Medical Policy: 02.04.13 

Original Effective Date: October 2007 

Reviewed: February 2018 

Revised: February 2016 

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

Bone turnover markers are biochemical markers of either bone formation or bone resorption. Commercially available tests 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) measurements in the diagnosis of osteoporosis and aid in treatment decisions. Bone turnover markers could also potentially be used to evaluate treatment effectiveness before changes in BMD can be observed. Also, bone turnover markers have been considered in the management of conditions associated with high bone turnover including but not limited to Paget's disease, primary hyperparathyroidism and renal osteodystrophy.

 

Background Information on Bone Turnover Markers

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 below summarizes the various bone turnover markers.
Formation MarkersResorption 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 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 (bone mineral density) 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.

 

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

 

The first step in assessing a medical test is to formulate the clinical content and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. For bone turnover markers to be considered clinically useful, studies need to demonstrate that tests for these 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 to change treatment in a way that improves patient outcomes.

 

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. 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 one or more follow-ups. Women with early menopause (ie, <40 years old), with a history of illness or medication known to affect bone metabolism, or with incomplete data were excluded. After exclusions, 522 women were evaluated.

 

Over a median follow-up 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, and urinary free deoxypyridinoline. For example, in a multivariate model adjusting for various 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 2009, Bauer et. al. completed a subgroup analysis of prospectively collected data from the Osteoporotic Fractures in Men (MrOS) study to test the hypothesis that men with higher levels of bone turnover would have accelerated bone loss and elevated risk of fracture. Baseline levels of bone turnover markers were compared in 384 men, ages 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 relations between any bone turnover marker and fracture risk. The authors concluded in this large prospective study of contemporary bone turnover markers (BTM), bone loss, and fracture in older men, it found that elevated serum levels of PINP, BCTX, and TRACP5b are associated with higher rates of hip bone loss, but the associations were insufficient strength to accurately predict bone loss in any individual subject. Although the data suggested that higher serum of PINP and BCTX at baseline are associated with an increased risk of subsequent hip and nonspine fracture in older men, none of the relationships between BTMs and fracture risk were statistically significant after accounting for baseline BMD. Additional prospective studies are warranted, particularly with novel biomarkers, but these results suggest that a single serum measurement of PINP, BCTX or TRACP5b does not strongly predict future fracture risk in men and should not be incorporated into evolving risk stratification methods.

 

Systematic reviews have examined the association between bone turnover markers and fracture risk, but have not analyzed the 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. 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. 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.

 

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. 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, urinary total deoxypyridinoline, and urinary free deoxypyridinoline and risk of incident vertebral fracture in women. Overall, the evidence does not suggest that any bone turnover markers is an independent predictor of fracture risk, beyond BMD.

 

Clinical Validity of Bone Turnover Markers and Response to Osteoporosis Treatment

A 2008 randomized trial assessing an osteoporosis treatment (N=43) found that urinary cross-linked N-terminal telopeptides (NTP) provided a more sensitive measure of treatment response than serum levels. Another small randomized trial from Japan measured OC levels in response to osteoporosis treatment in 109 postmenopausal women. Authors found that undercarboxylated OC levels in serum were significantly lower at 1 month in the group receiving active treatment for osteoporosis than 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. 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. Subsequently, additional study on this topic was published by Baxter et. al. (2013). This retrospective review evaluated 200 patients commencing treatment with bisphosphonates for osteoporosis or osteopenia. Investigators found a statistically significant inverse correlation between change in urine 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.

 

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

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. 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 ibandronate given monthly with a collagen cross-links test or usual care. 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, patients 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.

 

Summary Clinical Utility of Diagnosis and Management of Osteoporosis

There is a limited amount of evidence on the impact of bone turnover markers on the 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 such as primary hyperparathyroidism, Paget disease, renal osteodystrophy, 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. 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. Authors concluded that research with longer follow-up in patients with no known baseline chronic kidney disease stratified by high versus normal preoperative serum creatinine is recommended.

 

Paget Disease

A 2015 systematic review and meta-analysis by Al Nofal et. al. assessed the literature on bone turnover markers in Paget disease. Reviewers focused on the correlation between bone markers and disease activity before and after treatment with bisphosphonates. All study design types were included and bone scintigraphy was used as the reference standard. Reviewers identified 18 studies. Seven assessed bone markers in patients with Paget disease before treatment, six considered both the pre- and posttreatment associations, and five included only the posttreatment 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 receive measurement of bone turnover markers, the evidence includes observational studies on the association between markers and osteoporosis and fracture risk and systemic reviews of those studies. 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 for 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, and/or improves health outcomes such as reducing fracture rates. The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

For individuals with conditions associated with high rates of bone turnover other than age related osteoporosis (e.g. hyperparathyroidism, Paget disease, renal osteodystrophy) who receive measurement of bone turnover markers, the evidence includes observational studies on the association between markers and disease activity and systemic reviews of those studies. 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 the 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 the net health outcomes.

 

Practice Guidelines and Position Statements

National Osteoporosis Foundation

In 2014, the National Osteoporosis Foundation updated their guideline for prevention and treatment of osteoporosis. 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).

 

The North American Menopause Society

In 2010, the North American Menopause Society issued an updated position statement on the 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.”

 

International Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC)

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. 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 to 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 the International Osteoporosis Foundation (IOF)

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 “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. Preventative Services Task Force

The U.S. Preventative Services Task Force (USPSTF) recommendations on osteoporosis screening are in the process of being updated. The 2011 recommendation on osteoporosis screening addresses dual-energy x-ray absorptiometry (DXA) testing but does not mention bone turnover markers.

 

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, examples are listed below:

  • Pyrilinks test (Metra Biosystems, Santa Clara, CA) measures collagen type 1 cross-link, pyridium.
  • Osteomark test (Ostex International, Seattle, WA) measures cross-linked N-telopeptides of type 1 collagen (NTx).
  • Serum Crosslaps One-step ELISA (Immunodiagnostic Systems) test measures hydroxyproline.
  • Ostase (Beckman Coulter) measures bone-specific alkaline phosphatase (B-ALP).
  • N-MID Osteocalcin One-step ELISA (Osteometer Bio Tech) measures osteocalcin (OC)

 

Prior Approval:

Not applicable

 

Policy:

Measurement of bone turnover markers is considered investigational in the diagnosis and management of osteoporosis.

 

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, or improves health outcomes such as reducing fracture rates. Therefore, the use of bone turnover markers for the diagnosis and management of osteoporosis is considered investigational.

 

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.

 

There is little published literature on the use of bone turnover markers in the management of conditions associated with high rates of bone turnover. The evidence includes observational studies on the association between markers and disease activity and systemic reviews of those studies. There is a lack of evidence on how measurement of bone turnover markers can change patient management or improve health outcomes in patients with conditions associated with high bone turnover including but not limited to Paget’s disease, primary hyperparathyroidism, and renal osteodystrophy. Therefore, the evidence is insufficient to determine the effects on net health outcomes and utilization of bone turnover marker testing for these other conditions is considered investigational.

 

Procedure Codes and Billing Guidelines:

  • To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
  • 82523 collagen cross links, any method
  • 83937 osteocalcin (bone g1a protein)
  • 84080 phosphatase, alkaline; isoenzymes (used for Ostase test)

 

Selected References:

F

  • National Osteoporosis Foundation. Physician's guide to prevention and treatment of osteoporosis. April 2003.
  • Stepan JJ. Clinical utility of bone markers in the evaluation and follow-up of osteoporotic patients: why are the markers poorly accepted by clinicians? J Endocrinol Invest. 2003 May;26(5):458-63.
  • Meunier PJ, Roux C, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med. 2004 Jan 29;350(5):459-68.
  • Paschalis EP, Glass EV,et al. Bone mineral and collagen quality in iliac crest biopsies of patients given teriparatide: new results from the fracture prevention trial. J Clin Endocrinol Metab. 2005 Aug;90(8):4644-9.
  • Bauer DC, Garnero P, et al. Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the fracture intervention trial. J Bone Miner Res. 2006 Feb;21(2):292-9.
  • Black DM, Schwartz AV,et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006 Dec 27;296(24):2927-38.
  • Deane A, Constancio L, et al. The impact of vitamin D status on changes in bone mineral density during treatment with bisphosphonates and after discontinuation following long-term use in post-menopausal osteoporosis. BMC Musculoskelet Disord. 2007 Jan 10;8:3.
  • Bergmann P, Body JJ, Boonen S et al. Evidence-based guidelines for the use of biochemical markers of bone turnover in the selection and monitoring of bisphosphonate treatment in osteoporosis: a consensus document of the Belgian Bone Club. Int J Clin Pract 2008;63(1):19-26.
  • 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):333-40.
  • Management of osteoporosis in postmenopausal women 2010 position statement of the North American Menopause Society. Last accessed August 2011.
  • Funck-Brentano T, Biver E, Chopin F, Bouvard B, et al. Clinical utility of serum bone turnover markers in postmenopausal osteoporosis therapy monitoring: a systematic review. Semin Arthritis Rheum. 2011 Oct; 41(2):157-69.
  • Biver E, Chopin F, Coiffier G, Brentano TF, et al. Bone turnover markers for osteoporotic status assessment? A systematic review of their diagnosis value at baseline in osteoporosis. Joint Bone Spine. 2012 Jan;79(1):20-5.
  • UpToDate Use of Biochemical Markers of Bone Turnover in Osteoporosis. Harold N. Rosen, M.D. , Topic last updated January 17, 2018.
  • ECRI Institute Hotline Response. Biochemical Markers of Bone Turnover in Age Related Osteoporosis. January 2013.
  • National Guideline Clearinghouse American College of Obstetricians and Gynecologists (ACOG), practice bulletin; no 129, Osteoporosis and Osteoporotic Fractures.
  • Sonsoles Botella, Patricia Restituto, et. al. Traditional and Novel Bone Remodeling Markers in Premenopausal and Postmenopausal Women, Journal of Clinical Endocrinology & Metabolism September 3, 2013.
  • American Association for Clinical Chemistry (AACC). Bone Turnover Markers. July 2013.
  • International Society for Clinical Densitometry and International Osteoporosis Foundation, Interpretation and Use of FRAX in Clinical Practice.
  • U.S. Preventative Service Task Force (USPSTF) Osteoporosis Screening, January 2011.
  • Watts N, Bilezikian J, et. al. American Association of Clinical Endocrinologists (AACE) Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Postmenopausal Osteoporosis, Endocrine Practice Vol 16 (Suppl 3) November/December 2010
  • Bolland M, Cundy T. Paget’s Disease of Bone. J Clin Pathol. 2013;66(11):924-927. Available on Medscape
  • Wheater G, Elshahaly M, et. al. The clinical utility of bone marker measurements in osteoporosis Journal of Translational Medicine 2013. 11:201.
  • 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
  • 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
  • Al Nofal AA, Altayar O, BenKhadra K, et. al. Bone turnover markers in Paget’s disease of the bone: A systemic review and meta-analysis. Osteoporos Int. July 2015;26(7):1875-1891
  • Unnanuntana A, Gladnick B, Donnelly E, et. al. Current Concepts Review The Assessment of Fracture Risk, J Bone Joint Surg Am 2010;92:743-53
  • National Osteoporosis Foundation 2014 Clinician’s Guide to Prevention and Treatment of Osteoporosis, Released April 1, 2014.
  • International Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), 2011 Position Statement by a joint IOF-IFCC Bone Marker Standards Work Group.
  • CMS National Coverage Determinations. 190.19 Collagen Crosslinks, Any Method..
  • UpToDate Screening for Osteoporosis. Elaine W Yu, M.D., Topic last updated December 1, 2017.
  • UpToDate Primary Hyperparathyroidism: Diagnosis, Differential Diagnosis and Evaluation. Ghada El-Haji Fuleihan, M.D., MPH, Shonni J. Silverberg, M.D., Topic last updated November 20, 2017.
  • UpToDate Evaluation and Management of Aromatase Inhibitor Induced Bone Loss. Charles L. Shapiro, M.D., Shubham Pant, M.D., Topic last updated March 7, 2017.
  • UpToDate Treatment of Paget Disease of Bone. Julia F. Charles, PhD., Topic last updated June 15, 2016.
  • UpToDate Antiepileptic Drugs and Bone Disease. Alison M Pack, M.D., Elizabeth Shane, M.D., Topic last updated January 9, 2017.
  • UpToDate Bone Biopsy and the Diagnosis of Renal Osteodystrophy. L Darryl Quarles, M.D., Michael Berkoben MD., Topic last updated January 10, 2018.
  • Chubb SA, Byrnes E, Manning L, et. al. Reference intervals for bone turnover markers and their association with incident hip fractures in older men: The health in men study, J Clin Endocrinol Metab 2015 Jan;100(1):90-9
  • Michelsen J, Wallashofski H, Friedrich N, et. al. Reference intervals for serum concentrations of three bone turnover markers for men and women, Bone 2013 Dec:57(2):399-404
  • Lehmann G, Ott U, Kaemmerer D, et. al. Bone histomorphometry and biochemical markers of bone turnover in patients with chronic kidney disease stages 3-5, Clin Nephrol 2008 Oct:70(4):296-305
  • UpToDate. Bone Physiology and Biochemical Markers of Bone Turnover. Harold N Rosen M.D. Topic last updated October 16, 2017.
  • UpToDate. Osteoporosis in Patients with Chronic Kidney Disease: Diagnosis, Evaluation and Management. Paul D. Miller, M.D. Topic last updated January 3, 2018.
  • UpToDate. Clinical Manifestations, Diagnosis and Evaluation of Osteoporosis in Postmenopausal Women. Harold N Rosen M.D., Marc K. Drezner M.D. Topic last updated January 5, 2017.
  • 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
  • Baxter I, Rogers A, Eastell R, et. al. Evaluation of urinary N-telopeptide of type 1 collagen measurements in the management of osteoporosis in clinical practice. Osteoporos Int. Mar 2013;24(3):941-947. PMID 22872068
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Szulc P, Naylor K, Hoyle NR, et al. Use of CTX-I and PINP as bone turnover markers: National Bone Health Alliance recommendations to standardize sample handling and patient preparation to reduce pre-analytical variability. Osteoporos Int. Jun 19 2017. PMID 28631236

 

Policy History:

  • February 2018 - Annual Review, Policy Renewed
  • February 2017 - Annual Review, Policy Renewed
  • February 2016 - Annual Review, Policy Revised
  • March 2015 - Annual Review, Policy Revised
  • April 2014 - Annual Review, Policy Revised
  • May 2013 - Annual Review, Policy Revised
  • May 2012 - Annual Review, Policy Renewed
  • August 2011 - Annual Review, Policy Revised

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

*CPT® is a registered trademark of the American Medical Association.