Medical Policy: 02.04.13
Original Effective Date: October 2007
Reviewed: February 2018
Revised: February 2016
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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.
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.
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.
|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®)|
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.
Few studies have directly addressed whether any bone turnover markers beyond BMD measurements are independent predictors of fracture risk. One study conducted in men and another conducted in women are described next.
A 2013 analysis of the Japanese Population-based Osteoporosis (JPOS) study data included postmenopausal women and adjusted for BMD. The study involved baseline surveys, bone turnover marker assessment and BMD measurements, and 3 follow-ups over 10 years. At baseline, 851 women who participated were ages 50 years or older and eligible for vertebral fracture assessment. Of these, 730 women had BMD measurements taken at the initial examination and at one or more follow-ups. Women with early menopause (ie, <40 years old), with a history of illness or medication known to affect bone metabolism, or with incomplete data were excluded. After exclusions, 522 women were evaluated.
Over a median follow-up of 10 years, 81 (15.5%) of 522 women were found on imaging to have an incident vertebral fracture. Seventy-eight of the 81 women with radiographically detected vertebral fractures were more than 5 years from menopause at baseline. Risk of incident vertebral fractures adjusted for BMD T-scores was significantly associated with several bone turnover markers, specifically alkaline phosphatase (ALP), urinary total deoxypyridinoline, and urinary free deoxypyridinoline. For example, in a multivariate model adjusting for various covariates including femoral neck BMD, the risk of developing a fracture per standard deviation of change in ALP was increased by 33% (relative risk, 1.33; 95% confidence interval [CI], 1.06 to 1.66). Risk of incident vertebral fracture was not significantly associated with other bone turnover markers including osteocalcin (OC) and cross-linked C-telopeptide (CTX). It is not clear how generalizable findings from this study are, given the association between subsequent fracture risk and certain bone turnover markers, and the lack of association between fracture risk and other bone turnover markers. Study analysis also excluded a large number of women due to incomplete data.
In 2009, Bauer et. al. completed a subgroup analysis of prospectively collected data from the Osteoporotic Fractures in Men (MrOS) study to test the hypothesis that men with higher levels of bone turnover would have accelerated bone loss and elevated risk of fracture. Baseline levels of bone turnover markers were compared in 384 men, ages 65 years or older, who had nonspine fractures over an average follow-up of 5 years, with 885 men without nonspine fracture. A second analysis compared 72 hip fracture cases and 993 controls without hip fracture. After adjusting for age and recruitment site, the association between nonspine fracture and quartile of the bone turnover marker procollagen type 1 N-terminal propeptide (PINP) was statistically significant (for each analysis, p<0.05 was used). The associations between nonspine fracture and quartiles of the 2 other bone turnover markers, beta C-terminal cross-linked telopeptide of type 1 collagen (b-CTX) and tartrate-resistant acid phosphatase 5b (TRACP5b) were not statistically significant. Moreover, in the analysis adjusting only for age and recruitment site, when the highest quartile of bone turnover markers was compared with the lower 3 quartiles, the risk of nonspine and hip fractures was significantly increased for PINP and b-CTX, but not TRACP5b. After additional adjustment for baseline BMD, or baseline BMD and other potential confounders, there were no statistically significant relations between any bone turnover marker and fracture risk. The authors concluded in this large prospective study of contemporary bone turnover markers (BTM), bone loss, and fracture in older men, it found that elevated serum levels of PINP, BCTX, and TRACP5b are associated with higher rates of hip bone loss, but the associations were insufficient strength to accurately predict bone loss in any individual subject. Although the data suggested that higher serum of PINP and BCTX at baseline are associated with an increased risk of subsequent hip and nonspine fracture in older men, none of the relationships between BTMs and fracture risk were statistically significant after accounting for baseline BMD. Additional prospective studies are warranted, particularly with novel biomarkers, but these results suggest that a single serum measurement of PINP, BCTX or TRACP5b does not strongly predict future fracture risk in men and should not be incorporated into evolving risk stratification methods.
Systematic reviews have examined the association between bone turnover markers and fracture risk, but have not analyzed the predictive value beyond BMD. For example, a 2014 meta-analysis by Johansson et. al. focused on PINP and CTX markers and examined their ability to predict future fracture risk. Reviewers included 10 prospective cohort studies in which bone turnover markers were measured at baseline and incident fractures were recorded. Pooled analyses were performed on a subset of these studies. Meta-analysis of 3 studies found a statistically significant association between baseline PINP and subsequent fracture risk (hazard ratio [HR], 1.23; 95% CI, 1.09 to 1.39). Similarly, a meta-analysis of 6 studies found an association between CTX and fracture risk (HR=1.18; 95% 1.09 to 1.29). None of the individual studies adjusted for BMD and, consequently, the pooled analyses do not reflect the ability of bone turnover markers to predict fracture risk beyond BMD.
A 2012 systematic review by Biver et. al. did not find a statistically significant association between OC (another bone turnover marker) and fracture risk. When findings from 3 studies were pooled, the mean difference in OC levels in patients with and without vertebral fractures was 1.61 ng/mL (95% CI, -0.59 to 3.81 ng/mL). Both systematic reviews noted a high degree of heterogeneity among the published studies identified.
Some studies have found statistically significant associations between bone turnover markers and fracture risk, but there is insufficient literature on any specific marker. An analysis of MrOS data found a significant association between PINP and risk of nonspine fracture in men, and the JPOS study from Japan found a significant association between ALP, urinary total deoxypyridinoline, and urinary free deoxypyridinoline and risk of incident vertebral fracture in women. Overall, the evidence does not suggest that any bone turnover markers is an independent predictor of fracture risk, beyond BMD.
A 2008 randomized trial assessing an osteoporosis treatment (N=43) found that urinary cross-linked N-terminal telopeptides (NTP) provided a more sensitive measure of treatment response than serum levels. Another small randomized trial from Japan measured OC levels in response to osteoporosis treatment in 109 postmenopausal women. Authors found that undercarboxylated OC levels in serum were significantly lower at 1 month in the group receiving active treatment for osteoporosis than the control intervention; the implication for fracture prevention was not studied.
A 2011 systematic review by Funck-Brentano et. al. assessed whether early changes in serum biochemical bone turnover markers predict the efficacy of osteoporosis therapy. Reviewers included 24 studies that presented correlations between bone turnover markers and the outcomes of fracture risk reduction or change in BMD. Five studies (including the Bauer study, previously described) reported on fracture risk, and 20 studies reported on BMD changes. Reviewers discussed study findings qualitatively but did not pool study results. The evidence did not support a correlation between short-term changes in bone turnover markers and fracture risk reduction. In addition, few studies were available on this topic, leading to the conclusion that bone turnover markers “have shown limited value” as a technique to monitor osteoporosis therapy. Subsequently, additional study on this topic was published by Baxter et. al. (2013). This retrospective review evaluated 200 patients commencing treatment with bisphosphonates for osteoporosis or osteopenia. Investigators found a statistically significant inverse correlation between change in urine NTX at 4 months and change in spine BMD at 18 months (r=0.33, p<0.001). There was no significant association between change in urine NTX and hip BMD.
The available evidence on the association between any specific bone turnover marker and response to osteoporosis treatment is limited in quantity and quality. While some individual studies have reported positive correlations for markers (e.g. PINP in the FIT), a body of evidence in support of any specific marker is lacking. As a result, the evidence does not permit conclusions about whether bone turnover markers are an independent predictor of treatment response.
Several randomized controlled trials (RCTs) have addressed whether measurement of bone turnover markers can improve adherence to oral bisphosphonate treatment. A 2014 systematic review identified 5 RCTs and did not find significant differences in compliance rates between groups that did and did not receive feedback on bone turnover marker test results. Study data were not pooled. Reviewers noted a high baseline compliance rate that limited the studies ability to detect an impact of feedback. As an example, a 2012 industry-sponsored study by Roux et. al. from France randomized physicians to manage patients on oral ibandronate given monthly with a collagen cross-links test or usual care. In the collagen cross-links group, bone marker assessment was done at baseline and week 5 for the week 6 visit. A standardized message was delivered to patients regarding change in CTX since baseline. If the decrease in CTX was more than 30% of the baseline value, patients were told that the treatment effect was optimal. If not, they were told that the treatment effect was suboptimal and given additional advice. Patients told they had a suboptimal response were retested with CTX at week 13 for the week 14 visit. The primary outcome was the proportion of patients who were adherent at 1 year. After 1 year, rates of adherence to ibandronate were 74.8% in the collagen cross-links group and 75.1% in the usual care group; the difference between groups was not statistically significant (p=0.93). There was also no statistically significant difference in the proportion of patients having taken at least 10 of 12 pills (82.4% in the collagen cross-links group vs 80.0% in the usual care group). In this study, monitoring bone markers and providing this information to patients did not improve adherence to oral osteoporosis medication.
There is a limited amount of evidence on the impact of bone turnover markers on the management of osteoporosis. Individual RCTs and a meta-analysis of these RCTs have not found that feedback on bone turnover marker results improves adherence rates. No studies were identified that evaluated whether the use of bone turnover markers leads to management changes that are expected to improve outcomes.
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.
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.
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.
For individuals with osteoporosis or risk factors for age-related osteoporosis who receive measurement of bone turnover markers, the evidence includes observational studies on the association between markers and osteoporosis and fracture risk and systemic reviews of those studies. Studies have suggested that bone turnover marker levels may be independently associated with osteoporosis and fracture risk in some groups, but there is insufficient evidence reporting an association for any specific marker. Questions remain whether bone turnover markers are sufficiently sensitive to reliably determine individual treatment responses. In addition, controlled studies do not provide sufficient evidence that bone turnover marker measurement improves adherence to treatment, impacts management decisions, and/or improves health outcomes such as reducing fracture rates. The evidence is insufficient to determine the effects of the technology on net health outcomes.
For individuals with conditions associated with high rates of bone turnover other than age related osteoporosis (e.g. hyperparathyroidism, Paget disease, renal osteodystrophy) who receive measurement of bone turnover markers, the evidence includes observational studies on the association between markers and disease activity and systemic reviews of those studies. The largest amount of evidence has been published on Paget disease; a systematic review found correlations between several bone turnover markers and disease activity prior to and/or after bisphosphonate treatment. There is a lack of evidence on how the measurement of bone turnover markers can change patient management or improve health outcomes. The evidence is insufficient to determine the effects of the technology on the net health outcomes.
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:
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.”
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.”
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.”.
The U.S. Preventative Services Task Force (USPSTF) recommendations on osteoporosis screening are in the process of being updated. The 2011 recommendation on osteoporosis screening addresses dual-energy x-ray absorptiometry (DXA) testing but does not mention bone turnover markers.
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:
Measurement of bone turnover markers is considered investigational in the diagnosis and management of osteoporosis.
The literature suggests that bone turnover marker levels may be independently associated with osteoporosis and fracture risk in some groups, but there is insufficient evidence reporting an association for any specific marker. Questions remain about whether bone turnover markers are sufficiently sensitive to reliably determine individual treatment responses. In addition, there is insufficient evidence from controlled studies that bone turnover marker measurement improves adherence to treatment, impacts management decisions, or improves health outcomes such as reducing fracture rates. Therefore, the use of bone turnover markers for the diagnosis and management of osteoporosis is considered investigational.
Measurement of bone turnover markers is considered investigational in the management of patients with conditions associated with high rates of bone turnover, including but not limited to Paget’s disease, primary hyperparathyroidism and renal osteodystrophy.
There is little published literature on the use of bone turnover markers in the management of conditions associated with high rates of bone turnover. The evidence includes observational studies on the association between markers and disease activity and systemic reviews of those studies. There is a lack of evidence on how measurement of bone turnover markers can change patient management or improve health outcomes in patients with conditions associated with high bone turnover including but not limited to Paget’s disease, primary hyperparathyroidism, and renal osteodystrophy. Therefore, the evidence is insufficient to determine the effects on net health outcomes and utilization of bone turnover marker testing for these other conditions is considered investigational.
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