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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 9 3034-3039
Copyright © 1997 by The Endocrine Society

Original Studies

Short-Term Variations in Bone Remodeling Biochemical Markers: Cyclical Etidronate and Alendronate Effects Compared

P. Bettica, M. Bevilacqua, T. Vago, M. Masino, E. Cucinotta and G. Norbiato

Department of Endocrinology, University-Hospital "L. Sacco (P.B., M.B., T.V., G.N.), Milan; and Assay Laboratory, USSL 44 (M.M., E.C.), Voghera Italy

Address all correspondence and requests for reprints to: Paolo Bettica, M.D., Ph.D., Servizio di Endocrinologia, Ospedale "L. Sacco", Via G.B. Grassi 74, 20157 Milan, Italy.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Bone-remodeling markers have been proposed to monitor antiosteoporotic therapy, as substantial changes in these markers usually occur in a relatively short time interval. In this study we have evaluated the short term effects of two bisphosphonates on bone-remodeling markers with the aim of 1) defining the shortest reliable time interval after which markers should be measured, and 2) comparing the effects of different bisphophonates. To do so, 74 postmenopausal women with a lumbar spine t score of at least -1 were randomly allocated to 4 different treatments: calcium carbonate (500 mg/day; n = 18), 5 mg/day alendronate (A5; n = 18), 10 mg/day alendronate (A10; n = 20), and cyclical etidronate (CE; n = 18). Serum and 24-h urine samples were collected at baseline and 14, 28, 56, and 84 days after the beginning of therapy. Type I collagen N-terminal (NTx) and C-terminal (CTx) telopeptides and total deoxypyridinoline (tDPD) were measured in urine and normalized for urinary creatinine excretion. Osteocalcin and bone alkaline phosphatase in serum were measured. Alendronate (at both doses) and CE significantly decreased bone-remodeling markers, whereas calcium carbonate did not. Bone resorption markers reduction reached a plateau 14 (A10) or 28 (A5 and CE) days after the beginning of treatment, whereas osteocalcin and bone alkaline phosphatase were significantly reduced at 56 (A10) and 84 (CE) days. The global effects of alendronate and CE on NTx and CTx (calculated as the area under the curve) were significantly different from those of calcium (P < 0.05), but were not significantly different from each other. The percent change from baseline obtained with tDPD, NTx, or CTx during bisphosphonate treatment were significantly different (P < 0.05), but this difference disappeared when the variability in the calcium carbonate group was taken into account. In conclusion, this study shows that 1) etidronate and alendronate induce a significant and rapid reduction in bone-remodeling markers; 2) the changes in NTx, CTx, and tDPD urinary excretions reach a plateau after 2–4 wk of treatment; and 3) short term treatments with CE or alendronate induce similar changes in the urinary excretion of NTx and CTx.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
OSTEOPOROSIS is increasingly recognized as a common disease with a major social impact. New drugs for both the treatment and the prevention of osteoporosis are currently available or under investigation. Although the efficacy of any antiosteoporotic drug is defined by its ability to reduce the incidence of osteoporotic fracture, such a criterion cannot be used to check drug efficacy in the single patient. Biochemical markers of bone turnover usually show a substantial and rapid response to antiosteoporotic treatments, and for this reason, they have been proposed to monitor therapy after a short time interval (1).

New biochemical markers of bone remodeling have been developed in the last few years; in particular, the pyridinium cross-links and type I collagen telopeptides, as bone resorption markers, and osteocalcin (OC) and bone alkaline phosphatase (bALP), as bone formation markers, have raised a great interest. Regarding pyridinium cross-links, deoxypyridinoline (DPD) is relatively specific for bone (2) and derives only from collagen degradation. Type I collagen telopeptides are present in all tissues that contain type I collagen (3, 4), mostly in bone. OC is synthesized by osteoblasts and odontoblasts and is released mainly into matrix (5), although a small part is released into the bloodstream, where it can be measured (6, 7, 8). Circulating ALP derives from many different tissues; the main sources are bone and liver (9, 10). bALP isoenzyme is specific for bone and is released into the bloodstream by the osteoblast (11). Together, these data show that DPD, NTx, CTx, OC, and bALP can be considered relatively specific and sensitive bone-remodeling markers, and measurements of these markers have been proposed to evaluate the effects of antiosteoporotic therapies (1).

Bisphosphonates are a class of compounds characterized by the presence of a P-C-P bond, which is responsible for their strong binding affinity to hydroxyapatite (12). They are taken up almost exclusively by bone, where they inhibit bone resorption (13). Although the P-C-P bond is present in all bisphosphonates, different compounds of this drug family have different residues attached to the P-C-P bond; such residues may determine different potencies and degrees of absorption from the gut. Alendronate and etidronate are bisphosphonates currently approved for osteoporosis treatment in Italy.

In this study we compared the short term effects of calcium carbonate, cyclical etidronate (CE), and alendronate (at doses of 5 and 10 mg/day) on the urinary excretion of NTx, CTx and total DPD (tDPD) and on the serum concentrations of OC and bALP in 74 postmenopausal women with the aim of 1) defining which is the shortest reliable interval to check the effect of therapy by measuring bone biochemical markers, and 2) comparing the effects of different bisphosphonates on biochemical markers of bone remodeling.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

Seventy-four women, who consecutively came to our endocrinology out-patient clinic for assessment of bone mineral density, were within 10 yr after menopause and had a t score of at least -1 at the lumbar spine, were selected for the study. None of the selected women either had any disease (apart from postmenopausal osteopenia or osteoporosis) or had been taking any medication known to affect bone turnover during the 12 months before the study. All patients gave informed consent to the study. To check that the selected postmenopausal women had increased bone turnover, 24-h urine and serum samples were also collected from 52 women with regular menstrual cycles and regular ovulation (as demonstrated by a serum progesterone level >5 ng/mL around the 20th day of the cycle), recruited among the hospital personnel. None of them either had any disease or was taking any medication known to affect bone turnover. Baseline characteristics of the selected pre- and postmenopausal women are reported in Table 1Go.


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  		Table 1. Baseline data of the 74 postmenopausal women selected for the study and of 52 premenopausal controls

 
Using a computer-generated randomization list, the selected postmenopausal women were randomly allocated to the following treatments: calcium carbonate (500 mg/day; n = 18), CE [n = 18; i.e. etidronate disodium (400 mg/day) for 14 days followed by calcium carbonate (500 mg/day) for 76 days], 5 mg/day alendronate (A5; n = 18), or 10 mg/day alendronate (A10; n = 20). Bisphosphonates were taken on an empty stomach at least 30 min before breakfast with a full glass of water and in the upright position. On days -7, 0, 14, 28, 56, and 84, serum and 24-h urine samples were collected. Treatments were started on day 1 and were continued for 3 months. Blood was always collected between 0830–0930 h. Samples were aliquoted and stored at -25 C until used. All samples from a single patient were measured in the same assay.

Methods

NTx was measured using a commercial kit with a monoclonal antibody specific for the cross-linked type I collagen N-terminal telopeptide (NTx; Osteomark, Ostex, Seattle, WA). CTx was measured using a commercial kit (Crosslaps ELISA, Osteometer, Copenhagen, Denmark) with a polyclonal antibody raised against a synthetic sequence of type I collagen C-terminal telopeptide (CTx). tDPD was measured by high performance liquid chromatography, using a commercial assay (Chromlinks, Bio-Rad, Richmond, CA) currently available in some European countries. In this commercial kit, the high performance liquid chromatography method of Eyre et al. (14) has been standardized with minor modifications (i.e. preextraction is performed on prepacked columns; after preextraction, samples are not freeze-dried but they are diluted with 1.5 mL elution reagent; 100 µL are injected into the high performance liquid chromatograph). Creatinine (Cr) was measured by an automated assay based on the Jaffe’ method. The excretion of urinary markers was expressed as a ratio with creatinine excretion. OC was measured with a commercial competitive RIA, using a monoclonal antibody that binds the intact OC and fragments 1–43, 20–49, and 20–44 (Osteocalcina Myria, Technogenetics, Milan, Italy). bALP was measured with a commercial kit that uses a monoclonal antibody against bALP coated on strips and measures the enzymatic activity of the captured ALP (Alkphase-B, Metra, Milan, Italy).

Lumbar spine BMD was measured by dual x-ray absorptiometry using a Hologic QDR2000 densitometer (Hologic, Waltham, MA). The densitometer was calibrated every day with the Hologic spine phantom, and the in vitro coefficient of variation was within 0.5%. The t scores were calculated using the Caucasian normal women database provided by Hologic.

Statistics

For each marker, values at -7 and 0 min were not significantly different; therefore, their mean was used to calculate a baseline value. The significance of the percent changes from baseline of each bone resorption and formation marker during treatment was estimated by one-factor ANOVA, followed by Scheffe’s test, as a post-hoc comparison analysis. To compare the global effects of treatments on bone resorption and formation markers, we calculated the mean percent change from baseline (mean {Delta}%) as the area under the curve obtained by plotting the percent change in the marker from baseline (for each time point) vs. time divided by the days of the study (i.e. 84 days). The significance of the marker’s mean {Delta}% during different treatments was estimated by ANOVA, followed by either Scheffe’s test or Fisher’s probability of least significant difference (PLSD) test. A dose-dependent effect of alendronate on bone biochemical markers was evaluated by plotting the markers mean {Delta}% vs. the alendronate dose and by estimating the linear regression; the marker’s mean {Delta}% during calcium carbonate treatment was used for the zero dose point. Finally, we evaluated whether the mean {Delta}% obtained with one bone resorption marker was significantly different from that obtained with the others, and we tested whether this difference was still significant after normalizing for the variability seen in the calcium-treated group. Normalization was obtained with the following formula: mean {Delta}%(calcium group) = [mean {Delta}%(patient) - mean {Delta}%(calcium group)]/SD mean {Delta}%(calcium group). The significance of the difference in mean {Delta}% and mean {Delta}%(calcium group) of different markers during bisphosphonate treatments was estimated by ANOVA, followed by Fisher’s PLSD test. All statistical analyses were performed using StatView data analysis software (Abacus Concepts, Berkeley, CA).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Urinary excretion of NTx/Cr, CTx/Cr, and tDPD/Cr and serum concentrations of OC and bALP were significantly increased at baseline compared with results obtained in premenopausal controls (Table 1Go). Alendronate (5 and 10 mg/day) and CE significantly decreased the urinary excretion of NTx/Cr, CTx/Cr, and tDPD/Cr, whereas calcium did not (Table 2Go and Figs. 1Go-3). The percent changes from baseline were already significant (P < 0.05, by Scheffe’s test) at 14 (A10) and 28 days (CE and A5) of treatment. As expected, serum OC and bALP concentrations decreased later than bone resorption markers, and the percent changes from baseline reached statistical significance (P < 0.05, Scheffe’ test) after 56 (A10) or 84 (CE) days of bisphosphonate treatment (Table 2Go and Figs. 4Go and 5Go).


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  		Table 2. Percent variations in NTx, CTx, and tDPD urinary excretion (as ratios with Cr excretion) and OC and bALP serum concentrations during treatments

 


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  		Figure 1. Percent variation from baseline value in NTx/Cr during treatment with calcium carbonate (Ca), A5, A10, and CE. Results are the mean ± SD. *, P < 0.05 vs. baseline (by Scheffe’s test).

 


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  		Figure 4. Percent variation from baseline value in OC during treatment with calcium carbonate (Ca), A5, A10, and CE. Results are the mean ± SD. *, P < 0.05 vs. baseline (by Scheffe’s test).

 


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  		Figure 5. Percent variation from baseline value in bALP serum concentrations during treatment with calcium carbonate (Ca), A5, A10, and CE. Results are the mean ± SD. *, P < 0.05 vs. baseline (by Scheffe’s test).

 
NTx/Cr and CTx/Cr mean {Delta}% values during the use of alendronate (5 and 10 mg/day) and CE were significantly different from those during the use of calcium (P < 0.05, by Scheffe’s test), but were not significantly different from each other (Fig. 6Go). Regarding tDPD/Cr, only the mean {Delta}% during the use of alendronate (10 mg) was significantly different from that during the use of calcium (P < 0.05, by Scheffe’s test; Fig. 6Go). OC and bALP mean {Delta}% values were not significantly different in the different treatment groups (Fig. 6Go). A significant dose dependency in mean {Delta}% during alendronate treatment was found for NTx/Cr (r = -0.64; P < 0.0001), CTx/Cr (r = -0.59; P < 0.0001), tDPD/Cr (r = -0.4; P = 0.004), and OC (r = -0.28; P = 0.05).



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  		Figure 6. Mean {Delta}% values for urinary excretion of NTx/Cr, CTx/Cr, and tDPD/Cr and serum OC and bALP concentrations during treatment with calcium carbonate (Ca), A5, A10, and CE. Results are the mean ± SD. *, P < 0.05 vs. calcium carbonate (by Scheffe’s test).

 
For all bone resorption markers, mean {Delta}% values were highly correlated (Table 3Go); on the other hand, mean {Delta}% values for serum OC and bALP concentrations were weakly related and did not correlate with any of the bone resorption markers (Table 3Go). Although highly correlated, mean {Delta}% values in tDPD/Cr, NTx/Cr, and CTx/Cr during bisphosphonate treatments were significantly different (P < 0.05, by Fisher’s PLSD test; Table 4Go); however, when normalized for the variability obtained in the calcium carbonate-treated group (Table 4Go), this difference disappeared.


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  		Table 3. Correlations among mean {Delta}% of NTx, CTx, and tDPD urinary excretions and OC and bALP serum concentrations during treatments

 

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  		Table 4. Mean percent change from baseline in NTx/Cr, CTx/Cr, and tDPD/Cr during bisphosphonate treatments, before (mean {Delta}%) and after [mean {Delta}%(Ca)] normalization for the variability found in the calcium carbonate group

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Alendronate and CE significantly decreased bone resorption markers, which reached a plateau after 14–28 days of treatment. Previous studies have shown that bisphosphonates decrease bone resorption markers within 1–3 months from the beginning of therapy (15, 16, 17); in our study, we were able to show that only 2–4 wk are necessary for the maximal effect of bisphosphonates to be reached and that all of the bone resorption markers evaluated in this study display a similar pattern of bone resorption inhibition. As expected, as bone resorption inhibition is the bisphosphonates’ primary pharmacological effect, OC and bALP, two bone formation markers, were significantly reduced approximately 1 month after bone resorption markers. It is interesting to note that two different bisphosphonates, which are also administered with two different therapeutic regimens (continuous therapy for alendronate vs. cyclical therapy for etidronate), show a similar pattern of bone resorption inhibition.

In the present study, when we considered the global effect of bisphosphonate treatments, calculated as the area under the curve of marker % change vs. time divided by study duration (mean {Delta}%), we could demonstrate 1) that mean {Delta}% in NTx and CTx urinary excretion during alendronate and CE were significantly different from those during calcium administration; 2) that there was a dose-dependent effect for alendronate (for all markers except bALP); and 3) that there was no significant difference in the mean {Delta}% values of the markers between alendronate and CE. In previous reports, a dose-dependent effect on bone resorption markers was found by Harris and co-workers (17) in a short term alendronate dose-finding study, but it was not seen by Adami and co-workers (18) or by Chesnut and co-workers (19) in long term alendronate dose-finding studies. These and our results suggest that a dose-dependent effect may be seen during the first 2–3 months of alendronate therapy, but over a longer period, a dose of 5 or 10 mg/day alendronate induces similar reductions in bone resorption. In vitro and animal studies have shown that alendronate is severalfold more potent than etidronate in reducing bone resorption (20); however, to the best of our knowledge, only one study has compared the effects of alendronate and etidronate on bone resorption in humans (21). In this study in patients affected by active Paget’s disease of bone, Siris and co-workers have shown that alendronate (40 mg/day) induces a larger reduction in bone resorption markers than etidronate (400 mg/day). Our data from postmenopausal osteopenic-osteoporotic patients (i.e. lumbar spine t score less than -1), show that the global effect on bone resorption markers during etidronate treatment is not different from that obtained with alendronate. These data suggest that in humans in pathological conditions characterized by moderate increases in bone turnover, continuous alendronate and CE treatments probably inhibit bone resorption to a similar extent. Future studies should confirm this finding and also compare the effects of etidronate and alendronate on bone mass and fracture rates.

Our data show that percent changes in the urinary excretion of NTx/Cr, CTx/Cr, and tDPD/Cr induced by different treatments are highly correlated; however, the mean {Delta}% of bone resorption markers during bisphosphonate treatments were significantly different. To determine whether these differences were due to variability in biochemical markers, we normalized the results obtained during bisphosphonate treatments to the results obtained during calcium administration; after this normalization, the mean percent changes from baseline in bone resorption markers were no longer significantly different. In previous reports we were able to show that the clinical performance of tDPD in distinguishing subjects with a moderately increased bone resorption rate (postmenopausal women) from subjects with a normal bone resorption rate (premenopausal controls) was significantly greater than that of hydroxyproline (22, 23) and was comparable to those obtained with both NTx and CTx (24). In this latter study, percent differences in the urinary excretion of tDPD, NTx, and CTx between premenopausal and postmenopausal women were significantly different, but these differences disappeared when variabilities in bone markers were taken into account. This suggests that the different degrees of change in bone resorption markers that are reported for telopeptides and pyridinium cross-links may be due mainly to differences in the variability in these bone resorption markers. Although this may be due in part to the different precisions of the methods used to measure them, it is probably mainly due to the fact that NTx, CTx, and tDPD derive from different sources (although bone is the most important one for all of them) and that they may be processed in different ways from the moment they are released from tissues until they are excreted into urine.

In conclusion, this study shows that 1) etidronate and alendronate induce a significant reduction in the urinary excretion of NTx, CTx, and tDPD and in serum OC and bALP concentrations; 2) the changes in NTx, CTx, and tDPD urinary excretion are rapid and reach a plateau within 2–4 wk of treatment; and 3) short term treatments with cyclic eti-dronate (CE) or alendronate induce similar changes in the urinary excretion of NTx and CTx. Future studies should compare the effects of different bisphosphonates on bone mineral density and fracture incidence.



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  		Figure 2. Percent variation from baseline value in CTx/Cr during treatment with calcium carbonate (Ca), A5, A10, and CE. Results are the mean ± SD. *, P < 0.05 vs. baseline (by Scheffe’s test).

 


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  		Figure 3. Percent variation from baseline value in tDPD/Cr urinary excretion during treatment with calcium carbonate (Ca), A5, A10, and CE. Results are the mean ± SD. *, P < 0.05 vs. baseline (by Scheffe’s test).

 
Received November 15, 1996.

Revised April 17, 1997.

Accepted May 16, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Calvo MS, Eyre DR, Gundberg CM. 1996 Molecular basis and clinical application of biological markers of bone turnover. Endocr Rev. 17:333–368.[Abstract/Free Full Text]
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  3. Hanson DA, Weis MAE, Bollen AM, Maslan SL, Singer FR, Eyre DR. 1992 A specific immunoassay for monitoring human bone resorption: quantitation of type I collagen cross-linked N-telopeptides in urine. J Bone Miner Res. 7:1251–1258.[Medline]
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  5. Price PA, Otsuka AS, Poser JW, Kristaponis J, Raman N. 1976 Characterization of a gamma-carboxyglutamic acid-containing protein from bone. Proc Natl Acad Sci USA. 73:1447–1451.[Abstract/Free Full Text]
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  11. Stein GS, Lian JB, Owen TA. 1990 Relationship of cell growth to the regulation of tissue-specific gene expression during osteoblast differentiation. FASEB J. 4:3111–3123.[Abstract]
  12. Fleisch H. 1981 Diphosphonates: history and mechanisms of action. Metab Bone Dis. 4/5:279–299.
  13. Fleisch H, Russell RGG, Francis MD. 1969 Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resoprtion in vivo. Science. 165:1262–1264.[Abstract/Free Full Text]
  14. Eyre DR, Koob TJ, Van Ness KP. 1984 Quantification of hydroxypyridinium cross-links in collagen by high performance liquid chromatography. Anal Biochem. 137:380–388.[CrossRef][Medline]
  15. Garnero P, Ginetys E, Arbault P, Christiansen C, Delmas PD. 1995 Different effects of bisphosphonate and estrogen therapy on free and peptide-bound bone cross-links excretion. J Bone Miner Res. 10:641–649.[Medline]
  16. Garnero P, Shih WJ, Ginetys E, Karpf DB, Delmas P. 1994 Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment. J Clin Endocrinol Metab. 79:1693–1700.[Abstract]
  17. Harris ST, Gertz BJ, Genant HK, et al. 1993 The effect of short term treatment with alendronate on vertebral density and biochemical markers of bone remodeling in early postmenopausal women. J Clin Endocrinol Metab. 76:1399–1406.[Abstract]
  18. Adami S, Passeri M, Ortolani S, et al. 1995 Effects of oral alendronate and intranasal salmon calcitonin on bone mass and biochemical markers of bone turnover in postmenopausal women with osteoprosis. Bone. 17:383–390.[Medline]
  19. Chesnut CHI, McClung MR, Ensrud KE, et al. 1995 Alendronate treatment of the postmenopausal osteoporotic woman: effect of multiple dosages on bone mass and bone remodeling. Am J Med. 99:144–152.[CrossRef][Medline]
  20. Rodan GA, Seedor JG, Balena R 1993 Preclinical pharmacology of alendronate. Osteoporos Int. 3(Suppl 3):S7–S12.
  21. Siris E, Weinstein RS, Altman R, et al. 1996 Comparative study of alendronate versus etidronate for the treatment of Paget’s disease of bone. J Clin Endocrinol Metab. 81:961–967.[Abstract]
  22. Bettica P, Moro L, Robins S, et al. 1992 Bone resorption markers: galactosyl hydroxylysine, pyridinium crosslinks, hydroxyproline compared. Clin Chem. 38:2313–2318.[Abstract/Free Full Text]
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  24. Bettica P, Masino M, Cucinotta E, et al. 1997 Comparison of the clinical performances of the immunoenzimometric assays for N-terminal and C-terminal type I collagen telopeptides and the HPLC assay for pyridinium crosslinks. Eur J Clin Chem Clin Biochem. 35:63–68.[Medline]




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