Medical Policy: 02.04.13 

Original Effective Date: October 2007 

Reviewed: February 2020 

Revised: February 2020 

 

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 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

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)

 

Bone Density 

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 Context and Test Purpose

One potential purpose of measuring for bone turnover markers 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.

 

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 as an adjunct to bone mineral density (BMD). 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.

 

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: Bone Turnover Markers and Future Fracture Risk

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

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.

 

Summary

Few studies have directly addressed whether any bone turnover markers beyond bone mineral density (BMD) measurements are independent predictors of fractur risk. Some studies have found statistically significant association between bone turnover markers and fracture risk, but there is insufficient literature on any specific marker. An analysis of Osteoporotic Fractures in Men (MrOS) data found a significant association between procollagen type 1 N-terminal propeptide (PINP) and risk of nonspine fracture in men, and the Japanese Population-Based Osteoporosis (JPOS) study found a significant association between alkaline phosphatase (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.

 

Bone Turnover Markers and 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 in patients who have suspected osteoporosis is to inform a decision whether to change therapy.

 

Patients

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

 

Interventions

The test being considered is bone turnover markers as an indicator of response to therapy. 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.

 

Systematic Reviews

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.

 

Randomized Controlled Trails

In 2006, Bauer et. al. examined the effect of pretreatment bone turnover on the antifracture efficacy of daily alendronate given to postmenopausal women. They randomized women 55-80 years of age with femoral neck bone mineral density (BMD) T scores ≤ -1.6 to alendronate (ALN), 5-10 mg/day (n = 3105), or placebo (PBO; n = 3081). At baseline, 3495 women were osteoporotic (femoral neck BMD T score ≤ -2.5 or prevalent vertebral fracture), and 2689 were not osteoporotic (BMD T score > -2.5 and no prevalent vertebral fracture). Pretreatment levels of bone-specific alkaline phosphatase (BSALP), N-terminal propeptide of type 1 collagen (PINP), and C-terminal cross-linked telopeptide of type 1 collagen (sCTx) were measured in all participants using archived serum (20% fasting). The risk of incident spine and non-spine fracture was compared in ALN- and PBO-treated subjects stratified into tertiles of baseline bone marker level. During a mean follow-up of 3.2 years, 492 non-spine and 294 morphometric vertebral fractures were documented. Compared with placebo, the reduction in nonspine fractures with ALN treatment differed significantly among those with low, intermediate, and high pretreatment levels of PINP levels (p = 0.03 for trend). For example, among osteoporotic women in the lowest tertile of pretreatment PINP (<41.6 ng/ml), the ALN versus PBO relative hazard for nonspine fracture was 0.88 (95% CI: 0.65, 1.21) compared with a relative hazard of 0.54 (95% CI: 0.39, 0.74) among those in the highest tertile of PINP (>56.8 ng/ml). Results were similar among women without osteoporosis at baseline. Although they did not reach statistical significance, similar trends were observed with baseline levels of BSALP. Conversely, spine fracture treatment efficacy among osteoporotic women did not differ significantly according to pretreatment marker levels. Spine fracture treatment efficacy among non-osteoporotic women was related to baseline BSALP (p = 0.05 for trend). The authors concluded, alendronate non-spine fracture efficacy is greater among both osteoporotic and non-osteoporotic women with high pretreatment PINP. If confirmed in other studies, these findings suggest that bisphosphonate treatment may be most effective in women with elevated bone turnover.

 

A small open-label randomized placebo controlled trial in 2008 by Abe et. al. assessed the efficacy of urinary bone resportion marker measurements in assessing response to treatment for osteoporosis in postmenopausal women (N=43). Overall, 21 women in the osteoporosis treatment group and 19 women in the placebo group completed the study. There was a significant reduction in urinary NTX in the treatment group, which was detectable as early as 4 weeks and maintained until 16 weeks, compared with the placebo group. On the other hand, serum NTX did not show a significant reduction in the treatment group compared with the placebo group until 16 weeks. These results indicate that urinary NTX measurements are more sensitive and show higher efficacy than serum NTX measurements for assessing treatment effect during the early phase of osteoporosis treatment in postmenopausal women.

 

In 2009, Shiraki et. al. conducted a randomized prospective study on the effect of vitamin K(2) (menatetrenone) on bone turnover in postmenopausal patients with osteoporosis. A 6-month open-label, randomized prospective study was conducted in 109 patients. The control group (n = 53) received calcium aspartate (133.8 mg of elemental calcium daily), while the menatetrenone group (n = 56) received 45 mg of menatetrenone daily for 6 months. Serum and urinary levels of bone turnover markers were monitored. The serum level of undercarboxylated osteocalcin (uc-OC) was significantly lower (P < 0.001) in the menatetrenone group than in the control group (at 1 month), while there was a higher level of osteocalcin containing gamma-carboxylated glutamic acid (Gla-OC) in the menatetrenone group than the control group (P = 0.018). Significant differences of uc-OC and Gla-OC between the two groups were observed from 1 month onward. In addition, a higher level of intact osteocalcin was found in the menatetrenone group compared with the control group after 6 months (P = 0.006). Assessment of bone resorption markers showed that menatetrenone therapy was associated with significantly higher urinary N-telopeptide of type I collagen (NTX) excretion compared with the control group after 6 months, while there was no significant difference of urinary deoxypyridinoline excretion between the two groups. The authors concluded, one month of menatetrenone therapy enhanced the secretion and gamma-carboxylation of osteocalcin, while urinary NTX excretion was increased after 6 months of treatment. Further investigations are required to determine whether the effects of menatetrenone on bone turnover are associated with fracture prevention.

 

Summary

The available evidence on the association between any specific bone turnover marker and response to osteoporosis treatment is limited in quantity and quality. While some individual studies have reported positive correlations for markers N-terminal propeptide of type 1 collagen (PINP) in the Fracture Intervention Trial (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.

 

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

There is a limited amount of evidence on the impact of bone turnover markers on the management of osteoporosis. Individual randomized controlled trials (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.

 

Other Conditions Associated with High Rates of Bone Turnover

Clinical Context and Test Purpose

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

 

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 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.

 

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.

 

Summary

There is little published literature on use of bone turnover markers in the management of conditions associated with high rates of bone turnover (e.g. primary hyperparathyroidism, Paget disease, renal osteodystrophy), and many available studies were published 10 or more years ago. Large prospective trials are needed to establish clinical validity.

 

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.

 

Evidence is insufficient to support that results or bone marker tests would affect patient management, therefore, no inference can be made about clinical utility.

 

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 associated with high bone turnover. Although studies have demonstrated an association between bone markers and disease activity, the clinical utility of monitoring bone turnover markers for the management of diseases associated with high bone turnover is uncertain.

 

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. Overall, the evidence does not suggest that any bone turnover marker is an independent predictor of fracture risk, beyond BMD (bone mineral density). The evidence is insufficient to determine the effects of the technology on health outcomes.

 

For individuals who are being treated for osteoporosis who receive a measurement of bone turnover markers to determine response to therapy, the evidence includes observational studies on the association between markers and osteoporosis and fracture risk and systematic reviews of those studies. 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 improves treatment 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. 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. primary 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) 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 Endocrine Society

The 2019 guidelines from the Endocrine Society recommend that in postmenopausal women with a low BMD and at high-risk of fractures who are being treated for osteoporosis, monitoring should be conducted by dual-energy X-ray absorptiometry at the spine and hip every 1 to 3 years. The Society considers measuring bone turnover markers (serum CTX for antiresorptive therapy or P1NP for bone anabolic therapy) as an alternative way of monitoring for poor response or nonadherence to therapy. The society notes that there is uncertainty over what constitutes an optimal response to treatment, but some experts suggest that a meaningful change is approximately 40% when compared from before to 3 to 6 months after starting treatment.

 

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 to determine fracture risk in patients with osteoporosis or with age related risk factors for osteoporosis.

 

The evidence is insufficient that any bone turnover marker is an independent predictor of facture risk, beyond bone mineral density (BMD). The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

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

There is a limited amount of evidence on the impact of bone turnover markers on the management of osteoporosis and no studies that evaluated whether the use of bone turnover makers leads to management changes that are expected to improve outcomes. The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

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 a lack of evidence on how the measurement of bone turnover markers can change patient management or improve health outcomes in this patient population. 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)
  • 84080 phosphatase, alkaline; isoenzymes (used for Ostase test)

 

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

 

Policy History:

  • 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.