The biochemcial markers of bone formation and bone resorption are frequently called markers of "bone turnover." It is better to remember specifically which process is being measured, because sometimes the bone formation and resorption are not linked (for example, in steroid-induced osteoporosis, bone formation is low but bone resorption is high). These markers can NOT BE USED TO DIAGNOSE OSTEOPOROSIS! They help us understand the physiology of bone disease, especially in groups of patients or in clinical trials. For individual patients, the markers are of limited use and not recommended for screening or routine follow-up. They do provide information which can help decisions in complex cases.
| What are they? | As shown in the animation above, they are cross-linking molecules which are released with bone resorption and excreted by the urine.( Knott, L.)
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| Measure bone resorption | Calcium kinetic studies of bone formation and resorption show that the cross-links correlate highly with resorption. Also, these tests are higher in clinical situations previously known to have high bone resorption, such as Paget's disease and hyperthyroidism. (Weaver, C. M., Eastell, R.)
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| Very high levels in adolescents | Levels are high in children, who have a great deal of bone resorption associated with growth and modelling of the ends of the long bones. NTX levels reach a peak (xxx nmoles/mmol creat) at about age 14, then gradually decreases to adult values (xxx ). (Bollen, A. M., Mora, S., Marowska, J.)
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| Increase at menopause | Studies show a rise of about 80-90% after menopause (Garnero, P.,Melton, L. J., 3rd)
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| Diurnal variation | Bone resorption is highest at night, and the values of NTX or CTX are highest in the early morning. The highest and lowest values are 24% different from the mean 24-hour value. (Bollen, A. M.)
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| Correlations with BMD are modest | Correlation coefficients of NTX or CTX vs BMD in postmenopausal women vary from r = -0.3 to -0.5. These are statistically significant, but are not very useful for screening purposes. There are large errors in predicting the bone density for an individual person. (Marcus, R., Melton, L. J., 3rd, Scariano, J. K.)
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| Can't predict change in BMD | Most studies show that a value of NTX or CTX in a postmenopausal woman is not able to predict the change in BMD over the next one to three years. One would have expected that women with higher resorption rates would lose more bone, but the current techniques for measuring both resorption rate and bone density do not show such a relationship. Even if the techniques were perfect, they might not show a predictable relationship because the rates of bone formation also influence the change in the bone density. (Bauer, D. C., Marcus, R.)
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| Decrease with anti-resorptive therapy | Studies consistently show either NTX or CTX decrease about xx% with estrogen therapy and about 40-60% with alendronate. Furthermore, over 90% of patients who take the drugs have a decrease in the biochemical markers. There is no disagreement about these facts, but there are major differences in application to the clinical situation. Some think that the markers should be measured in women before and after starting therapy to identify non-compliant patients. If the marker does not decrease, the woman should be "confronted." Others (myself included) argue that we could skip the tests, at about $40 each, and just ask the patient if he or she had any difficulty taking the medication. (Ravn, P., Greenspan, S. L.)
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| Changes with therapy weakly predict BMD | If you perform a clinical trial with an effective antiresorptive drug (such as estrogen or alendronate), then the placebo group will have little change in NTX with losses of BMD, whereas the treated group would have decreases in NTX and increases in BMD. Analyzing all of the patients in the study will result in a "dumb-bell" curve, with a cluster of points for the placebo group and another cluster for the treated group, and overall there would be a significant inverse correlation between NTX and BMD. This method of analysis is not useful. Instead, the change in NTX should be compared to the change in BMD in the group who actually took the medication. With this approach, several studies have found signficant correlations between the drop in NTX and the increase in BMD, but the ability to predict changes in an individual patient is very limited. (Greenspan, S. L.)
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| Related to fractures ? | Of course this will be the most important, because fractures are what matters, not bone density tests. However, it is easy to study BMD changes and difficult to study fracture rates. Not many studies are large enough to allow fracture prediction. In a large prospective cohort of 7598 women older then 75, a high C-telopeptide level was associated with an increased risk of hip fracture with an odds ratio of 2.2. During the two years of study, 3% of those with a high C-telopeptide had a hip fracture. (Garnero, P.)
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| Other bone diseases | NTX or CTX tests help to assess the activity of other diseases such as Paget's disease or metastatic bone lesions.
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| My recommendations | I do not think these tests should be used for routine screening for osteoporosis. Neither do I recommend using them to see if a patient is taking his or her osteoporosis medication (to find that out, I ask the patient!). However, in complex patients, where every piece of information can be helpful in making a decision, I will measure the NTX. Also, when a patient is taking her medications but bone density is not improving, or fracture occurs, I often check a NTX to see if addition of further medications might be helpful.
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| What are they? |
Osteoblastic activity is associated with serum osteocalcin, one of the proteins found in relatively high concentration in bone. Bone specific alkaline phosphatase (measured by radioimmunoassay, not by iso-enzyme analysis of alkaline phosphatase) is more sensitive and specific than alkaline phosphatase, this enzyme is made only by active osteoblasts. Another relatively new test is the propeptide of type I collagen (PICP). Like many other proteins, collagen is secreted as a propeptide, and the ends are removed to synthesize collagen.
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| Measure bone formation |
These tests have been shown to correlate with bone formation as measured by bone histomorphometry or calcium kinetic studies in normal individuals. Osteocalcin appears to be more closely related to formation of osteoid than to formation of mineralized bone. Thus, in osteomalacia or disease where there is excess osteoid such as Paget's disease, the osteocalcin may be inaccurate. Osteocalcin is excreted by the kidneys, and serum values are increased in renal failure. This may occur in elderly patients with normal creatinines who have low glomerular filtration rates. Assays which measure the intact protein are less influenced by the glomerular filtration rate. Bone specific alkaline phosphatase is not influenced by renal failure (it is frequently elevated, but that is because the bone formation rate is actually high).
(Weaver, C. M.)
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| Relationship to resorption |
In normal individuals the markers of bone formation follow the same pattern as the markers of bone resorption, because the two processes are coupled during bone remodeling. The levels are high during childhood and adolescence, low during adult years, and increase after menopause. They decrease following treatment with hormone replacement therapy or anti-resorptive drugs, but there is a lag between the decrease in the bone resorption markers and the bone formation markers.
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| Response to anti-resorptive therapy |
Theoretically, patients with low bone formation should not respond as well to anti-resorptive drugs, because the osteoblasts would not be expected to completely fill the resorbed cavities. This has not been shown in clinical trials, except one small study using calcitonin. The markers may not be sensitive enough in individual cases. In most cases, the bone formation markers are not as sensitive to anti-resorptive therapy as the bone resorption markers, but they tend to follow the same pattern. (Marcus, R.)
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| Response to other therapy | Osteocalcin usually increases after treatment with 1,25-vitamin D. This may not represent increased bone formation, however, because histomorphometric studies of bone biopsies from women with osteoporosis treated with calcitriol have not shown any increase in tetracycline labelling. Fluoride causes increases in bone formation and in osteocalcin or bone alkaline phosphatase. PTH results in marked increases in these markers.
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| Clinical utility |
The role of these markers in diagnosis or treatment of osteoporosis is still uncertain. In complex or high-risk cases they may help to define the bone physiology. Perhaps in the future drugs which stimulate bone formation will be available, and the markers would be able to guide therapy.
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