Evaluation of ability of biochemical markers of bone turnover to predict a response to increased doses of HRT.

Antiresorptive therapy is usually given in a fixed dose, and we hypothesized that some patients receiving standard doses of hormone replacement therapy (HRT) might benefit from a higher dose, particularly if their bone turnover decreases after increasing the dose of HRT. Eighty-eight women who had been receiving standard-dose (0.625 mg/day) conjugated equine estrogens (CEE) for at least one year were randomized to take either standard-dose (0.625 mg/day, n = 36) or high-dose (1.25 mg/day, n = 52) therapy. Subjects with a uterus were allowed to take either 10 mg of medroxyprogesterone cyclically or 5 mg daily, according to personal preference. Bone Mineral Density (BMD) and biochemical markers of bone turnover were followed for 2 years. Mean bone turnover decreased significantly (-4.1% to -19.1%) after 6 months of high-dose CEE. Decreases in serum BSAP (bone-specific alkaline phosphatase) and serum or urine NTX ( N-terminal telopeptide crosslink of type I collagen) on high-dose therapy were not predictive of an improvement in BMD, but a decrease in serum CrossLaps did predict an improvement in BMD. Mean change in BMD in subjects with a significant decrease in serum CrossLaps at the anteroposterior spine was 3.1% +/- 3.9% versus 1.2% +/- 2.9% for subjects with no significant change in CrossLaps, P < 0.02. There was, however, a wide range of changes in BMD in patients with or without a significant change in CTX on high-dose HRT, making it impossible to predict an improvement in BMD based on an individual's changes in turnover. Measuring of bone density and bone turnover with better precision might be more successful in guiding individual dosing of antiresorptive therapy.

Serum CTX: a new marker of bone resorption that shows treatment effect more often than other markers because of low coefficient of variability and large changes with bisphosphonate therapy.

Serum CrossLaps is a new assay for measuring carboxy-terminal collagen crosslinks (CTX) in serum. This measurement is reported to be more specific to bone resorption than other measurements. However, the utility of this and other markers in monitoring patients on antiresorptive therapy depends on how often changes anticipated with therapy exceed changes attributable to random variability. In a study where subjects received either placebo or pamidronate, we calculated the minimum significant change (MSC), that is, the change that was sufficiently large that it was unlikely to be due to spontaneous variability. We also examined the changes in markers of bone turnover in subjects treated with pamidronate (APD) (30 mg i.v. in 500 ml D5W over 4 hours) to see how often observed changes in turnover after treatment exceeded the MSC. The MSC for serum CTX was 30.2%, and was significantly (P < 0.05) lower than the MSC for urinary NTX (54.0%), and not significantly different from the MSC of urinary DPD (20.6%). Ninety percent of subjects treated with APD had a decline in serum CTX that exceeded the MSC, compared with 74% for bone-specific alkaline phophatase (BSAP), 57% for urinary N-telopeptide cross-links (NTX), and 48% for free deoxypyridinoline. Changes in serum CTX correlated reasonably well with changes in spine BMD after 2 years (r = 0.47), but this correlation did not quite reach statistical significance because of the small number of subjects. In conclusion, the serum CTX assay shows greater utility for assessing efficacy of antiresorptive treatment than some previously described markers.