Predictive Value of Biochemical Markers of Bone Turnover for BMD
Abstract & Commentary
Synopsis: Baseline urinary N-telopeptide and serum osteocalcin levels were the most sensitive predictors of change in spine bone mineral density after one year of either hormone replacement therapy or calcium supplementation.
Source: Rosen CJ. J Clin Endocrinol Metab 1997; 82:1904-1910.
Not all women exhibit rapid bone loss in the years immediately following menopause. More worrisome is that some women show minimal or no skeletal response to hormone replacement therapy. Assessing the change in bone mineral density (BMD) at one or more skeletal sites during hormone replacement therapy (HRT) still remains the accepted standard for determining an individual’s response to a given intervention. Controversy exists as to whether biochemical markers of bone turnover predict the skeletal response to an intervention. This multicenter study of early postmenopausal women was designed to address this controversy.
Individual biochemical markers reflect different aspects of the bone-remodeling cycle. Components of skeletal breakdown are N-telopeptide (NTx), which measures collagen cross-links, and fDpd, which measures free pyridinoline cross-links. Osteocalcin (OC) and bone-specific alkaline phosphatase (BSAP) are markers of bone formation. When bone turnover is high, markers of bone resorption and formation are both elevated. When bone mass accrues in response to an intervention, bone resorption is reduced to a lesser extent than bone formation so that there is a net gain in bone mass. Eventually, however, reduced bone resorption leads to reduced formation because the resorption and formation processes are coupled.
The present study was comprised of 227 recently menopausal women in good health who were randomized to either calcium supplementation or HRT. HRT regimens varied, but all women received conjugated equine estrogens at a dose of 0.625 mg or its equivalent. Bone density was determined in the lumbar spine and femoral neck by dual energy x-ray absorptiometry (DEXA), and bone markers were measured at one, three, six, and 12 months after the start of therapy.
Overall, in the HRT group, gain in BMD was 2.5% in the spine and 1% in the femoral neck. Interestingly, one-third of women receiving HRT showed a suppression of FSH below 30 IU/L, although two-thirds had a gain in BMD. The percent change in NTx provided a better discrimination of losers vs. gainers than did OC, BSAP, or fDpd. Similarly, baseline NTx values were higher in women who gained bone while on HRT or who lost bone while taking calcium supplementation. OC level was the next best predictor in these settings.
COMMENT BY SARAH L. BERGA, MD
Predicting who is at risk for osteoporosis and who will respond to therapy is big business these days. Physicians, patients, and insurers wonder how much of this new technology to use. The present study is well done and provides partial answers to the important questions about how to know who needs treatment and about who is benefiting from that treatment. Because the study was done in recently menopausal women, however, the results are limited to that group. Twenty percent of the women lost BMD while on HRT. The unresponsive women had lower bone turnover at baseline as evidenced by lower levels of all biochemical markers. However, the bone marker that best predicted a response to HRT was either the baseline level of or the percent change in urinary NTx. Most of the women in the study had relatively normal bone mass for age at baseline, so the results also may not apply to women who are markedly osteopenic. Interestingly, there was discordance between FSH suppression and bone response to HRT. Thus, the level of estrogen that is sufficient for one tissue, such as the pituitary, may not be adequate for another, such as the bone. When thinking about the benefits of HRT, the best bet is to prioritize the therapeutic aims and to adjust the dose to achieve the goals of highest priority. To my way of thinking, the only way to know how to prioritize the bone is to image the clinically relevant skeletal sites so as to determine who is at greatest risk for osteoporosis. If the results of the present study hold, those most likely to gain bone on therapy or most likely to lose bone off therapy are those who have high bone turnover as evidenced by a high urinary level of NTx. The present study suggests that the response to therapy might be predicted as soon as 3-6 months after the initiation of therapy. To determine if there is an increase in BMD by DEXA, one generally must wait 12 months to be able to detect a change. However, this study does not address the thorny issue as to whether improvement at one skeletal site, such as the spine, tends to be accompanied by an increase in BMD at other skeletal sites. For instance, a woman with adequate spine bone density, low hip bone density, and a high urinary NTx might be losing bone from her spine, and treatment might augment spine density and lower NTx without augmenting hip BMD. Thus, although this study addresses an important topic, the results must be considered preliminary. Further research should be directed at determining whether the predictive power of NTx holds for amenorrheic athletes, for women many years past menopause, for women taking bisphosphonates, for those with discordance in BMD between the spine and hip, and those with marked osteopenia.
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