Medical Policy: 02.04.13 

Original Effective Date: October 2007 

Reviewed: February 2021 

Revised: February 2021 

 

Notice:

This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.

 

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 (BTMs) 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 (measure collagen breakdown products and other molecules released from osteoclasts and osteoblasts during the process of bone resorption and formation). The use  of bone turnover markers (BTMs) is proposed to supplement bone mineral density (BMD) measurements in the diagnosis and the effects of osteoporosis (bone loss and fracture risk), aid in treatment decisions (response/effectiveness) to osteoporosis treatment, improve compliance with treatment, monitor response to osteoporosis treatment and determine whether or when patients should discontinue treatment or whether or when they should resume treatment. 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, renal osteodystrophy, diabetes and other endocrine disorders, oncologic indications including the monitoring of metastatic disease, rheumatologic conditions and vitamin D deficiency. 

 

Background Information on Bone Turnover

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 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)

 

Bone turnover makers (BTMs) have been primarily studied as an adjunct, not an alternative, to measurements of bone mineral density (BMD) to estimate fracture risk and document the need for preventive or therapeutic strategies for osteoporosis. 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. The use of bone turnover markers (BTMs) 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 may predict rate of bone loss and risk of fracture however, their role in the care of individual patients is not well established. Biologic and assay variability in BTM values has complicated the use in clinical practice: 

  • There are many different ways to measure these metabolites of collagen. Assay variability and poor standardization have limited the use of BTMs. Also, because BTM results vary with different laboratories patients need to have all their measurements performed in the same laboratory.  
  • There are a number of physiologic conditions that increase or decrease bone turnover and therefore, alter BTMs and these factors must be considered when interpreting BTMs which include the following:
    • There is diurnal variation in bone turnover and a strong circadian rhythm to several indices of bone remodeling. The serum concentration or urinary excretion of most markers peak around 6 AM and nadirs around 6 PM. The only marker that is not influenced by diurnal variation is serum BSAP (bone specific alkaline phosphatase).
    • Lower body mass index (BMI) and smoking are associated with high bone turnover and, therefore, higher BTMs.
    • BTMs are increased around the time of ovulation and decreased by use of oral contraceptives.  
    • Recent food consumption suppresses BTMs.
    • Exercise and physical activity may be associated with decreased bone turnover (lower BTMs).
    • Bone remodeling is important for fracture healing. BTMs remain elevated for up to four months after fracture. 

 

Also, several criteria must be fulfilled for a particular measurement to have value as a marker of BTMs: 

  • The substance must change in parallel with changes in bone turnover as measured by histomorphometry and calcium kinetics.
  • The serum concentration or urinary excretion of the substance must be high in conditions characterized by high bone turnover, such has hyperparathyroidism, hyperthyroidism and Paget disease of bone.
  • The serum concentration of urinary excretion of the substance mut be low in conditions characterized by low bone turnover, as occurs after the administration of antiresorptive drugs.

 

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 (BTMs) 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 Context and Test Purpose

One potential purpose of measuring bone turnover markers (BTMs) in patients who have osteoporosis or who are at risk of age-related osteoporosis is to inform a decision whether to begin, continue or discontinue therapy (duration of therapy).

 

Patients

The relevant population of interest is individuals with osteoporosis or age-related risk factors for osteoporosis.

 

Interventions

The test being considered is bone turnover markers (BTMs) as an adjunct to bone mineral density (BMD).

Variability in the measurement of bone turnover markers (BTMs) is related to a number of factors/conditions including sample handling and diurnal variation, postprandial status, menopausal status, exercise, alcohol use, medications, health conditions and recent fractures.

 

Outcomes

The general outcomes of interest are test validity and morbid events, more specifically, the association between test results and bone health, and the impact of the test results on bone fracture and health.

 

The beneficial outcome of a true test result is confirming effective treatment. The beneficial outcome of true negative test is to modify ineffective treatment.

 

Harmful outcomes of a false-positive result are not receiving correct treatment. Harmful outcomes of a false-negative test are receiving unnecessary treatment.

 

Changes in bone turnover are expected to be observed in 3 months. The impact of changes in treatment on bone strength would be observed in 2 to 5 years.

 

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

 

Systematic Reviews

Systematic reviews have examined the association between bone turnover markers and fracture risk but have not analyzed the predictive value beyond bone mineral density (BMD).

 

A 2012 systematic review by Biver et. al. evaluated bone turnover markers (BMTs) for osteoporotic status assessment for the positive and etiological diagnosis of osteoporosis at baseline, and their predictive value for past asymptomatic vertebral fractures. Conducted meta-analyses on BTMs levels according to osteoporotic status using random effects models. Moderate and negative correlations were found, mainly in postmenopausal women, between BTMs and BMD, especially with bone alkaline phosphatase (bone ALP), osteocalcin, serum C-terminal and urine N-terminal crosslinking telopeptides of type I collagen (sCTX and uNTX). Bone ALP and sCTX levels are higher in osteoporotic patients compared to controls. High levels of bone ALP in primary hyperparathyroidism and low levels of osteocalcin in endogenous hypercorticism are the most relevant data reported in endocrine diseases associated with osteoporosis. High levels of BTMs, especially osteocalcin, bone ALP or sCTX, may be associated with prevalent vertebral fractures. The authors concluded, the diagnosis value of BTMs at baseline in osteoporosis is very low. The interest of BTMs for the etiological diagnostic of secondary osteoporosis has not been demonstrated. Data are lacking to address the interest of BTMs assessment to screen for vertebral fractures in asymptomatic patients with high risk factors of fractures.

 

A 2014 meta-analysis by Johansson et. al. focused on the performance characteristics of serum procollagen type I N propeptide (s-PINP) and serum C-terminal cross-linking telopeptide of type I collagen (s-CTX) in fracture risk prediction in untreated individuals in prospective cohort studies. Cross-section studies were excluded. Reviewers included 10 prospective cohort studies. 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 bone mineral density (BMD) and, consequently, the pooled analyses do not reflect the ability of bone turnover markers to predict fracture risk beyond BMD.

 

Prospective and Retrospective Studies

Crandall et al. (2018) performed a prospective case-control study that included 800 participants (400 cases with hip fracture and 400 matched controls) to determine the associations of serum C-terminal telopeptide of type one collagen (CTX) and serum procollagen type I aminoterminal propetitide (PINP) with hip fracture risk. This study was nested in the Women's Health Initiative (WHI) Observational Study, which enrolled participants across 40 US clinical centers. Ages for participants were 50-79 years with an absence of serious medical conditions. Information for the participants with hip fractures was collected by annual self-questionnaires, but confirmed by medical record review. Participants in the control case group provided 12 hour fasting morning serum samples for CTX and PINP. The author analysis identified the serum CTX and PINP was not significantly associated with risk of hip fracture. Limitations of the study included the inability to adjust for bone mineral density since this study was part of the larger WHI study and no sample stability data regarding the stored serum samples. However the study had several strengths including prospective design, long term follow up, medical record follow for fracture information and fasting serum samples. In summary, the authors concluded the results did not support the utility of serum CTX level or PINP level to predict hip fracture risk in women in this age group.

 

A 2013 analysis of the Japanese Population-based Osteoporosis (JPOS) study data by Tamaki et. al. included postmenopausal women and adjusted for bone mineral density (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 bone mineral density (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.

 

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcomes can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

 

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs). No randomized controlled trials were identified that evaluated the effect of measurement of bone turnover markers on health outcomes.

 

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

 

To provide clinical utility, bone turnover markers would have to provide information, beyond that offered by BMD measurements, that has an impact on treatment decisions, and/or that leads to improved health outcomes. Bone turnover markers can be measured more frequently than BMD and thus could provide information with clinical utility. For example, biochemical markers of bone turnover might be used to predict the extent of fracture risk reduction when measured 3 to 6 months after starting osteoporosis treatments approved by the Food and Drug Administration.

 

In 2017, Greenbelt et. al. in a systematic review summarized the utility of bone turnover markers (BTMs) in the clinical management of osteoporosis, focusing primarily on postmenopausal osteoporosis. Testing using BTMs has to take into account the large number of preanalytic factors and comorbid clinical conditions influencing BTM levels. BTMs respond rapidly to changes in bone physiology, therefore, they have utility in determining patient response to and compliance with therapies for osteoporosis. However, they concluded that although BTMs are a useful adjunct for the diagnosis and therapeutic monitoring of bone metabolic disorders, their use has to be tempered by the known limitations in their clinical utility and preanalytic variables complicating interpretation. Glendenning et al. (2018) drew similar conclusions regarding the clinical usage of BTMs, noting that data is inconsistent.

 

Summary

Bone turnover markers (BTMs) are predictive of the rate of bone loss and in some studies risk of fracture, however, individual rates of bone loss and fracture are variable, limiting the usefulness of BTMs in predicting an individual’s fracture risk. Based on limited evidence in the literature there currently is no clinical utility for use BTMs in selecting candidates for bone density testing or for osteoporosis therapy. The decision to measure bone density should be based upon age and the presence of clinical risk factors for fracture. Similarly, the decision to treat patients should be based upon fracture risk assessment using bone mineral density (BMD) and clinical risk factors. Also, biologic and assay variability in BTM values has complicated their use in clinical practice. 

 

Bone Turnover Markers and Monitoring Response to Osteoporosis Treatment

Clinical Context and Test Purpose

Bone turnover makers might provide a more immediate assessment of treatment response and predict a change in bone mineral density (BMD) in response to treatment. Treatment-related changes in BMD occur very slowly. This fact, coupled with the precision of BMD technologies, has suggested that clinically significant changes in BMD could not be reliably detected until at least 2 years. In contrast, changes in bone turnover markers could be anticipated after 3 to 6 months of therapy.

 

The purpose of measuring for bone turnover markers (BTMs) in patients who have osteoporosis is to inform a decision on the effectiveness/response of the ostoporosis therapy, compliance of therapy, and duration of therapy (whether or when therapy should be discontinued and whether or when therapy should be resumed).

 

Patients

The relevant population of interest is individuals who are being treated for osteoporosis.

 

Interventions

The test being considered is bone turnover markers (BMTs) as an indicator of effictiveness/response to therapy, complince of therapy, and duration of therapy (whether or when therapy should be discontinued and whether or when therapy should be resumed). The variability in the measurement of bone turnover markers is related to a number of factors including sample handling and diurnal variation, postprandial status, menopausal status, exercise, alcohol use, medications, health conditions, and recent fractures.

 

Comparators

The following practice is currently being used to manage osteoporosis: BMD (bone mineral density) and DXA.

 

Outcomes

The general outcomes of interest are test validity and morbid events, more specifically, the association between test results and bone health, and the impact of the test results on bone fracture and health.

 

The beneficial outcome of a true test result is confirming effective treatment. The beneficial outcome of a true-negative test is to modify ineffective treatment.

 

Harmful outcomes of a false-positive result are not receiving the correct treatment. Harmful outcomes of a false-negative test are receiving unnecessary treatment.

 

Changes in bone turnover are expected to be observed in 3 to 6 months. The impact of changes in treatment on bone strength would be observed in 2 to 5 years.

 

Clinically Valid

Studies have examined the ability of bone turnover markers to evaluate response to osteoporosis treatment.

 

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

 

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

 

To provide clinical utility, bone turnover markers would have to provide information beyond that offered by bone mineral density (BMD) measurements, that has an impact on treatment decisions, and/or that leads to improved health outcomes. Bone turnover markers can be measured more frequency than BMD and thus could provide information with clinical utility.

 

Several randomized controlled trials (RCTs) have addressed whether measurement of bone turnover markers can improve adherence to oral bisphosphonate treatment. A 2014 systematic review by Burch et.al. (2014) 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 versus 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

While bone turnover markers (BTMs) may show a response to osteoporosis treatments, the optimal threshold for each marker is not well established or standardized. Their role in monitoring osteoporosis therapy relies upon defining the threshold reduction in BTM to attain optimal effects (i.e. fracture reduction), such thresholds are not universally accepted. While there are a number of approaches for monitoring response to antiresorptive therapy, there is no consensus on the optimal approach, and there are no prospective trials to define how to best incorporate markers into monitoring strategies. Also, biologic and assay variability in BTM values has complicated their use in clinical practice. There is also an interest in using BTMs to determine whether or when patients should discontinue bisphosphonates and whether or when they should resume therapy, however, there is currently no data to support this approach.  

 

Other Conditions Associated with High Rates of Bone Turnover

Clinical Context and Test Purpose

Bone turnover markers (BTMs) have been evaluated as markers of diseases associated with markedly high levels of bone turnover, such as Paget disease, primary hyperparathyroidism, renal osteodystrophy, diabetes and other endocrine disorders, oncologic indications including the monitoring of metastatic disease, rheumatologic conditions and vitamin D deficiency. The purpose of measuring bone turnover markers in patients who have conditions associated with high rates of bone turnover is to inform a decision whether to alter management.

 

Patients

The relevant population of interest is individuals who have conditions associated with high rates of bone turnover.

 

Interventions

The test being considered is bone turnover markers (BTMs).

 

Comparators

The following practices are currently being used to manage other conditions associated with high rates of bone turnover: bone density measurements (BMD) with dual energy x-ray absorptiometry and bone scintigraphy.

 

Outcomes

The general outcomes of interest are test validity and morbid events, more specifically, the association between rest results and bone health, and the impact of test results on bone fracture and health.

 

The beneficial outcome of a true test is undergoing correct treatment. The beneficial outcome of a true-negative test is to avoid an unnecessary or incorrect treatment.

 

Harmful outcomes of a false-positive result are unnecessary treatment. Harmful outcomes of a false-negative are not receiving correct treatment.

 

Timing

Changes in bone turnover are expected to be observed in 3 months. The impact of changes in treatment of bone strength would be observed within 2 to 5 years.

 

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

 

There is little published literature on use of bone turnover markers (BTMs) in the management of conditions associated with high rates of bone turnover such as primary hyperparathyroidism, Paget disease, renal osteodystrophy, diabetes and other endocrine disorders, oncologic indications including the monitoring of metastatic disease, rheumatologic conditions and vitamin D deficiency and many available studies were published 10 or more years ago.

 

Retrospective Studies

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.

 

Systematic Review

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.

 

Clinically Useful

A test is clinically useful if the use of the results inform management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

 

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because there are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

 

No RCTs of bone turnover markers in these conditions have been identified.

 

Indirect evidence on clinical utility rests on clinical validity and evidence that test results would change patient management. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

 

In 2017, Greenblatt et. al. completed a systematic review regarding bone turnover markers (BTMs) in the diagnosis and monitoring of metabolic bone disease to include the following conditions associated with high rates of bone turnover: renal disease (renal osteodystrophy and chronic kidney disease); oncologic indications including the monitoring of metastatic disease; rheumatologic conditions (rheumatoid arthritis); Paget’s disease; and secondary bone loss caused by diabetes, hyperparathyroidism and vitamin D deficiency that can predispose an individual to risk of fractures. Currently the literature is limited in the use of BTMs for identifying patients at risk of rapid bone loss. Comorbid clinical conditions can alter the relationship between BTMs to predict fracture risk, one of the best studied examples, BMD measurements underestimate facture risk in individuals with diabetes and how to best apply BTMs to estimate fracture risk in diabetic patients represents an area of active investigation. Despite findings linking increased concentrations of resorptive BTMs and fracture risk for conditions associate with high rates of bone turnover, few data exist regarding the utility of such measurement in routine clinical practice. The author concluded while BTMs may be a useful adjunct to diagnosis and therapeutic monitoring or bone metabolic disorders, their use has to be tempered by the known limitations in their clinical utility and preanalytic variables complicating interpretation. 

 

Summary

There is lack of evidence on how measurement of bone turnover markers can change management or improve health outcomes in patients who have disease/conditions associated with high bone turnover. Despite findings linking increased concentrations of resorptive BTMs and fracture risk for conditions associate with high rates of bone turnover, few data exist regarding the utility of such measurement in routine clinical practice. Biologic and assay variability in BTM values has also complicated their use in clinical practice.  

 

Summary of Evidence

Bone turnover markers (BTMs) in the serum or urine are sometimes used to assess risk of fracture, predict bone loss or assess response to antiresorptive therapy. BTMs such as pyridinoline, telopeptides and urinary cross-linked N-telopeptide of type I collagen (NTx) (which measure bone resorption) and osteocalcin and bone alkaline phosphatase (which measure bone formation) are obtained through minimally invasive tests involving serum and urine, making BTMs an attractive method for determining risk of fracture especially for osteoporosis management. Specifically, the information obtained could potentially be used to measure the rate of bone loss, assist in determining osteoporosis management, monitor changes in bone metabolism and density resulting from therapy, and manage osteoporosis therapy as needed for the individual patient. However, BTMs are controversial because of the complexity of interpreting the values for individual patients related to the intricacies inherent in bone metabolism, and the lack of standardization, which has led to unacceptable levels of variation between processing laboratories. 

 

While bone turnover markers (BTMs) may show a response to osteoporosis treatments, the optimal threshold for each marker is not well established or standardized. Their role in monitoring osteoporosis therapy relies upon defining the threshold reduction in BTM to attain optimal effects (i.e. fracture reduction), such thresholds are not universally accepted. While there are a number of approaches for monitoring response to antiresorptive therapy, there is no consensus on the optimal approach, and there are no prospective trials to define how to best incorporate markers into monitoring strategies. Also, biologic and assay variability in BTM values has complicated their use in clinical practice. There is also an interest in using BTMs to determine whether or when patients should discontinue bisphosphonates and whether or when they should resume therapy, however, there is currently no data to support this approach. The evidence is insufficient to determine the effects of the technology on health outcomes. 

 

For individuals with conditions associated with high rates of bone turnover other than age related osteoporosis (e.g. primary hyperparathyroidism, Paget disease, renal osteodystrophy, diabetes and other endocrine disorders, oncologic indications including the monitoring of metastatic disease, rheumatologic conditions and vitamin D deficiency) who receive measurement of bone turnover markers, (BTMs), despite findings linking increased concentrations of resorptive BTMs and fracture risk for conditions associate with high rates of bone turnover, few data exist regarding the utility of such measurement in routine clinical practice.  Biologic and assay variability in BTM values has also complicated their use in clinical practice.There is a lack of evidence on how the measurement of bone turnover markers (BTMs) can change patient management or improve net 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.”.

 

American College of Obstetrician and Gynecologists (ACOG)

In 2012; reaffirmed in 2016 the American College of Obstetrician and Gynecologists (ACOG) practice bulletin addresses the use of biochemical markers (bone turnover markers) to predict bone turnover in osteoporosis. The guideline states that bone turnover markers cannot be used to diagnose osteoporosis, and the usefulness of markers as an incentive for adherence has been questioned

 

U.S. Preventative Services Task Force

The U.S. Preventative Services Task Force (USPSTF) updated the 2011 recommendation on June 2018 regarding osteoporosis screening to prevent fractures. The 2018, recommendation recommends screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in women 65 years and older and in postmenopausal women younger than 65 years who are at increased risk of osteoporosis, as determined by a formal clinical risk assessment tool.

 

Clinical considerations of the recommendation states, the most commonly used bone measurement test used to screen for osteoporosis is central DXA. The screening testing information does not mention the use of bone turnover markers.

 

The American Association of Endocrinologists and American College of Endocrinology

In 2020, the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) updated their clinical practice guideline for the diagnosis and treatment of postmenopausal osteoporosis, the AACE and ACE remark that Bone turnover markers (BTMs) provide a dynamic assessment of skeletal activity and are useful modalities for skeletal assessment. Although they cannot be used to diagnose osteoporosis, elevated levels can predict more rapid rates of bone loss and are associated with increased fracture risk independent of BMD in some studies. Problems with the use of BTMs include their high cost (and variable insurance coverage), lack of appropriate reference ranges reported by commercial labs, and the influence of renal insufficiency on all markers except bone-specific alkaline phosphatase. Some experts routinely utilize BTMs in clinical practice, while others do not. 

 

Recommendations include the following: 

Q2. When Osteoporosis Is Diagnosed, What Is an Appropriate Evaluation? 

R7. Evaluate for causes of secondary osteoporosis (Grade B; BEL 1, downgraded due to limited evidence). 

R8. Evaluate for prevalent vertebral fractures (Grade B; BEL 2). 

R9. Consider using bone turnover markers in the initial evaluation and follow-up of osteoporosis patients. Elevated levels can predict more rapid rates of bone loss and higher fracture risk (Grade A; BEL 1).

 

Q6. How Is Treatment Monitored? 

R27. Obtain a baseline axial (lumbar spine and hip; 1/3 radius if indicated) dual-energy X-ray absorptiometry (DXA) and repeat DXA every 1 to 2 years until findings are stable. The 1/3 radius may be considered as an alternate site when the lumbar spine/hip are not evaluable or as an additional site in patients with primary hyperparathyroid¬ism. Continue with follow-up DXA every 1 to 2 years or at a less frequent interval, depending on clinical circum¬stances (Grade B; BEL 2). 

R28. Monitor serial changes in lumbar spine, total hip, or femoral neck bone mineral density; if lumbar spine, hip, or both are not evaluable, monitoring with 1/3 radius site may be acceptable but is limited by a small area and a very large least significant change (LSC) (Grade B; BEL 1, down¬graded due to limited evidence). 

R29. Follow-up of patients should ideally be conducted in the same facility with the same dual-energy X-ray absorp¬tiometry (DXA) system, provided the acquisition, analy¬sis, and interpretation adhere to International Society for Clinical Densitometry DXA best practices (Grade C; BEL 2, downgraded due to limited evidence).

30. Consider using bone turnover markers (BTMs) for assessment of patient compliance and efficacy of therapy. Significant reductions in BTMs are seen with antiresorp¬tive therapy and have been associated with fracture reduc¬tion, and significant increases indicate good response to anabolic therapy (Grade B; BEL 1, adjusted down due to limited evidence).

 

Q7. What Is Successful Treatment of Osteoporosis? 

R31. Consider stable or increasing bone mineral density, with no evidence of new fractures or vertebral fracture progression as a response to therapy for osteoporosis (Grade A; BEL 1). 

R32. Consider bone turnover markers at or below the medi¬an value for premenopausal women as a target for response to therapy for patients taking antiresorptive agents. Consider significant increases in bone formation markers as a pharmacologic response to anabolic therapy (Grade B; BEL 1, adjusted down due to limited evidence).

R33. Consider alternative therapy or reassessment for causes of secondary osteoporosis in patients who have recurrent fractures or significant bone loss while on ther¬apy. Although a single fracture while on therapy is not necessarily evidence of treatment failure, consider two or more fragility fractures are evidence of treatment failure (Grade B; BEL 1, downgraded due to limited evidence).

 

Q2.1. What Laboratory Testing Is Recommended to Assess for Causes of Secondary Osteoporosis? 

An appropriate medical evaluation is indicated in all women with postmenopausal osteoporosis and at high fracture risk to identify coexisting medical conditions that cause or contribute to bone loss. Some of these disorders may be asymptomatic and require laboratory testing for detection. 

 

Because of the high prevalence of causes of second¬ary osteoporosis even in apparently healthy, postmeno¬pausal women, laboratory testing should be considered for all women with osteoporosis. This is reasonable, as a few simple laboratory tests provided useful information in 40 to 85% of women who did not have clinical evidence of secondary osteoporosis in several studies. If medical history, physical findings, or laboratory test results suggest causes of secondary osteoporosis, additional labo¬ratory evaluation is warranted and may include, but is not limited to: a complete blood count, comprehensive metabolic panel, 25-hydroxyvitamin D (25[OH]D), intact parathyroid hormone (PTH), phos¬phate, and a 24-hour urine collection for calcium, sodium, and creatinine. The 24-hour urine calcium collection must occur after the patient is replete of vitamin D and has been on a reasonable calcium intake (1,000 to 1,200 mg/d) for at least 2 weeks. If the patient is receiving thyroid hormone or there is a suspicion for hyperthyroidism, thyroid-stimulat¬ing hormone should also be obtained. Celiac antibodies or serum/urine protein electrophoresis could also be obtained.

 

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 (BTMs) is considered investigational to determine fracture risk in patients with osteoporosis or with age related risk factors for diagnosing osteoporosis.

 

Measurement of bone turnover markers (BTMs) is considered investigational to determine response to therapy or duration of therapy in patients who are being treated for osteoporosis.

 

While bone turnover markers (BTMs) may show a response to osteoporosis treatments, the optimal threshold for each marker is not well established or standardized. Their role in monitoring osteoporosis therapy relies upon defining the threshold reduction in bone turnover markers (BTM) to attain optimal effects (i.e. fracture reduction), such thresholds are not universally accepted. While there are a number of approaches for monitoring response to antiresorptive therapy, there is no consensus on the optimal approach, and there are no prospective trials to define how to best incorporate markers into monitoring strategies. Also, biologic and assay variability in bone turnover markers (BTM) values has complicated their use in clinical practice. There is also an interest in using bone turnover markers (BTMs) to determine whether or when patients should discontinue bisphosphonates and whether or when they should resume therapy, however, there is currently no data to support this approach. The evidence is insufficient to determine the effects of the technology on health outcomes. 

 

Measurement of bone turnover markers (BTMs) is considered investigational in the management of patients with conditions associated with high rates of bone turnover, including but not limited to the following:

  • Paget’s disease
  • Primary hyperparathyroidism
  • Renal osteodystrophy
  • Diabetes
  • Oncologic indications including the monitoring of metastatic disease
  • Rheumatologic conditions
  • Vitamin D deficiency

 

For individuals with conditions associated with high rates of bone turnover other than age related osteoporosis who receive measurement of bone turnover markers (BTMs), despite findings linking increased concentrations of resorptive bone turnover markers (BTMs) and fracture risk for these conditions, few data exist regarding the clinical utility of such measurement in routine clinical practice. Biologic and assay variability in bone turnover maker (BTM) values has also complicated their use in clinical practice. There is a lack of evidence on how the measurement of bone turnover markers (BTMs) can change patient management or improve net health outcomes. The evidence is insufficient to determine the effects of the technology on net health outcomes. 

 

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)

 

Selected References:

  • 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 May 30, 2018.
  • 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
  • Abe Y, Ishikawa H, Fukao A. Higher efficacy of urinary bone resorption marker measurements in assessing response to treatment for osteoporosis in postmenopausal women. Tohoku J Exp Med Jan 2008;21491):51-59. PMID 18212487
  • United States Preventative Services Task Force. Osteoporosis to Prevent Fractures: Screening. Updated June 2018.
  • UpToDate. Clinical Manifestations and Diagnosis of Paget Disease of Bone. Julia F. Charles M.D., PhD. Topic last updated February 7, 2018.
  • North American Menopause Society. Management of Osteoporosis in Postmenopausal women: 2010 position statement. Menopause Jan-Feb 2010;17(1):25-54. PMID 20061894
  • Eastell R, Rosen CJ, Black DM, et. al. Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2019 Mar 16;104(5). PMID 30907953
  • Camacho P, Petak S, Binkley N, et. al. American Association of Clinical Endocrinologists/American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis 2020 Update. Endocr Pract 2020 May;26(Suppl 1):1:46. PMID 32427503
  • UpToDate. Use of Biochemical Markers of Bone Turnover in Osteoporosis. Harold N. Rosen M.D. Topic last updated November 12, 2019. 
  • UpToDate. Bone Physiology and Biochemical Markers of Bone Turnover. Harold N. Rosen M.D. Topic last updated August 29, 2019.
  • Talwar S., Griffing G. et. al. Born Markers in Osteoporosis. MedScape. Updated September 11, 2020
  • Greenblatt M, Tsai J, Wein M, et. al. Bone turnover markers in the diagnosis and monitoring of metabolic bone disease. Clin Chem 2017 Feb;63(2):464-474. PMID 27940448
  • Glendenning P, Chubb SAP, Vasikaran S. Clinical utility of bone turnover markers in the management of common metabolic bone diseases in adults. Clin Chim Acta 2018 Jun;481:161-170. PMID 29544749
  • Crandall C, Vasan S, LaCroix A, et. al. Bone turnover markers are not associated with hip fracture risk: a case-control study in the Women’s Health Initiative. J Bone Miner Res 2018 Jul;33(7):1199-1208. PMID 29923225

 

Policy History:

  • February 2021 - Annual Review, Policy Revised
  • February 2020 - Annual Review, Policy Revised
  • February 2019 - Annual Review, Policy Renewed
  • 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.