The Predictive Value of Biochemical Markers of Bone Turnover
April 1, 1998
The Predictive Value of Biochemical Markers of Bone Turnover
ABSTRACT & COMMENTARY
Synopsis: Both urinary C-telopeptide and N-telopeptide correlated well with bone loss induced in premenopausal women by GnRH-agonist use, but rapid bone loss could not be identified with these markers until 24 weeks after the initiation of GnRH-agonist therapy.
Source: Amama EA, J Clin Endocrinol Metab 1998;83:333-338.
In this study, 68 premenopausal japanese women undergoing a six-month course of GnRH-agonist therapy for endometriosis or uterine leiomyomata were followed. Five markers of bone resorption and two markers of bone formation were assessed before and during therapy at 4, 12, 16, and 24 weeks. Lumbar spine bone density was assessed before and at 24 weeks after therapy by dual energy x-ray absorptiometry (DEXA).
The five markers of bone resorption were hydro-xyproline, pyridinoline, deoxypyridinoline, C-telopeptide, and N-telopeptide. The markers of bone formation were osteocalcin and total alkaline phosphatase. Urinary measurements of the cross-links of mature collagen, pyridinoline, and deoxypyridinoline have been found to reflect bone resorption, but their use as predictors of bone loss lacks specificity and sensitivity. Type I collagen degradation products, urinary C-telopeptide (CTX) and N-telopeptide (NTX), have been reported to be more sensitive and specific markers of bone loss and of cessation of bone loss following estrogen or bisphosphonate treatment.
The present study was undertaken to determine if these markers could be used to identify women who should receive add-back hormone therapy when being treated with GnRH-agonists. Patients were designated as rapid losers or slow losers of bone mass if bone loss documented by DEXA was above or below the mean, respectively. The mean bone loss was 3.8%. The rapid losers lost a mean of 5.9% and the slow losers 1.5%. The bone density of the two groups did not differ at baseline, and ovarian suppression induced by GnRH-agonist therapy was comparable in both groups. Regardless of the statistical approach used to analyze the data, increases in urinary CTX (162%) and NTX (86%) were the best predictors of bone loss. Osteocalcin, a reliable marker of bone formation, was increased comparably in both groups (42%), indicating that rapid bone loss was due to excess bone resorption.
Amama and associates conclude that urinary CTX and NTX cannot be used to discriminate rapid from slow losers of bone density during a standard course of GnRH-agonist therapy because a significant difference between the groups was not evident until 24 weeks after the initiation of GnRH-agonist use.
COMMENT BY SARAH L. BERGA, MD
The search for reliable and convenient markers of bone loss continues. Unfortunately, CTX and NTX were not useful for determining which patients will sustain large decreases in bone density while undergoing a six-month course of GnRH-agonist therapy. Do the data offer hope that these tests might prove worthwhile in other clinical contexts, such as assessing bone accretion in response to hormone or bisphosphonate therapy? As noted recently (OB/GYN Clin Alert 1997;14:29-30), not all menopausal women receiving standard doses of estrogens accrue bone, and some continue to lose bone. If a hypogonadal or menopausal woman was found to have osteoporosis at a clinically relevant site by DEXA, it would be important to know if she responded to the planned intervention.
Currently, the best way to assess response to interventions is to repeat the bone density at 12 months. Urinary CTX or NTX might allow response to therapy to be gauged earlier but only if CTX or NTX levels were elevated before therapy and then fell rapidly in response to therapy. A major drawback to the use as screening tools of any marker of bone loss is that they will be elevated only when there is active bone loss. A patient can have osteoporosis but not be actively losing bone. To make matters worse, this study indicates that clinically significant elevations in urinary markers are not detectable until 24 weeks of hypoestrogenism. This observation raises the possibility that it will be equally long before response to therapy can be reliably detected with these markers.
A further drawback to the use of urinary markers is that a change may not guarantee that bone density is increasing in the site or sites with documented osteoporosis. The present study reinforces my impression that urinary markers do not have the sensitivity or specificity to be useful for detecting clinically relevant bone loss or response to interventions aimed at improving bone mass.
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