyrilinks®)  
Serum procollagen type 1 N-terminal propeptide (PINP)   Urinary-free deoxypyridinoline (f-dPyr, also known as Pyrilinks-D®)  
Bone sialoprotein   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 (TRAP or TRACP)  

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 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, 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 by the U.S. Food and Drug Administration (FDA) using the 510(k) process.

Collagen cross-links tests:

1995: Pyrilinks test (Metra Biosystems, Santa Clara, CA) measures collagen type 1 cross-link, pyridinium

1996: Osteomark test (Ostex International, Seattle, WA) measures cross-linked N-telopeptides of type 1 collagen (NTx)

1999: Serum Crosslaps One-step ELISA test measures hydroxyproline

Other bone turnover tests:

2000: Ostase® (Beckman Coulter) measures bone-specific alkaline phosphatase (B-ALP)

2001: N-MID Osteocalcin One-Step ELISA (Osteometer Bio Tech) measures osteocalcin (OC)


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.


In general, to be considered clinically useful, studies need to demonstrate that tests for bone turnover markers are accurate and reliable and that their use can result in improved health outcomes. For example, to evaluate their utility for diagnosing osteoporosis as an adjunct to bone mineral density (BMD) measurements with dual energy x-ray absorptiometry (DXA), studies would moreover 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 need to impact the decision to continue or change treatment in a way that leads to improved patient outcomes.

This policy was created in 1999 and updated regularly with literature reviews using MEDLINE. Most recently, the literature was searched through July 23, 2014. Following is a summary of key literature on bone turnover markers published to date:

Diagnosis and Management of Osteoporosis

Do bone turnover markers independently predict fracture risk beyond BMD measurements?

Few studies have directly addressed the question of whether any bone turnover markers are independent predictors of fracture risk. One study conducted in men and one conducted in women are described next.

A 2013 analysis of population-based data in Japan 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 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 (ie, <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 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 SD of change in ALP was increased by 33% (risk ratio, 1.33;
95% CI, 1.06 to 1.66). Risk of incident vertebral fracture was not significantly associated with other bone turnover markers including osteocalcin (OC) and crosslinked C-telopeptide (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.

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, age 65 years or older, who had nonspine fractures over an average follow-up of 5 years with 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 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.

Systematic reviews have examined the association between bone turnover markers and fracture risk, but have not included analyses on the additional predictive value beyond BMD. For example, a 2014 metaanalysis by Johansson et al focused on the markers PINP and CTx and examined their ability to predict future fracture risk.3
The review 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. A meta-analysis of 3 studies found a statistically significant association between baseline PINP and subsequent fracture risk (hazard ratio [HR], 1.23; 95% confidence interval [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 previous systematic review, published in 2012 by Biver et al, did not find a statistically significant association between another bone turnover marker, OC and fracture risk.4 When findings from 3 studies were pooled, the mean difference in OC levels in patients with and without vertebral fractures was1.61 ng/mL (95% CI, -0.59 to 3.81). Both systematic reviews noted a high degree of heterogeneity among the published studies identified.

Section Summary

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. Moreover, there is insufficient evidence that any bone turnover marker is an
independent predictor of fracture risk, beyond BMD.

Do bone turnover markers independently predict response to osteoporosis treatment?

Studies have also examined the ability of bone turnover markers to evaluate response to osteoporosis treatment. For example, a subanalysis of the randomized Fracture Intervention Trial (n=6184) by Bauer et al 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 those in the lowest tercile (<41.6 ng/mL). Baseline bone turnover rates were not associated with alendronate efficacy in reducing vertebral fractures. The authors indicated that this result needed confirmation in additional studies, and, even if verified, the impact on treatment recommendations is not clear. A small randomized trial of an osteoporosis treatment (n=43) found that urinary crosslinked Nterminal telopeptides provided a more sensitive measure of treatment response than serum levels.6 Another small randomized trial from Japan measured levels of OC in response to osteoporosis treatment in 109 postmenopausal women.7 The authors found that undercarboxylated osteocalcin (uc-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 addressed the issue of whether early changes in serum biochemical bone turnover markers predict the efficacy of osteoporosis therapy.8 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, previously described) 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 et al in 2013.9 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 product-moment correlation r=0.33, p<0.001). There was not a significant association between change in urine NTx and hip BMD.

Section Summary

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, such as PINP in the Fracture Intervention Trial, a body of evidence in support of any specific marker is lacking. As a result, the evidence is insufficient to conclude whether bone turnover markers are an independent predictor of treatment response.

Does information provided by bone turnover markers improve treatment decisions and/or improve health outcomes?

To provide clinical utility, bone turnover markers would need 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 potentially provide information with clinical utility. For example, the 2013 guideline from the National Osteoporosis Foundation states 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 the issue of 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. The authors noted a high baseline compliance rate that limited the studies’ ability to detect an impact of feedback. As an example, a 2011 industry-sponsored study by Roux et al from France randomized physicians to manage patients on oral monthly ibandronate with a collagen crosslinks test (CTx) or usual care.12 In the CTx 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 they were 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 CTx group and 75.1% in the usual care group; the difference between groups was not statistically significant (p=0.93). There was also not a statistically significant difference in the proportion of patients having taken at least 10 of 12 pills; 82.4% in the CTx group and 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

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 evaluate whether the use of bone turnover markers lead 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, such as Paget disease, primary hyperparathyroidism, and renal osteodystrophy. Moreover, very few studies on this topic have been published since 2000. One recent study, published in 2012 by Rainon et al, reported on 198 patients with primary hyperparathyroidism who underwent parathyroidectomy.13 The authors 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. In addition, several studies published 2000 or later were identified that tested bone turnover levels in patients with Paget disease before and after treatment with bisphosphonates.14-16 For example, Alvarez et al 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 ALP, serum bonespecific alkaline phosphatase, and PINP and urinary hydroxyproline, 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.

Summary of Evidence

The literature suggests 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 for any specific marker. Questions remain about whether bone turnover markers are sufficiently sensitive to reliably determine individual treatment responses. In addition, there is insufficient evidence from controlled studies that bone turnover marker measurement improves adherence to treatment, impacts
management decisions, and/or improves health outcomes such as reducing fracture rates. Thus, the use of bone turnover markers for the diagnosis and management of osteoporosis is considered investigational.

There is insufficient evidence that measurement of bone turnover markers improves patient management or health outcomes in patients with conditions associated with high bone turnover including Paget disease, primary hyperparathyroidism, and renal osteodystrophy. Thus, bone turnover marker testing for these other conditions is considered investigational.

Practice Guidelines and Position Statements
In 2014, the National Osteoporosis Foundation updated their guideline for prevention and treatment of osteoporosis.10 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 FDAapproved 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).

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.”17

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 Bone Marker Standards Working Group.18 The aim of the group was to evaluate evidence on using bone turnover markers for fracture risk assessment and monitoring of treatment. The group’s 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.”

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 statement19 : “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
The U.S. Preventive Services Task Force 2011 recommendations on osteoporosis screening address DXA testing but do not mention bone turnover markers.20

Medicare National Coverage
On November 25, 2002, the Centers for Medicare and Medicaid Services (CMS) issued a National Coverage Determination (NCD) on collagen crosslinks.21 The CMS NCD identifies a set of clinical conditions for which collagen crosslinks would be considered eligible for coverage. The CMS NCD is limited to urine-based collagen crosslink tests and does not address serum-based collagen crosslink tests.

The Federal Register22 notes that Medicare carriers have discretion to make their own determinations on the medical necessity of serum-based collagen crosslink tests for assessing or monitoring bone loss therapy. The Federal Register also notes that FDA approved the serum-based collagen crosslink tests under 510(k) review, as substantially equivalent to the urine-based collagen crosslink test. It should be noted that the serum-based collagen crosslink tests are more commonly performed than urine collagen cross-link tests.

The Medicare NCD analysis focused on the technical feasibility of collagen crosslinks and anticipated outcomes. The discussion above focused on the impact on health outcomes as documented in controlled studies.


  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 Mineral Res. 2009;24(12):2032-2038. PMID
  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. PMID21724445
  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. 2006;21(2):292-299. PMID
  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. 2008;214(1):51-59.PMID
  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
  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. Accessed July, 2014.
  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 2011;79(4):389-392. PMID
  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. Woitge HW, Oberwittler H, Heichel S, et al. Short- and long-term effects of ibandronate treatment on bone turnover in Paget disease of bone. Clin Chem. May 2000;46(5):684-690. PMID 10794751
  15. Reid IR, Davidson JS, Wattie D, et al. Comparative responses of bone turnover markers to bisphosphonate therapy in Paget's disease of bone. Bone. Jul 2004;35(1):224-230. PMID 15207761
  16. Alvarez L, Guanabens N, Peris P, et al. Usefulness of biochemical markers of bone turnover in assessing response to the treatment of Paget's disease. Bone. Nov 2001;29(5):447-452. PMID 11704497
  17. North American Menopause Society. Management of osteoporosis in postmenopausal women: 2010 position statement of the North American Menopause Society.
  18. 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. 2011;49(8):1271-1274. PMID
  19. 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
  20. U.S. Preventive Services Task Force (USPSTF). Screening for Osteoporosis. 2011; Accessed July, 2014.
  21. CMS National Coverage Determinations. 190.19 Collagen Crosslinks, Any Method. Accessed July, 2014.
  22. Federal Register, November 23, 2001. Rules and Regulations.66(No. 226). PMID






Collagen cross links, any method 

  83937 Osteocalcin (bone g1a protein)
  84080 Phosphatase, alkaline; isoenzymes

ICD-9 Diagnosis 






ICD-10-CM (effective 10/1/15)     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 10/1/15)    Not applicable. No ICD procedure codes for laboratory tests. 

Type of Service 


Place of Service 



Bone Turnover Markers
Collagen Cross links, Osteoporosis
Osteoporosis, Bone Turnover Markers

Policy History

Date Action Reason
07/16/99 Add to Pathology section New policy
07/12/02 Replace policy Policy reviewed; expanded discussion, additional references, no change in policy statement
10/08/02 Replace policy Policy statement revised to be consistent with policy title
07/17/03 Replace policy Policy updated with information on CMS policy; policy statement unchanged
11/9/04 Replace policy Policy updated; no change in policy statement; references added
08/17/05 Replace policy Policy updated with literature search; no change in policy statement
4/25/06 Replace policy – error correction only Corrected table in description section to remove 2nd listing of urinary hydroxyproline and apply asterisk to serum and urinary hydroxyproline entry
10/10/06 Replace policy Policy updated with literature search; policy statement unchanged. Reference numbers 21 and 22 added.
05/08/08 Replace policy Policy updated with literature search; references reordered; references 21-24 added; earlier rationale summarized; no change in policy statement.
09/10/09 Replace policy Policy updated with literature search; scope changed to include bone turnover markers other than collagen cross links; title and policy statement changed to reflect expanded scope. Reference numbers 10 and 12 added and other references renumbered/removed.
09/16/10 Replace policy Policy updated with literature search; No change to policy statement; references 8 and 14 added.
9/01/11 Replace policy Policy updated with literature search; no change in policy statement. References 8, 9, 13 and 17 added; other references renumbered or removed.
10/11/12 Replace Policy Policy updated with literature search. Title changed to “Bone Turnover Markers for the Diagnosis and Management of Osteoporosis and Diseases Associated with High Bone Turnover.” Policy statement added that bone turnover markers considered investigational in the management of conditions associated with high bone turnover. References 13, 14, 16-19 and 23 added; other references renumbered.
10/10/13 Replace policy Policy updated with literature search through September 5, 2013. No change to policy statements. References 4, 9, and 10 added; other references renumbered or removed.
9/11/14 Replace policy Policy updated with literature review through July 23, 2014. No change to policy statements. References 3, 11, and 20 added.


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