Differences in the Capacity of Several Biochemical Bone Markers to Assess High Bone Turnover in Early Menopause and Response to Alendronate Therapy

Abstract

We measured bone mineral density (BMD), four markers of bone formation [bone alkaline phosphatase (bAP), osteocalcin (Oc), N- and C-terminal propeptide of type I procollagen (PINP and PICP respectively)] and five markers of bone resorption [serum C-terminal telopeptide of type I collagen (CTx), urinary CTx, N-terminal cross-linked telopeptide (NTx), free and total deoxypyridinoline (fDpd and tDpd respectively)] in 28 healthy premenopausal women (45.7 +/- 3.0 years), 15 early (< 7 years) healthy menopausal women (53.8 +/- 3.1 years) and 20 osteoporotic women (65.3 +/- 8.2 years). Bone markers and BMD were also measured in the osteoporotic women 4.1 +/- 0.2 and 12.6 +/- 1.2 months after the beginning of alendronate therapy (Fosamax, 10 mg/day) respectively (BMD in 16/20). We calculated the intra-individual coefficient of variation (iCV) and the least significant change (LSC) for each bone marker from a subset of 9 healthy premenopausal women (32 +/- 5 years) who had a first and a second morning void urine collection (FMV and SMV respectively) and a blood sample on 4 nonconsecutive days (mean interval 14 +/- 3 days). None of the bone markers was correlated with BMD (except p = 0.043 between serum Oc and hip BMD). All markers, except fDpd, were increased significantly in early menopausal women when compared with the premenopausal group. Serum CTx presented the highest increase at menopause (+67.8%) and identified the highest rate (11/15) of early menopausal women with bone turnover above the premenopausal range. The iCVs for bone formation markers (7.2-14.4%) were lower than those for bone resorption markers (14.6-22.3%). The iCVs obtained on FMV and SMV were not different. The decrease after 4 months of alendronate was significant for each bone marker but variable from one marker to another. Serum CTx showed the largest decrease (70.8%) and identified the highest number of biologically responding patients (change > LSC; n = 17/20). A significant change in serum CTx after 4 months of alendronate was the best predictor of a significant gain in spine BMD (i.e., > or = 27 mg/cm2) after 1 year of therapy, allowing 15 of 16 patients (94%) to be classified correctly (one false-positive). Urinary NTx/Cr was the second best predictor. Despite a moderately high iCV (20.6%), serum CTx appeared the most effective of the markers tested and could be of interest for the detection of high bone turnover and the longitudinal monitoring of alendronate therapy in the individual patient. It must be stressed that serum PINP and urinary NTx and tDpd compared very similarly with serum CTx for monitoring alendronate therapy.

The potential value of monitoring bone turnover markers among women on alendronate

“…These figures are based on within-person SDs for a single measurement occasion of BAP and NTX of 18.2% and 30%, respectively, similar to estimates reported previously for these two markers. (25)(26)(27)(28) This large within-person variation means that the number of measurements of NTX needed to be certain of a woman's baseline level of the marker is prohibitively large (seven measurements are needed for the observed values to be within 20% of the true level with 95% certainty; if three measurements are used then observed levels are only within 31% of the true level with 95% certainty). This means that monitoring change in the marker is challenging, even though under certain circumstances, relatively few (sometimes only one) repeated measurements are needed after treatment to estimate the true treatment effect once we are certain of the baseline level.…”

Role of biochemical markers of bone turnover as prognostic indicator of successful osteoporosis therapy

“…Alendronate [10,17,18,19,20,21] Formation: BALP, PINP, PICP, OC Fracture, BMD Resorption: sCTX, uNTX, DPD Risedronate [12,22] Resorption: uDPD, uCTX, uNTX, Fracture, BMD Teriparatide [13,14,15,33] Formation: BALP, PICP, PINP Fracture, BMD Resorption: uDPD, uNTX, sCTX Raloxifene [30,31,32] Formation: BALP, PINP, OC Fracture Resorption: uCTX Early changes in BTM to monitor anti-osteoporosis therapy Similar to most chronic diseases, monitoring the efficacy of treatment of osteoporosis is a challenge. In contrast to BMD, which typically changes in response to therapy less than 2-5% per year, or a maximum of 3% in 3-6 months, most of osteoporosis therapies act by reducing or increasing individual BTM levels or their ratios by 30-200% within 3-6 months.…”

“…In contrast, the poor specificity and negative predictive value of these percentual cut-offs of BTM changes implied that a change in NTX or OC above the cut-point was a poor predictor of bone loss during alendronate treatment [17]. In a smaller cohort of French osteoporotic women, the authors claimed, from observation of changes in BALP, OC, P1CP, P1NP, sCTX, uNTX, total and free DPD after 4 months of alendronate, that sCTX, and to a lesser extend, uNTX, were the best predictors of a significant gain in spine BMD after 1 year of therapy [18]. Early changes of uNTX (3 months) were also shown to be good predictors of 12-month lumbar spine BMD response to alendronate in Korean postmenopausal women with osteoporosis [19].…”

Bone Turnover Markers Relations to Postmenopausal Osteoporosis

“…By using ROC curve analysis, very high specificity and sensitivity of the investigated biochemical bone markers CTX and OC in the diagnosis of postme nopausal osteoporosis were proven (4). Increased bone markers by 67% were discovered in women in early meno pause compared to premenopausal women (24). CTX determined by the same method Elecsys, ECLIA in the study of Garnero (25) was higher by 39% in perimenopausal women in compa rison to preme no pausal women and higher by 86% in postmeno pausal women.…”