TO THE INSURANCE COMPANY OF  ---------------------------

My patient informed me that you have refused to pay for markers of bone resorption (collagen crosslinks) because you claim that these tests are "experimental".   This is not true.  A paper published in 2012 has reviewed 43 original research studies that related the relationship between the markers and either bone loss or fracture rates.  They showed that the markers can significantly predict future fractures in elderly patients, and that the markers are correlated with the bone loss, especially in older patients1.  In addition, biochemical markers have been reported in virtually every major clinical trial of an osteoporosis medication, and in hundreds of studies about osteoporosis and other metabolic bone diseases.  The effective anti-resorptive medications (estrogen, bisphosphonates, raloxifene, denosumab, calcitonin) all decrease the collagen-based markers (N-telopeptide and C-telopeptide).  The bisphosphonates reduce these markers dramatically. The test has FDA approval since 2002 and is covered by Medicare.  This test should cost about $50, but some labs charge more than that.

This lab test is indicated for -------------------------------- because 

At the University of Washington Metabolic Bone Clinic, we do not advocate using these tests for screening, because they have not been studied as extensively as bone density.  We also do not use them for routine followup of patients who are on therapy and who have no problems.  At this time, we also do not use them to decide initial treatment in ordinary cases.  However, there has been one report from the Fracture Intervention Trial which showed that patients with low bone turnover did not have fewer fractures with alendronate (compared to placebo), whereas those with high bone turnover had a very significant reduction in fractures2.   Thus, in complex cases or patients with secondary osteoporosis, it is necessary to know the bone resorption rate.

Bone turnover markers are indicated in complicated patients in whom the treatment decisions are difficult.  Examples are patients who have been on bisphosphonates for greater than five years, patients taking aromatase inhibitors, patients with malabsorption, patients with inherited diseases that cause bone pain and fractures, patients with other chronic medical problems that also affect the skeleton.  With bisphosphonates, longer durations or use are associated with risks of brittle bone and femur fractures.  The FDA has recently concluded that the fracture risk is not further reduced by continuing the medication beyond five years.  The N-telopeptide remains low for up to five years after discontinuation, and this is the best way to tell if the drug is still active.  Bone density is more expensive and it decreases even when the bone resorption is still suppressed.

There is a compelling rationale to use the collagen-based turnover markers in situations where decisions must be made when there is not enough evidence.   In the FIT trial of alendronate, we reported that the change in bone turnover markers was significantly related to the reduction in fracture risk, and the effect was at least as strong as that observed with a one-year change in bone density.  Those with a 30% decrease in the bone alkaline phosphatase had a significant reduction in fracture risk3.

Similarly, with risedronate the change in NTX accounted for half of the effect on fracture reduction during the clinical trial, and there was little further improvement in fracture benefit below a decrease of 35-40%4.  The baseline NTX in these clinical trials was about 70 mol BCE/mmol in the risedronate study and 60 in the alendronate study, and in both the fracture reduction was seen at a level below 40mol BCE/mmol.  The FLEX study measured the NTX after 5 years and the average was 19 mol BCE/mmol.  This increased to 22 mol BCE/mmol after 3 years without alendronate.  At 5 years the turnover markers had gradually increased but were still 7 to 24% lower than baseline5. These markers have a diurnal rhythm and daily variation, but despite these small errors they do help identify low bone resorption.  For example, the daily variation is approximately 20%, but alendronate decreases the value by over 60%.  The NTX is the most economical marker, and my patients prefer a urine sample to a blood test. Therefore, we measure the NTX and consider values lower than 40 mol BCE/mmol to be satisfactory.

This test should be covered by insurance when it is used for diagnostic purposes in challenging clinical situations.  It is indicated for follow up of patients after prolonged bisphosphonate use6, or in patients who show signs of failure to respond to treatment.  This is less expensive than bone density testing, which is covered by all the insurance plans.  There have been hundreds of studies using these markers and they are not experimental. All of the clinicians I know who are experts in metabolic bone disease use markers of bone turnover to guide therapy for their complicated patients.

	1. Chopin Fl, Biver Em, Funck-Brentano, et al. Prognostic interest of bone turnover markers in the management of postmenopausal osteoporosis. Joint Bone Spine 2012;79:26-31.
	2. Bauer DC, Garnero P, Hochberg MC, et al. Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the fracture intervention trial. J Bone Miner Res 2006;21:292-9.
	3. Bauer DC, Black DM, Garnero P, et al. Change in bone turnover and hip, non-spine, and vertebral fracture in alendronate-treated women: the fracture intervention trial. J Bone Miner Res 2004;19:1250-8.
	4. Eastell R, Hannon RA, Garnero P, Campbell MJ, Delmas PD. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate: review of statistical analysis. J Bone Miner Res 2007;22:1656-60.
	5. Ensrud KE, Barrett-Connor EL, Schwartz A, et al. Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the Fracture Intervention Trial long-term extension. J Bone Miner Res 2004;19:1259-69.
	6. Ott, SM. What is the optimal duration of bisphosphonate therapy? Cleve Clin J Med 2011; 78:619-30.