The effect of 25-dihydroxyvitamin D on the bone mineral metabolism of elderly women with hip fracture

M. Sosa, P. Láinez, A. Arbelo and M. C. Navarro

University of Las Palmas de Gran Canaria, Department of Medicine and Hospital Universitario Insular, Bone Metabolic Unit, Las Palmas, Canary Islands, Spain


    Abstract
 Top
 Abstract
 Introduction
 Patients, materials and methods
 Results
 Discussion
 References
 
As there is little evidence of the efficacy of 25-hydroxyvitamin D3 (25-HCC) in reducing the risk of new fractures in osteoporotic women, we performed an open, prospective study with a follow-up of 1 yr in 58 females over 65 yr of age with osteoporosis and proximal femoral fractures. The patient group received 1 g calcium per day and 10 640 IU 25-HCC per week, while the control group received 1 g calcium daily. Biochemical markers of bone remodelling, serum calcium and parathyroid hormone were determined. Bone mineral density was assessed in the lumbar spine and in the proximal femur by two methods. After 1 yr of treatment, 25-HCC corrected secondary hyperparathyroidism, increased urine calcium excretion, and increased bone mass in the femoral neck, but had no effect upon the appearance of new fractures.

KEY WORDS: Proximal femoral fracture, Osteoporosis, Vitamin D, 25-hydroxyvitamin D, Biochemical markers of bone remodelling, Parathyroid hormone, Bone mineral density, Fractures.


    Introduction
 Top
 Abstract
 Introduction
 Patients, materials and methods
 Results
 Discussion
 References
 
Osteoporosis is a metabolic disease of the entire skeleton characterized by a diminution in bone mass, associated with changes in bone microstructure which produce increased fragility of the skeleton and an associated increased risk of fractures [1]. It is a quantitative disorder of bone mass, as the quality of the remaining bone is normal [2]. Fracture of the proximal femur (FPF) is the most serious complication of osteoporosis, as it causes significant morbidity and mortality [3]. Although falls are probably the most important cause of FPF, low bone mineral density also plays a fundamental role [4]. Both transverse and prospective studies demonstrate that elderly people who suffer FPF have a femoral bone density lower than controls of the same age and sex, and that elderly patients followed for several years have a higher risk of fracture when their femoral bone density is low [5].

It has been reported that vitamin D supplements reduce the loss of bone mass in the femoral neck of post-menopausal women [6], and a recently published study shows that supplementary calcium and vitamin D produce a slowing of the loss of bone mass and a reduction in non-vertebral fractures in patients aged more than 65 yr of both sexes [7]. These studies were carried out using cholecalciferol, the active metabolite of vitamin D. There are fewer studies using 25-hydroxycholecalciferol (25-HCC) in elderly osteoporotic women who have suffered FPF.

For this reason, we studied women who had suffered FPF, with the object of studying whether 25-HCC together with calcium would produce changes in bone mineral metabolism or reduce the loss of bone mass and the rate of appearance of new fractures.


    Patients, materials and methods
 Top
 Abstract
 Introduction
 Patients, materials and methods
 Results
 Discussion
 References
 
Selection of patients
We chose 70 women who had suffered a fracture of the proximal femur between May 1994 and December 1997 in Gran Canaria, Canary Islands. The patients were chosen consecutively as they were diagnosed. We excluded patients confined to bed and accepted only those who were able to walk. They were informed of the objectives of the study, their written consent was obtained, and they were classified randomly in two groups. The 25-HCC group received 1 g calcium orally, daily, divided into two doses, and one ampoule of 25-hydroxycholecalciferol (Hidroferol), containing a dose of 0.622 mg (10 640 IU), once a week. The control group received 1 g calcium orally, divided into two doses.

Twelve patients were excluded or abandoned the study for different reasons: non-compliance with the treatment (three patients), commencing another therapy which would influence bone mineral metabolism, such as steroids, alendronate and thiazide diuretics (six patients), readmission to hospital for other reasons (two patients) and voluntarily leaving the study (one patient). Seven of these patients belonged to the 25-HCC group and five to the control group. To avoid interference of bed-related complications and surgical procedures with bone mineral metabolism, the study and treatment of each patient were undertaken 1 month after the patient had been discharged from hospital. In all, 58 patients completed the study; 28 constituted the 25-HCC group and 30 the control group.

Patient characteristics
All the women included in the study were given a questionnaire designed to collect data concerning their lifestyle, risk factors for osteoporosis and gynaecological history. A complete physical examination, including height and weight with light clothing, was also performed. To assess possible obesity, the body mass index (BMI) was used, defined as body weight (in kg) divided by height (in m) squared. A patient was deemed overweight when the index was equal to or greater than 25 kg/m2 and obese when the index was greater than or equal to 30 kg/m2.

Current calcium intake was estimated from a 24-h checklist survey, as previously described [8]. Patients were encouraged not to change their usual dietary habits during the study.

The functional capacity of the patients was assessed at the beginning of the study with the Rapid Disability Rating Scale 2 (RDRS-2) [9].

Analytical studies
Venous blood was taken after the patient had fasted for 12 h and had consumed a diet containing gelatin during the previous 48 h. Blood samples were stored in vacutainers without additives between 8 and 9 a.m. Plasma was separated and stored at -20°C until the biochemical analyses were performed. Urine samples were taken after 2 h and 12 h of fasting. The calcium and hydroxyproline concentrations were determined, and the results were divided by the concentration of creatinine. Parathyroid hormone (PTH) was determined by radioimmunoassay (RIA) using Allegro intact PTH, which measures the biological activity of the intact chain of 84 PTH amino acids. Intra- and interassay variation was less than 3.5 and 6% respectively. The sensitivity of the assay was established at 1 pg/ml. In our laboratory we have established that the range of normal values is between 15 and 65 ng/ml. Serum osteocalcin (GLA) was also determined by RIA (Nichols). Intra- and interassay variation was 14.8 and 9.2% respectively.

Serum calcium, alkaline phosphate (ALP), phosphorus, urea, creatinine and total proteins were measured using automated techniques in an autoanalyser (Kodak Ektachem Clinical Chemistry Slides). Tartrate-resistant acid phosphatase (TRAP) was determined by spectrophotometry after inactivation with sodium tartrate L(+ ). Hydroxyproline in urine was determined by spectrophotometric ion exchange. Serum calcium levels were corrected for total proteins using the Parfitt formula: corrected calcium = previous calcium/(0.55 + total proteins/16).

Bone mass measurements
Quantitative computerized tomography (QCT).
The bone mineral content was determined at the third lumbar vertebra (L3) using a Toshiba 600 HQ model computerized axial tomograph, employing a modified version of Cann and Genant [10, 11]. The patients were placed with the lumbar spine over the plastic-and-water simulator containing several salt and water solutions. Each burst of simple energy was carried out at 120 kV, 80 mA, with 4 s exposure. Various cuts were taken; they were 10 mm thick in the middle of the third lumbar vertebrae. The images obtained were used to delimit an elliptical region of the pure trabecular bone at the axial level to determine bone mass. The Hounsfield values obtained in this way were compared with those obtained by simultaneous exposure to the simulator and were analysed using a calibration curve obtained from the standard for each patient. The results are expressed in milligrams of mineral equivalent per millilitre of volume of trabecular bone. In clinical studies, accuracy was 5–8% and the precision error was in the same range [12, 13].

Dual-energy, X-ray absorptiometry (DEXA).
Bone mineral density of the lumbar spine and the proximal femur was measured with a Hologic QDR-1000 densitometer. This technique uses an X-ray tube as the source of photons and the source of radiation and energy pulses alternately at 70 and 140 kVp, and is transmitted through a tube with a peak of 2 mA. We have previously reported a coefficient of variation of 0.75 + 0.16% with a densitometric range of 0.6–1.13% with this densitometer [14]. All these measurements were obtained by the same operator, so there was no inter-observer variation.

The Z score and T score were calculated using the following formulae: Z score = (observed value–theoretical value for age and sex group)/typical theoretical deviation for age and sex group; T score = (observed value–theoretical value at 30 yr)/typical theoretical deviation for 30-yr-old).

The mean theoretical value and typical deviation of each age group were obtained from values considered normal for the Canarian population [14].

In accordance with WHO criteria, osteoporosis was diagnosed when densitometry indicated that bone mass was more than 2.5 standard deviations below the T score [15].

Radiologic
Lateral dorsolumbar radiography was carried out on every patient studied. The spinal deformity index (SDI) was determined [16] to establish the existence of fractures or vertebral deformities.

Statistical analysis
The data from the survey were entered in a database designed using the DBase IV program. From there they were exported to SPSS for Windows 95. Numerial results are expressed as mean ± S.D. unless specified. The Kolmogorov–Smirnov non-parametric test was used to ascertain whether the numerical variables followed the normal distribution in each of the groups. To compare numerical variables we used Student's t-test when the data followed a normal distribution and the equivalent Wilcoxon non-parametric test when they did not. To study associations between numerical variables we used the Pearson correlation coefficient and calculated odds ratios [17]. To analyse the effect of treatment on the appearance of new fractures, we used the proportions test of Student's t for paired samples. In all cases 5% (P < 0.05) was the level of significance.


    Results
 Top
 Abstract
 Introduction
 Patients, materials and methods
 Results
 Discussion
 References
 
Table 1Go shows the characteristics of the patients who completed the study: age, height, weight, body surface area, BMI, current calcium intake and functional capacity. Comparing the results for the two groups, we found no significant statistical differences in any of the variables, so we may affirm that this is a homogeneous population. We also found no significant statistical differences between the two groups for total and ionized calcium, total proteins, phosphate, urea, creatinine and calcium corrected for total proteins. All these results were in the normal range for our laboratory.


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TABLE 1. Baseline characteristics of patients who completed the study

 
Table 2Go presents data on biochemical markers of bone remodelling. We used ALP and GLA as bone formation markers and TRAP and the calcium/creatinine and hydroxyproline/creatinine ratios determined from 2-h urine sample tests as bone reabsorption markers. No statistically significant differences were detected between the two groups in any of the variables studied. However, the PTH values obtained, although homogeneous in the patients of our study, were above the range considered as normal in our laboratory (up to 65 pg/ml).


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TABLE 2. Biochemical markers of bone remodelling and PTH values

 
Table 3Go shows the bone density levels, determined by densitometry (lumbar spine and femoral neck) and QCT in the lumbar spine (L2–L3). Z and T scores are also shown. Bone mineral densities in the lumbar spine and proximal femur did not differ significantly between the two groups.


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TABLE 3. Bone mineral density values at the outset of the study

 
In Table 4Go the differences obtained between the final and initial values of the biochemical markers of bone remodelling are shown, expressed as percentages. Regarding bone formation markers, there was a significant increase in ALP in control group patients. There were no statistically significant differences for GLA. Among the bone reabsorption markers, calciuria was increased in the patients who received 25-HCC, but no differences were observed for TRAP and the hydroxyproline/creatinine ratio. This table also shows a marked PTH reduction in the patients who received 25-HCC (a decrease of 12.2% compared with the basal value 1 yr previously), whereas in the control group PTH continued to increase.


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TABLE 4. Percentage changes in biochemical markers of bone remodelling compared with basal values

 
Figure 1Go shows the differences in bone density values obtained at the beginning and end of the study period. There were no significant statistical differences between the two groups in the lumbar spine after 1 yr of treatment, by DEXA or QCT. In the femoral neck, an increase of 2.1% was observed in bone density in the women treated with 25-HCC and calcium (25-HCC group), whereas the patients treated only with calcium (control group) showed a loss of 1.8% (P < 0.05).



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FIG. 1. Differences between the final and initial values for bone mineral density, expressed as percentages.

 
In Table 5Go, the newly diagnosed fractures are listed after 1 yr of treatment. New vertebral fractures appeared in both groups, with no significant differences. Regarding non-vertebral fractures, only one new fracture was reported: a Colles fracture appeared in a patient of the control group who suffered frequent falls.


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TABLE 5. Number of fractures observed at the outset of the study and after 1 yr of follow-up

 
Figure 2Go shows the changes in PTH levels after 1 yr of treatment. Patients who received 25-HCC showed a statistically significant decrease in PTH serum level compared with the basal level, while those who received only calcium (controls) had PTH values similar to the basal level.



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FIG. 2. Changes in PTH serum levels after 1 yr of treatment.

 


    Discussion
 Top
 Abstract
 Introduction
 Patients, materials and methods
 Results
 Discussion
 References
 
The present study was carried out on patients with osteoporosis who had suffered fractures previously. The primary aim was to study the influence of 25-HCC on mineral metabolism, bone mass and the appearance of new fractures after 1 yr of management. Once the two groups were randomly formed, we confirmed that they were homogeneous. As Table 1Go indicates, there were no statistically significant differences in age, weight, height, body surface, BMI and current calcium intake. This was also the case for biochemical values and for the biochemical markers of bone remodelling shown in Table 2Go. Although PTH levels were similar in the two groups of women, levels were significantly greater than that established as normal in our laboratory (up to 65 pg/ml). An increased concentration of PTH in patients with type II osteoporosis, which is what our patients had, has been reported previously. Regarding the classification of osteoporosis into types I and II, Riggs and Melton [18] indicate that type II may also include parathyroid hyperactivity.

It has been reported that increased PTH secretion in elderly women may increase the risk of fractures, and hypovitaminosis D and low intake of calcium are the main determinants of senile hyperparathyroidism [19], which could play a role in the pathogenesis of bone loss [20]. In our patients, we confirmed the existence of raised levels of PTH with normal serum levels of calcium, and found that, after treatment with calcium and 25-HCC, there were significant decreases in calcium and 25-HCC levels in the 25-HCC group (Table 2Go). In the control group, after 1 yr of treatment with only calcium, PTH remained either unchanged or showed a slight increase (1.2%). An improved PTH level after vitamin D administration in elderly women has been reported extensively. Indeed, a dose of 400–800 IU/day of vitamin D3 has been recommended as necessary to normalize initially high levels of PTH [21, 22]. This is especially indicated in patients who are admitted to nursing homes or similar centres for the chronically ill and for those who have limited previous exposure to sunlight.

Table 3Go shows the values obtained when bone mass was determined by two different methods: DEXA and QCT. Analysing densitometric findings, we found that in patients with FPF the loss of bone mass was significantly higher in the femoral neck than in the lumbar spine. The results were not surprising given that the women studied had suffered FPF. In fact, in the female Caucasian population over 80 yr of age and without fractures, Looker et al. [23], determining only bone mass in FPF, found that 100% were more than 1 standard deviation below the normal mean. Our patients’ average age was 78.4 yr and the bone mass of the femoral neck was almost 3 standard deviations below the T score. There was also a loss of bone mass in the lumbar spine, although this was of a lesser value.

Analysing the response to 25-HCC treatment, regarding biochemical markers of bone remodelling, Table 4Go reveals that ALP was higher in both groups compared with basal levels, but this increase was more marked in the patients who only received calcium. Currently, total ALP is not the best marker of bone formation. Others, such as the bone alkaline phosphatase isoenzyme and type I procollagen [24], are more sensitive and specific. We used ALP here because we did not have any other bone formation markers at our disposal at the time of the study. This hypothesis is consistent with the facts that GLA, a better specific marker of bone formation, does not present significant statistical modifications (Table 4Go) and that the resorption markers TRAP and hydroxyproline, expressed as a ratio with creatinine in urine after 2 h of fasting, does not show changes. Similarly, Chapuy et al. [21] did not report modifications in the levels of GLA after 18 months of follow-up in elderly women treated with calcium, vitamin D or placebo, but Dawson-Hughes et al. [7] found a decrease in GLA in vitamin D-treated patients.

These results indicate either that (i) modifications in bone remodelling are rare in elderly women with FPF, whether they receive calcium and 25-HCC or only calcium, or (ii) that the modifications which occur were not detected by the biochemical markers of bone remodelling we used. We tend to favour this latter possibility, given that we have observed, by densitometry, an increase of 2.1% in bone mass at the level of the femoral neck, as we will discuss below. Perhaps, with the newer markers of bone remodelling being developed, this problem may be solved in the near future.

By analysing the changes in bone mass that had occurred during 1 yr of treatment, we observe (Fig. 1Go) that the trabecular bone was not modified, and there were no significant differences between the initial and final values in the lumbar spine (by densitometry and QCT), whereas patients who received calcium and 25-HCC showed a 2.5% increase at the level of the femoral neck. This contrasts with the patients receiving only calcium, who showed a loss of 1.8% in the same period. In their study, Chapuy et al. [21] obtained a 2.7% increase in the femoral neck after vitamin D3 treatment, while in the group treated with placebo a loss of 4.6% was reported. In our patients who received calcium and 25-HCC the increase was similar (2.1%) but in the control group the decrease observed was less (1.8%). This may be due to the fact that this group received calcium (1 g per day) instead of placebo. Dawson-Hughes et al. [25, 26] have shown that in women over the age of 65 yr, calcium supplements reduce bone mass loss in the femoral neck as well as in other parts of the skeleton.

The present study has not demonstrated a favourable effect on the appearance of new fractures. After 1 yr of treatment, the number of fractures was similar in the two groups. In the literature there are some favourable results of treatment with vitamin D3 and with 1 alpha cholecalciferol (1{alpha} HCC) and 1,25 dihydroxycholecalciferol (1,25 DHCC), showing reductions in the appearance of vertebral fractures as well as FPF [21, 27, 28], but some studies have described indifferent [29, 30] and even negative results [31, 32]. We have been unable to locate any specific reference to the effect of 25-HCC on bone mineral density and on the incidence of new fractures in a Medline search (1980–1999).

In conclusion, daily treatment with 1 g calcium together with 25-HCC at a weekly dose of 0.266 mg (10 640 IU) reduces previously high serum levels of PTH without modifying calcaemia, and increases calcuria and bone mineral density in the femoral neck of elderly women who have suffered FPF. It does not produce changes in biochemical markers of bone remodelling or in the bone mineral density of the lumbar spine, and does not reduce the rate of appearance of new fractures. However, we realize that the number of patients in this study is small and the follow-up was too short for us to conclude that this intervention would not be able to reduce fractures in an at-risk population. Further studies with a greater number of patients and with at least 3 yr of follow-up are therefore desirable.


    Notes
 
Correspondence to: M. Sosa, University of Las Palmas de Gran Canaria, Department of Medicine, Bone Metabolic Unit, Avenida del Dr Pasteur s/n, 35016, Las Palmas de Gran Canaria, Canary Islands, Spain. Back


    References
 Top
 Abstract
 Introduction
 Patients, materials and methods
 Results
 Discussion
 References
 

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Submitted 6 December 1999; revised version accepted 19 May 2000.



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