Calcium and Vitamin D3 Supplementation Prevents Bone Loss in the Spine Secondary to Low-Dose Corticosteroids in Patients with Rheumatoid Arthritis

A Randomized, Double-Blind, Placebo-Controlled Trial

  1. Lenore M. Buckley, MD, MPH;
  2. Edward S. Leib, MD;
  3. Kathryn S. Cartularo, RN;
  4. Pamela M. Vacek, PhD; and
  5. Sheldon M. Cooper, MD
  1. From Medical College of Virginia, Richmond, Virginia; and the University of Vermont, College of Medicine, Burlington, Vermont. Acknowledgments: The authors thank John Orav, PhD, and Bruce Hillner, MD, for their advice and comments; Mary Merchant, RN, for research assistance; and Maia Eckler for secretarial assistance. Requests for Reprints: Lenore M. Buckley, MD, MPH, Medical College of Virginia, 1200 East Broad Street, PO Box 980102, Richmond, VA 23298-0102. Current Author Addresses: Dr. Buckley: Medical College of Virginia, 1200 East Broad Street, PO Box 980102, Richmond, VA 23298-0102.
     
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    Abstract

    Background: Therapy with low-dose corticosteroids is commonly used to treat allergic and autoimmune diseases. Long-term use of corticosteroids can lead to loss of bone mineral density and higher risk for vertebral fractures. Calcium and vitamin D3 supplementation is rational therapy for minimizing bone loss, but little evidence for its effectiveness exists.

    Objective: To assess 1) the effects of supplemental calcium and vitamin D3 on bone mineral density of patients with rheumatoid arthritis and 2) the relation between the effects of this supplementation and corticosteroid use.

    Design: 2-year randomized, double-blind, placebo-controlled trial.

    Setting: University outpatient-care facility.

    Patients: 96 patients with rheumatoid arthritis, 65 of whom were receiving treatment with corticosteroids (mean dosage, 5.6 mg/d).

    Intervention: Calcium carbonate (1000 mg/d) and vitamin D3 (500 IU/d) or placebo.

    Measurements: Bone mineral densities of the lumbar spine and femur were determined annually.

    Results: Patients receiving prednisone therapy who were given placebo lost bone mineral density in the lumbar spine and trochanter at a rate of 2.0% and 0.9% per year, respectively. Patients receiving prednisone therapy who were given calcium and vitamin D3 gained bone mineral density in the lumbar spine and trochanter at a rate of 0.72% (P = 0.005) and 0.85% (P = 0.024) per year, respectively. In patients receiving prednisone therapy, bone mineral densities of the femoral neck and the Ward triangle did not increase significantly with calcium and vitamin D3. Calcium and vitamin D3 did not improve bone mineral density, at any site in patients who were not receiving corticosteroids.

    Conclusion: Calcium and vitamin D3 prevented loss of bone mineral density in the lumbar spine and trochanter in patients with rheumatoid arthritis who were treated with low-dose corticosteroids.

    Long-term administration of low doses of corticosteroids is common in the treatment of autoimmune diseases, chronic obstructive lung disease, asthma, and allergic conditions. Although treatment with high doses of corticosteroids causes osteoporosis (especially in trabecular bone, such as that found in the lumbar spine [1]), use of corticosteroids in low doses (<10 mg/d) was thought to be associated with few substantial side effects [2]. However, recent research suggests that use of low doses of corticosteroids is also associated with loss of bone mineral density in the lumbar spine [3-6] and that patients receiving continuous therapy with low-dose corticosteroids have a higher rate of vertebral fracture [7-9].

    Corticosteroids cause osteoporosis by several mechanisms, such as decreasing levels of sex steroids [10, 11] and direct effects on osteoblast [12] and osteoclast function [13]. Use of corticosteroids also decreases absorption of intestinal calcium [14-17], thereby causing secondary hyperparathyroidism [18]. Some studies [19, 20] have shown that vitamin D3 and its more potent analogues can improve calcium absorption in patients receiving corticosteroids. Treatment with 1,25-dihydroxyvitamin D3 (calcitriol) and calcium stabilized bone mineral density in the lumbar spine in patients receiving moderate to high doses of corticosteroids [21]. However, calcitriol is a potent vitamin D analogue that can cause hypercalcemia and hypercalciuria [22]. The associated toxicity and expense make it impractical for widespread use for prevention of bone loss in all patients receiving long-term treatment with low-dose corticosteroids.

    Vitamin D3, the parent compound, is generally well tolerated and rarely causes side effects when used in the recommended dosage (400 to 800 IU/d). It has been suggested that vitamin D3 and calcium should be given to all patients receiving long-term corticosteroid therapy [23]. However, few data support this approach. Early studies [24] suggested that calcium and pharmacologic dosages of vitamin D3 (50 000 IU three times a week) increased bone mineral density in patients taking long-term corticosteroids, but bone mineral density was measured only in the radius. Adachi and colleagues [25] recently reported that treatment with calcium (1000 mg/d) and vitamin D3 (50 000 IU/wk) did not prevent bone loss associated with moderate- to high-dose treatment with corticosteroids, but Healy and colleagues [26] found that calcium and vitamin D3 prevented substantial loss of bone mineral density in a similar group of patients starting corticosteroid treatment. No randomized, controlled, clinical trials have shown the effectiveness of calcium and vitamin D3 supplementation for prevention of bone loss secondary to long-term low-dose corticosteroid treatment. Therefore, we studied the effects of calcium (1000 mg/d) and vitamin D3 (500 IU/d) supplementation on the bone mineral density of patients with rheumatoid arthritis and contrasted the efficacy of this supplementation in patients who were and those who were not receiving corticosteroids.

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    Methods

    Patients

    Patients with rheumatoid arthritis who were followed at the University of Vermont, College of Medicine (n = 354) were identified through a computer listing by diagnostic code. All identified patients were contacted by mail and asked whether they were interested in participating in a study of the effects of rheumatoid arthritis and medication on bone mineral density. Patients were eligible if they were between 18 and 65 years of age and had a diagnosis of rheumatoid arthritis as defined by the revised American College of Rheumatology criteria [27], serum creatinine level less than 176.8 µmol/L, and normal liver function. Patients were excluded if they were receiving an anticonvulsant medication, hydrochlorothiazide, bisphosphonates, fluoride, calcitonin, or calcitriol or if they had a history of malabsorption, hyperparathyroidism, immobilization, metabolic bone disease, or thyroid disease with an abnormal thyroid-stimulating hormone. One hundred thirty patients met these criteria, agreed to participate, and entered the study between January 1991 and January 1992.

    Study Design

    The study was approved by the Committee on Human Research of the University of Vermont, and informed consent was obtained as patients entered the study. Patients were stratified by sex, menopausal status (premenopausal, postmenopausal without estrogen replacement, or postmenopausal with estrogen replacement), and current dosage of prednisone (<10 mg/d or ≥ 10 mg/d). Patients were randomly assigned in blocks of four to a treatment group using a random-number table. Group assignment was kept in sealed envelopes to ensure blinding. Patients received either calcium carbonate (1000 mg/d) and vitamin D3 (500 IU/d) (two tablets twice a day of Os-Cal 250 + D, SmithKline Beecham Healthcare, Pittsburgh, Pennsylvania) or an identical placebo. Study medication was taken with breakfast and dinner.

    Measurement

    Demographic information and information about risk factors for osteoporosis, such as smoking history, use of alcohol, menstrual history, parity, fracture history, and use of medications (including thyroid medication and estrogen replacement therapy) were obtained from questionnaires given at the beginning of the study and annually thereafter. Calcium intake was assessed using the Food Frequency Questionnaire [28] and 3-day dietary history. Disease-related information included activity level, measured by the Framingham Activity Index [29]; disease severity, measured by the Health Assessment Questionnaire [30]; and a severity score, based on radiologic findings [31]. Information about disease duration and use of prednisone or disease-modifying antirheumatic drugs was ascertained by chart review.

    Bone mineral densities of the femur (femoral neck, Ward triangle, and trochanter) and lumbar spine were measured in all patients by dual-energy x-ray absorptiometry (Lunar Corp., Madison, Wisconsin) at the beginning of the study and at yearly follow-up visits. All studies were done using the same machine. Stability of measurement was assured with daily quality-assurance calibration by the manufacturer, weekly Lunar aluminum phantom in water bath, and Hologic spine phantom three times weekly. The coefficient of variation (calculated using 11 patients and three measurements) was 1.2% for the anteroposterior spine and 2.2% for the femoral neck. At the start of the study, the lateral scan of the spine was thought to be the most sensitive measurement for detecting changes induced by cortico-steroids [32]. However, we and others [33] have found the reproducibility of this view with the available technology to be suboptimal, especially in patients with arthritis, because correct positioning is difficult. We subsequently obtained anteroposterior scans of the spine. For patients from whom only the lateral view of the spine was available at baseline (n = 48 [20 patients in the treatment group and 28 in the placebo group]), we determined the anteroposterior value by adding the difference between the anteroposterior and lateral scans obtained after the first year of the study to the lateral scan obtained at baseline. This provided adequate measurement because the differences between anteroposterior and lateral views for each patient remained relatively constant (within 0.10 ± 0.07 g/cm2 for 87% of patients).

    Patients were seen by the study coordinator at 6-month intervals to assess compliance. At these visits, pills were counted and patients were questioned about side effects of medication.

    Statistical Analysis

    Because loss of bone mineral density over time is presumed to be proportional to the amount of bone mineral density remaining, the yearly rate of change (κ) was estimated using data from the three time points (baseline, year 1, and year 2) in the following equation: Equation 1

    Formula

    Differences in rates for the two treatment groups were assessed by using the t-test. The effect of treatment after adjustment for group differences in disease severity and duration was examined by linear regression analysis. Patients who received prednisone during the study and those who did not were analyzed separately and in combination. Clinical characteristics of the two treatment groups were compared using t-tests and chi-square tests. Potential interactions between treatment effects and patient characteristics were examined by analysis of variance. All analyses were done using SPS statistical software (SPS, Inc., Chicago, Illinois).

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    Results

    Baseline characteristics of the patients completing both years of the study are listed in Table 1. The patients studied were primarily middle-aged white women. Although study groups were similar for most characteristics, the patients receiving calcium and vitamin D3 tended to have disease of greater severity (by radiologic stage) and longer duration than did those receiving placebo. Among patients who were receiving corticosteroids, the mean dosage of prednisone at the initial visit was 5.9 mg/d for the calcium and vitamin D3 group and 5.0 mg/d for the placebo group. During the first year of study, 68% of patients were taking prednisone (mean dosage, 5.5 mg/d; range, 1 to 20 mg/d); during the second year, 65% were taking prednisone (mean dosage, 5.6 mg/d; range, 0.5 to 20 mg/d).

    View this table:
    Table 1. Baseline Characteristics of Patients Who Had Bone Mineral Density Measurements Available for All Time Points*

    During the 2-year study period, 29 of the original 130 patients (22%) dropped out of the study. Fifteen of the patients who dropped out had been in the calcium and vitamin D3 group and 14 had been in the placebo group. Fourteen patients withdrew for personal reasons, 1 patient died, and 3 patients developed serious illness (inflammatory bowel disease, cancer, and amyotrophic lateral sclerosis). Eleven patients (7 in the calcium and vitamin D3 group and 4 in the placebo group) dropped out of the study because of gastrointestinal toxicity. The most common gastrointestinal symptoms in treated patients were indigestion (n = 6) and constipation (n = 1). No cases of nephrolithiasis or hypercalcemia were seen in either group. Data are presented for the 96 patients who remained in the study and who had evaluable data at all three time points. Of these patients, only 9 (4 in the calcium and D3 group and 5 in the placebo group) took less than 80% of their medication, as assessed by pill count.

    Bone Densitometry of the Lumbar Spine

    The annual rate of change in bone mineral density is shown in Figure 1. Patients in the calcium and vitamin D3 group had an average increase in bone mineral density in the lumbar spine of 0.63% per year, and those in the placebo group had an average decrease of 1.31% per year (P = 0.015). The results of analyses done separately for patients who were receiving prednisone and those who were not indicate that this difference was attributable to the effects of calcium and vitamin D3 supplementation in patients receiving prednisone. Patients who received prednisone during the study showed a larger treatment effect attributable to calcium and vitamin D3 than did those who did not receive prednisone. The difference in the annual rate of change in bone mineral density between patients in the calcium and vitamin D3 group and those in the placebo group is shown in Table 2. A positive value indicates an increase in the rate of change in bone mineral density in patients in the calcium and vitamin D3 group compared with that in patients in the placebo group. The difference in the annual rate of change in bone mineral density of the lumbar spine between patients in the calcium and vitamin D3 group and those in the placebo group was 2.65% per year (adjusted for differences in disease severity and duration). During the 2 years of the study, bone mineral density changed only slightly in the lumbar spine of patients who did not receive prednisone (Figure 1). No statistically significant difference in the annual rate of change in bone mineral density in the lumbar spine was seen between patients in both groups who did not receive prednisone (Table 2).

    Figure 1. All patients. Patients receiving prednisone. Patients not receiving prednisone. Solid lines indicate values for patients in the calcium and vitamin D group; dashed lines indicate values for patients in the placebo group. Bars represent 95% Cls. A significant difference was seen between the rate of change in bone mineral densities of the spine and trochanter over 2 years in all patients and in patients receiving prednisone.
    View larger version:
    Figure 1. All patients. Patients receiving prednisone. Patients not receiving prednisone. Solid lines indicate values for patients in the calcium and vitamin D group; dashed lines indicate values for patients in the placebo group. Bars represent 95% Cls. A significant difference was seen between the rate of change in bone mineral densities of the spine and trochanter over 2 years in all patients and in patients receiving prednisone. Change in bone mineral density during the 2-year study period in patients with rheumatoid arthritis. Top.Middle.Bottom.3
    View this table:
    Table 2. Difference in Annual Rate of Change in Bone Mineral Density between the Calcium and Vitamin D3 Group and the Placebo Group*

    Bone Densitometry of the Femur

    Treatment also had a statistically significant effect at the trochanter in patients treated with corticosteroids. Patients who received placebo lost 0.90% of their bone mineral density per year, whereas patients who received calcium and vitamin D3 had a gain of 0.85% per year (P = 0.024) (Figure 1). The difference in the adjusted annual rate of change between patients in the calcium and vitamin D3 and placebo groups was 2.08% per year (Table 2). Bone mineral densities of the femoral neck and Ward triangle were relatively stable during the 2 years of the study in patients treated with corticosteroids, and no difference was seen between treatment groups in rates of change in bone mineral density in these areas. No statistically significant benefit of calcium and vitamin D3 supplementation was seen at any femoral site in patients who were not treated with corticosteroids.

    Analysis of variance did not show statistically significant interactions for change in bone mineral density of the lumbar spine between the effect of treatment with calcium and vitamin D3 and sex (P > 0.2), menopausal status (P > 0.2), baseline calcium intake (P > 0.2), or estrogen status (premenopausal and postmenopausal women receiving estrogen replacement therapy compared with postmenopausal women not receiving estrogen replacement therapy) (P = 0.144).

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    Discussion

    Corticosteroids lead to a decrease in bone mineral density, particularly in areas rich in trabecular bone, such as the lumbar spine and trochanter [1]. Dietary supplementation with calcium (calcium carbonate, 1000 mg/d) and vitamin D (3) (500 IU/d) stabilized bone mineral density in the lumbar spine and trochanter during 2 years of treatment in a group of patients with rheumatoid arthritis who were receiving long-term low-dose prednisone therapy (mean dosage, 5.6 mg/d). In patients treated with corticosteroids who did not receive calcium and vitamin D3, bone mineral densities of the lumbar spine and the trochanter decreased by 2.0% and 0.9% per year, respectively. Bone mineral densities of the femoral neck and Ward triangle were relatively stable in patients treated with corticosteroids and were unaffected by treatment with calcium and vitamin D3. Patients who were not receiving corticosteroids had stable bone mineral density in the lumbar spine and femur during the 2 years of the study, and treatment with calcium and vitamin D3 did not substantially improve bone mineral density in these patients.

    The treatment effect seen in this group of patients was probably not caused by correction of vitamin D deficiency. Although levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were not measured at baseline in our study, vitamin D deficiency was rarely found in patients with osteoporosis in this age group at our center (Leib E. Unpublished data). In addition, intake of calcium and vitamin D3 in this group of patients was greater than the national average, and conversion of vitamin D3 to its active metabolites is not affected by corticosteroid use [34-37].

    The design of this study limits its generalizability. First, it is unclear whether the benefits of calcium and vitamin D3 supplementation continue beyond 2 years. Second, bone mineral density is a surrogate measure for the clinical outcomes of major interest: pain, disability, and fracture related to osteoporosis. Third, because we studied only patients who were receiving low-dose corticosteroids, it is still unclear whether calcium and vitamin D3 supplementation prevents or minimizes loss of bone mineral density associated with moderate- to high-dose corticosteroid therapy [25, 26].

    Bone loss during treatment with corticosteroids varies because of differences in corticosteroid use (dose, timing, and duration) and such patient-specific risk factors as age, sex, hormonal status, baseline value of bone mineral density, and genetic and other factors that have not yet been determined. We found no statistically significant relation between sex, calcium intake, estrogen use, or menopausal status and treatment effect; however, because the numbers of men, women taking estrogen replacement therapy, and patients with low intake of calcium were small, our study could not answer these questions. The effects of calcium supplementation may differ between men and women. Calcium supplementation may be less important in women who are estrogen replete (premenopausal women or postmenopausal women receiving estrogen replacement therapy) than in those who are estrogen deficient. Lukert [38] and Hall [39] and their colleagues have shown the positive effects of estrogen replacement on bone mineral density in women receiving corticosteroids.

    Another limitation of our study is that half of the baseline values of bone mineral density of the anteroposterior spine were imputed from the baseline values of bone mineral density of the lateral spine. The rate of change of bone mineral density of the spine was determined by regressing data from all three time points so that determination of the baseline value of bone mineral density of the spine in some patients had much less effect on the overall rate. This type of conversion should introduce random error. Despite the conversion, we found a statistically significant difference in the change in bone mineral density at the lumbar spine in the patients treated with calcium and vitamin D3 compared with patients who received placebo. Bone mineral density measurements at the trochanter were not imputed, and a significant difference in the change in bone mineral density in the patients treated with calcium and vitamin D3 was also seen in this area. Both areas are rich in trabecular bone, in which the detrimental effects of corticosteroids should be greatest and treatment effects would be expected to be most significant.

    The deterioration of bone mineral density in patients not treated with corticosteroids does not mean that calcium and vitamin D supplementation is not beneficial in these patients. Reid [40] and Dawson-Hughes [41] and their colleagues have shown the benefits of calcium supplementation in postmenopausal women, particularly those with low calcium intake. We studied a more diverse group of patients (men and pre- and postmenopausal women), and dietary intake of calcium among our participants was average.

    This study was not strictly an intention-to-treat study: We did not have complete data on bone mineral density for patients who dropped out of the study. Therefore, data from these patients could not be included in the analysis. Our results show the effects of calcium and vitamin D3 supplementation in a group of patients who were relatively motivated and compliant.

    Long-term, low-dose corticosteroid therapy is frequently used to treat rheumatoid and other types of inflammatory arthritis, polymyalgia rheumatica, and lupus erythematosus. Corticosteroids are prescribed by generalists who treat asthma and chronic obstructive lung disease as well as those who treat such autoimmune and allergic diseases as multiple sclerosis, inflammatory bowel disease, vasculitis, and dermatologic conditions. An increasing number of persons are taking corticosteroids for an indefinite period after bone marrow or organ transplantation [42-44]. Corticosteroid use is associated with lower bone mineral density in the spine and can result in painful vertebral fractures that substantially decrease quality of life [45, 46]. These fractures are a delayed complication, often occurring years after treatment with corticosteroids, when bone mineral density has decreased substantially below fracture threshold. Years of treatment are required to significantly increase bone mass after a fracture occurs. Thus, stabilization of bone mineral density during treatment with corticosteroids appears to be the optimal strategy for prevention of fractures induced by corticosteroid use.

    Because corticosteroids decrease absorption of calcium from the gastrointestinal tract, supplementation with calcium and vitamin D3 is one strategy to prevent bone loss induced by corticosteroids. Calcium supplementation has been reported to suppress biochemical markers of bone resorption in patients treated with corticosteroids [25, 47]. Recently, Sambrook and colleagues [21] found that treatment with calcium and 1,25-dihydroxyvitamin D stabilized bone mineral density of the lumbar spine in patients treated with moderate to high doses of corticosteroids. Although the more potent vitamin D analogues may preserve bone mineral density in the lumbar spine during moderate- to high-dose corticosteroid treatment [48], the expense and toxicity associated with the use of these analogues have precluded widespread patient and provider acceptance. Calcitonin, estrogen, and the bisphosphonates appear to be effective in the prevention and treatment of osteoporosis induced by the use of corticosteroids [38, 39, 49-52], but cost and patient preference tend to limit widespread use of these agents in preventing development of osteoporosis secondary to long-term, low-dose corticosteroid treatment.

    The ideal preventive strategy should be effective, inexpensive, uncomplicated, and safe. Calcium carbonate and vitamin D3 supplements can be purchased without prescription and have low toxicity. Our results suggest that 1000 mg of calcium carbonate and 500 IU of vitamin D3 per day will stabilize bone mineral density in the lumbar spine and trochanter during low-dose prednisone treatment and may therefore lead to a decrease in the vertebral fracture rate in patients with diseases necessitating long-term corticosteroid use.

    Drs. Leib, Vacek, and Cooper and Ms. Cartularo: University of Vermont, College of Medicine, Given D301, Burlington, VT 05405.

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    1. Ann Intern Med December 15, 1996 vol. 125 no. 12 961-968
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