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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 3 1194-1198
Copyright © 2001 by The Endocrine Society

Original Studies

Analysis of the Contribution of Dydrogesterone to Bone Turnover Changes in Postmenopausal Women Commencing Hormone Replacement Therapy1

Jonathan H. Tobias, Shane Clarke, Kathryn Mitchell, Simon Robins, Hanya Amer and William D. Fraser

Rheumatology Unit, University of Bristol Division of Medicine, Rowett Research Institute (S.R.), Aberdeen, United Kingdom AB21 9SB; and Department of Clinical Chemistry, Royal Liverpool University Hospital (W.D.F.), Liverpool, United Kingdom L69 3GA

Address all correspondence and requests for reprints to: Dr. J. Tobias, Rheumatology Unit, Bristol Royal Infirmary, Bristol, United Kingdom BS2 8HW. E-mail: jon.tobias{at}bristol.ac.uk


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Although gestagens have been reported to influence bone metabolism, whether these contribute to the beneficial effects of hormone replacement therapy (HRT) on the skeleton of postmenopausal women is currently unclear. To address this question, we compared changes in bone turnover markers after commencing HRT in 26 postmenopausal women randomized to receive 8 weeks of treatment with 2 mg estradiol daily or 2 mg estradiol plus 10 mg dydrogesterone daily. Serum and second morning void urine samples were obtained at baseline (twice) and after 1, 2, 4, and 8 weeks. Serum estradiol was measured by RIA, urinary total deoxypyridinoline (DPD) excretion by high pressure liquid chromatography, and serum osteocalcin and C-terminal procollagen peptide by enzyme-linked immunosorbent assay. The increase in serum estradiol after treatment with estradiol alone was slightly, but significantly, greater than that in the combination group (P = 0.04). Although estradiol suppressed urinary DPD excretion to a greater extent when given alone (P = 0.02), osteocalcin levels were significantly higher in this group than in women receiving combination therapy (P = 0.04). To assess the effect of dydrogesterone on the balance between formation and resorption in more detail, we subsequently compared the ratio between formation and resorption markers in the two treatment groups. We found that osteocalcin/DPD and C-terminal procollagen peptide/DPD ratios were significantly higher in women treated with estradiol alone (P < 0.0001 and P = 0.002, respectively), suggesting that dydrogesterone may reduce formation relative to resorption. These results suggest that gestagens may reduce estrogen’s beneficial effects on the skeleton of postmenopausal women, as assessed over the first 8 weeks of replacement therapy.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
HORMONE REPLACEMENT therapy (HRT) is known to reduce bone loss in postmenopausal women (1, 2), leading to a reduction in fracture rate (3, 4). This beneficial effect on the skeleton is thought to be mediated by the estrogen component, in view of evidence from clinical and laboratory studies that estrogen influences bone metabolism when given alone (5, 6, 7, 8). Thus, in postmenopausal women with previous hysterectomy in whom progesterone is not indicated, HRT is generally administered as an estrogen only formulation on the assumption that gestagens do not contribute significantly to the beneficial effects of HRT on the skeleton and other organs.

Previous clinical and laboratory studies suggest that gestagens also exert a significant bone-sparing action in states of ovarian deficiency when administered alone (9, 10, 11, 12). Whether gestagens also enhance the skeletal response to estrogen is unclear. Studies comparing the effect estrogen with or without gestagen on bone mass in postmenopausal women have yielded conflicting results (13, 14, 15). To our knowledge, no previous study has examined whether gestagens contribute to effects of HRT on other indexes of skeletal metabolism, such as measurements of bone turnover.

Analysis of early effects on bone turnover may provide useful insights into the biological action of therapeutic agents on bone. For example, how quickly drugs decrease resorption markers may provide a measure of their antiresorptive potency (16). Estrogen’s inhibitory effect on bone resorption also results in the suppression of formation markers due to the close coupling between these two processes (17, 18). However, it is also possible to detect stimulatory effects of estrogen on osteoblast function by analyzing bone formation markers shortly after commencing treatment before these have responded to changes in bone resorption (19, 20).

In the present study we assessed the contribution made by gestagens to early changes in bone turnover after commencing HRT in postmenopausal women. We performed a double blind, randomized, control study in which we compared changes in bone turnover markers in postmenopausal women treated for 8 weeks with estrogen with or without dydrogesterone.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Postmenopausal women who wanted to commence HRT were recruited to the study over a 12-month period. Postmenopausal status was defined as amenorrhea for a minimum duration of 6 months and was confirmed in the case of hysterectomized subjects by finding of a serum estradiol level below 50 pmol/L. Exclusion criteria were as follows: HRT within the previous 6 months, contraindication to HRT, or disease or treatment associated with altered bone metabolism. Local ethics committee approval for the experimental protocol was obtained before commencement of the study.

After giving their written informed consent, patients were randomized to receive treatment for 8 weeks with 2 mg estradiol daily (administered as a Zumenon, 2-mg tablet) or 2 mg estradiol plus 10 mg dydrogesterone daily (administered as tablet from the second cycle of the Femoston 2/10 combination pack; these drugs were a gift from Solvay Healthcare Ltd., Southampton, UK). Patients in the latter group were given continuous combined therapy, as opposed to the cyclical progesterone that is more commonly prescribed, to improve our ability to detect any effect of dydrogesterone on bone turnover. Both patients and investigators were blind to treatment group. Second morning void urine collections and serum samples were obtained on two separate occasions 1 week apart before the start of therapy, and 1, 2, 4, and 8 weeks thereafter. Venesection was performed at the same time of day for each subject. Serum and urine samples were subsequently stored in multiple aliquots at -70 C. Adverse events were recorded at each attendance.

To determine whether both treatment regimens produced similar elevations in serum 17ß-estradiol (E2), the latter was measured by RIA [Orion Diagnostica, Espoo, Finland; detection limit, 5 pmol/L; interassay coefficient of variation (CV), <10%]. To study changes in serum markers of bone formation as assessed by enzyme-linked immunosorbent assay, serum osteocalcin was measured to provide an index of osteoblast differentiation (Metra Biosystems, Paolo Alto, CA; interassay CV, <7%), and type I collagen propeptide was determined to analyze osteoblast synthetic function (PICP) (Orion Diagnostica; interassay CV, <7%). To assess bone resorption, total urinary deoxypyridinoline (DPD) was measured by high pressure liquid chromatography using a fully automated method (21). Analyses were performed on urine samples hydrolyzed in 6 mol/L HCl, with prefractionation on cellulose CC31 columns and additional solvent extraction (tetrahydrofuran) to allow direct transfer to the high pressure liquid chromatography column with O-acetylpyridinoline as the internal standard. The interassay variation for this method is less than 2% (21). Results were expressed relative to creatinine as measured by standard methodology on an autoanalyzer.

To compare changes in bone turnover markers between the two treatment groups, for each subject the result at a given time point was divided by the mean of the two pretreatment values and multiplied by 100. To study possible changes in the balance between bone formation and bone resorption, we also calculated the ratio between osteocalcin and DPD values derived in this way, and that between PICP and DPD. Baseline characteristics of subjects in the two treatment groups were compared by unpaired Student’s t test.

To determine whether there was a statistically significant effect of time or treatment group, two-way ANOVA was performed on bone marker data (StatView 5.0, SAS Institute, Inc., Cary, NC). Where a significant effect of treatment group was observed, one-way ANOVA with Fisher’s least significant difference test was used to compare results between groups at individual time points. The threshold for statistical significance was taken as P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Twenty-six women were entered into the study, all of whom completed it. No significant differences were observed between baseline characteristics of the subjects randomized to the two treatment groups (Table 1Go). A relatively high proportion of patients in the combined treatment group reported PV bleeding and breast tenderness compared with patients receiving estrogen alone (50% vs. 10% and 44% vs. 20%, respectively). For all subjects, adherence rates, as assessed by self-report, were greater than 80%.


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  		Table 1. Baseline characteristics of subjects randomized to receive estrogen alone (E) or estrogen plus dydrogesterone (E+D)

 
HRT rapidly increased serum E2 concentrations in both treatment groups (Table 2Go and Fig. 1Go). A small, but significant, trend toward higher values was observed in the estrogen only group. As expected, HRT decreased bone resorption, as assessed by measurement of total urinary DPD excretion (Table 2Go and Fig. 2Go). DPD excretion tended to be lower in the estrogen only group; this difference was most marked at week 1. Subjects in the estrogen only group also showed a significant trend toward higher concentrations of serum osteocalcin compared with patients treated with combination therapy (Table 2Go and Fig. 3Go). Results for PICP showed no significant differences between treatment groups (Table 2Go and Fig. 4Go).


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  		Table 2. Mean ± SD for serum estradiol (E2), urinary deoxypyridinoline excretion (DPD), serum osteocalcin (Oc), serum C-terminal procollagen peptide (PICP), Oc/DPD ratio, and PICP/DPD ratio

 


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  		Figure 1. Results show the mean ± SEM serum estradiol (picomoles per L) in subjects treated with HRT over an 8-week period. {square}, Estrogen group; {blacksquare}, estrogen plus dydrogesterone. Significant effects of time (P < 0.0001) and treatment group (P = 0.04) were observed (by two-way ANOVA).

 


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  		Figure 2. Results show the mean ± SEM urinary deoxypyridinoline excretion in subjects treated with HRT over an 8-week period. Results were corrected for creatinine excretion and are expressed as the percent change compared with the mean pretreatment value (DPD%). {square}, Estrogen group; {blacksquare}, estrogen plus dydrogesterone. Significant effects of time (P < 0.0001) and treatment group (P = 0.02) were observed (by two-way ANOVA).

 


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  		Figure 3. Results show the mean ± SEM serum osteocalcin in subjects treated with HRT over an 8-week period. Results are expressed as the percent change compared with the mean pretreatment value. {square}, Estrogen group; {blacksquare}, estrogen plus dydrogesterone. A significant effect of treatment group was observed (P = 0.04, by two-way ANOVA).

 


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  		Figure 4. Results show the mean ± SEM serum C-terminal procollagen peptide in subjects treated with HRT over an 8-week period. Results are expressed as the percent change compared with the mean pretreatment value (PICP%). {square}, Estrogen group; {blacksquare}, estrogen plus dydrogesterone. No significant effects of time or treatment group were observed.

 
Therefore, when given alone, estrogen appeared to be associated with significantly higher osteocalcin levels, but significantly reduced DPD excretion, compared with those in women receiving combination therapy. To further examine the possible effects of treatment on the balance between bone formation and resorption, we subsequently analyzed changes in the ratio between formation and resorption markers in the two treatment groups. The ratio between serum osteocalcin and DPD excretion showed a highly significant increase in the estrogen only group, particularly at weeks 1 and 2 (Table 2Go and Fig. 5Go). The ratio between serum PICP and DPD excretion also tended to be higher in the estrogen only group, which was most marked at week 1 (Table 2Go and Fig. 6).



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  		Figure 5. Results show the mean ± SEM osteocalcin/DPD ratio in subjects treated with HRT over an 8-week period. {square}, Estrogen group; {blacksquare}, estrogen plus dydrogesterone. Significant effects of time (P < 0.0001) and treatment group (P < 0.0001) were observed (by two-way ANOVA).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our observation that HRT reduced urinary DPD excretion is consistent with previous findings that HRT inhibits bone resorption as assessed by several variables, including urinary resorption markers (17, 22, 23). Urinary DPD excretion was suppressed to a greater extent after estrogen alone compared with combination therapy, suggesting that if anything, dydrogesterone reduces estrogen’s antiresorptive action in postmenopausal women commencing HRT. Whether gestagens influence estrogen’s effects on skeletal metabolism, as assessed by analysis of bone turnover markers immediately after starting therapy, has not previously been investigated. However, the suggestion from these results that dydrogesterone reduces estrogen’s tendency to suppress bone resorption is somewhat surprising in view of previous reports that gestagens given alone either have no effect on bone turnover (24) or possess significant antiresorptive activity (9, 10, 11, 12).

Serum E2 concentrations in subjects receiving estrogen alone were slightly, but significantly, greater than those in the combined group, which may have contributed to the greater reduction in DPD excretion in the former. Consistent with this possibility, regression analysis of pooled data revealed that DPD excretion was negatively correlated with serum E2 concentration (r2 = 0.21; P < 0.0001). Although the basis for the difference in serum E2 concentrations between groups is unclear, a possible explanation is that this reflected small differences in estrogen bioavailability between formulations administered to the estrogen only and combined treatment groups. However, we cannot conclude that the differences in serum total estradiol between groups that we observed were responsible for differences in bone turnover, as neither sex hormone-binding globulin nor free or biologically active estradiol was measured in the present study.

Any tendency for bone resorption to decrease more rapidly after estrogen alone is expected to be associated with a more rapid decrease in formation markers, as bone formation is generally closely coupled to resorption (17, 18). However, osteocalcin levels were significantly higher in the latter group than in those receiving estrogen and progesterone in combination. Although no significant difference was observed in PICP response between the two treatment groups, if anything our results suggested that concentrations of this osteoblast marker were also higher in the estrogen only group. Analysis of the ratio between formation and resorption markers provides further support for the conclusion that progesterone, given as dydrogesterone, alters the balance between bone formation and resorption in favor of resorption in postmenopausal women commencing estrogen therapy.

Theoretically, suppression of bone resorption may transiently increase the number of reversal sites available for osteoblast recruitment, producing a paradoxical initial rise in bone formation after commencing treatment. Therefore, the suggestion from our results that formation was increased compared with resorption to a greater extent in subjects receiving estrogen alone may have simply been a consequence of the greater suppression of bone resorption in this group. However, against this suggestion, potent antiresorptive agents, such as bisphosphonates, are not associated with transient elevations in osteoblast markers within the first few weeks of initiating therapy (25, 26, 27).

Estrogen may prevent bone loss by stimulating bone formation as well as suppressing bone resorption (5, 28, 29). Thus, the differences in the ratio of bone formation to resorption between treatment groups that we observed may also have reflected modulation by dydrogesterone of a tendency for estrogen to stimulate osteoblast function. However, any suggestion from our results that dydrogesterone inhibits the stimulatory action of estrogen on osteoblast function would appear to be at odds with previous reports that, if anything, gestagens of similar biological activity stimulate osteoblast function (30, 31, 32, 33).

Previous findings that transdermal and intranasal estrogen transiently increase serum osteocalcin and PICP (22, 20) support the possibility that analysis of biochemical markers of bone formation can be used to study stimulatory effects of estrogen on osteoblast function in postmenopausal women. In the studies by Ho et al. (20) and Hannon et al. (22), transdermal estrogen was associated with a transient increase in osteoblast markers despite the use of a combined HRT formulation. However, in these two studies, estrogen was administered with norethisterone, which, unlike dydrogesterone, possesses significant androgenic activity. In view of previous observations that testosterone significantly increases serum levels of osteoblast markers in women commencing estrogen therapy (34), it is possible that the associated androgenic activity of gestagens such as norethisterone modifies their overall effect on the skeleton.

If any tendency for dydrogesterone to decrease estrogen’s action on bone metabolism is sustained over longer durations of treatment, bone mass would be predicted to be lower in postmenopausal women treated with combination therapy than in those given estrogen alone. However, the addition of medroxyprogesterone, which has similar biological activity to dydrogesterone, has previously been reported to have either no effect on the bone mass of postmenopausal women receiving estrogen therapy over 1 yr (13) or to produce a greater increment (15). Thus, gestagens may not suppress estrogen’s effects on bone metabolism when treatment is sustained for 12 months, suggesting that the differences in bone turnover markers we observed between estrogen only and combined groups are likely to be relatively transient.

In the present study differences in DPD excretion and serum OC between treatment groups appeared to be more marked at earlier time points, which is consistent with the suggestion that dydrogesterone’s effect on bone turnover markers is relatively transient. This possibility is also supported by the previous finding that the response to HRT is not influenced by dydrogesterone as assessed 3 months after commencing therapy (35). If dydrogesterone delays the onset of estrogen’s effects on the skeleton, as opposed to reducing the absolute magnitude of the final response, such an action may have relatively little effect on ultimate clinical efficacy.

In summary, we compared changes in bone turnover markers in postmenopausal women treated for 8 weeks with estrogen with or without dydrogesterone. When given alone, estrogen was associated with significantly greater suppression of urinary DPD excretion, but, in contrast, serum osteocalcin levels were significantly higher. These results suggest that in postmenopausal women, dydrogesterone both reduces estrogen’s effects on bone resorption and alters the balance between formation and resorption in favor of resorption. Further studies are required to determine whether these differences are sustained when treatment is continued for longer, and whether a similar effect is observed with other gestagens.



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  		Figure 6. Results show the mean ± SEM PICP/DPD ratio in subjects treated with HRT over an 8-week period. {square}, Estrogen group; {blacksquare}, estrogen plus dydrogesterone. Significant effects of time (P < 0001) and treatment group (P = 0.002) were observed (by two-way ANOVA).

 

   Footnotes
 
1 This work was supported by the National Osteoporosis Society and Solvay Healthcare Ltd. Back

Received April 19, 2000.

Revised October 18, 2000.

Accepted November 6, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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