Men's Osteoporosis Support Group

The use of biochemical markers in osteoporosis

Clin Lab Med.  2004 Mar;24(1):175-97, Hammett-Stabler CA, PMID:15157562. When reading the osteoporosis literature there are very frequent references to the use of biochemical markers to track what is happening to the bone metabolism.  These markers are generally divided into two main categories:  Markers of bone resorption and formation.  Within those main headings, biochemical markers are used to measure bone metabolism  products (analytes) either in the  serum, plasma, or urine. The author notes that, "The two processes of resorption and formation are closely linked and not independent of each other."  Additionally, also confounding their use for osteoporosis, one should realize that none of the markers is unique to bone and that many variables influence bone turnover, including: hormones, sunlight exposure, weight-bearing exercise, immobility, and nutritional status.  Readers must realize, "Release of the markers into the circulation reflects the influence of these variables, where their measurement depends upon metabolism and, if measured in urine, on renal function."  Understanding these confounders should help explain why biochemical markers are not totally reliable. . Based upon the Hammett-Stabler paper, my intent with this page is to summarize the types of biochemical markers available, what they are markers for, how they are used, and, if possible, how important and useful each one is. I hope men reading this page will have valuable information about if or when they might want biochemical markers used in the diagnosis and treatment of their osteoporosis.

What is normal for biochemical marker levels?  Obviously, you can't determine if biochemical markers are abnormal unless you have a normal standard.  Since bone metabolism isn't stable throughout life, the norm varies according to age and other factors.  The highest concentration of biochemical markers is encountered in the immediate neonatal period. From about age 3 months to 3 years, levels decline as growth slows. At puberty, concentrations of bone markers rise and typically peak from 12 to 14 years of age with girls peaking earlier than boys. About age 18 to 20 years individuals achieve 95% of their bone density and biochemical markers decline to adult levels. Levels remain fairly stable for the next 20 to 30 years with fluctuation in response to diurnal and seasonal changes in bone remodeling. Turnover increases in women after menopause with a slowing after 4 to 8 years.  Turnover then slows but remains higher than premenopausal levels.  Men's levels are the lowest between 50 and 60 years of age, remaining fairly constant after that.  There are also normal daily patterns with the highest concentrations in both serum and urine in the early morning.  Urine analytes tend to have the greatest intra-individual and intra-day variation.

Markers of Resorption.  Note that many resorption markers identify collagen cross-links (CCL) which are formed between neighboring collagen molecules and act to strengthen and stabilize type I collagen of bone. Think of collagen as the meshwork around which calcium phosphate is inserted to create solid bone.  A good analogy would be collagen acting like the iron rods that reinforce concrete. During bone resorption the CCLs are released into the circulation and secreted in sera and urine where they can be measured.

Markers of bone formation:

NOTES:  There are daily, seasonal, and intra-individual fluctuations in markers which complicates interpretation of results. Best use of these tests is to test effectiveness of drug therapy, especially since marker of resorption test analyte changes occur within 1 to 3 months and markers of formation within 3 to 6 months. Bone mineral density (BMD) with dual-energy X-ray absorptiometry (DXA), however, can take up to two years to detect changes. The author  notes, "None of the currently used biochemical markers has sufficient specificity to be diagnostic for any metabolic bone disease, including osteoporosis, because the products we measure are not unique to bone." Urinary NTx has been the most popular test because, up until the FDA approval of Forteo, all the approved osteoporosis medications blocked the resorption of bone.  The favored marker for Forteo will probably require the use of OC, but this is still a questionable area where more research is needed.

Editor's comments:  There are several times when measuring markers of bone metabolism might be effective:  1) When you first start therapy with an approved medication; 2) When you change from one approved medication to another; 3) When you stop therapy, e.g., if you reach normal BMD levels and stop using a bisphosphonate, remaining only on testosterone therapy.  The best way to monitor the effectiveness of therapy using markers, in my opinion, would be to have a baseline test done and then follow up at three-month intervals.  If a couple of three-month tests with, e.g.,  NTx reveal the desired effect, then you would want to test the results with DXA in one to two years.  If the markers don't show the expected improvement, then you and your physician might want to consider an alternate medication.  Or, had you attempted to stop treatment with, e.g., Fosamax and go with only testosterone, but NTx showed considerable increase in bone resorption, you would want to strongly consider going back on Fosamax rather than waiting for one or two years to do a DXA.  Of course, any of these methods should be discussed with your physician who may or may not agree that using markers is desirable. 

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