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PraÈvention der Kortikosteroid- induzierten Osteoporose durch Alfacalcidol. Summary We studied the effect of alphacalcidol (1-α-hydroxycholecal- ciferol) on ...

Z Rheumatol 59:Suppl 1 I/48±52 (2000) ° Steinkopff Verlag 2000

P. Lakatos Z. Nagy L. Kiss C. Horvath I. Takacs J. Foldes G. Speer A. Bossanyi

PraÈvention der Kortikosteroidinduzierten Osteoporose durch Alfacalcidol Summary We studied the effect of alphacalcidol (1-a-hydroxycholecalciferol) on bone metabolism in patients who were placed on glucocorticoid therapy. We selected 41 women (age: 32±52 yrs) who were recently diagnosed with systemic lupus erythematodes, multiple sclerosis, rheumatoid arthritis or asthma bronchiale. Patients did not have

P. Lakatos ()) ´ Z. Nagy ´ C. Horvath I. Takacs ´ J. Foldes 1st Department of Medicine Semmelweis University Medical School Koranyi 2/a H-1083 Budapest, Hungary L. Kiss HeteÂnyi GreÂza County Hospital Szolnok, Hungary A. Bossanyi Department of Orthopedics Semmelweis University Medical School H-1083 Budapest, Hungary

Prevention of corticosteroid-induced osteoporosis by alfacalcidol

other disease or take drugs known to influence bone metabolism. Patients were randomly enrolled into two groups and were given 5± 25 mg prednisone daily. After 4 weeks, group A (n = 21) received 0.5±1.0 lg (mean = 0.54 Ô 0.03 lg) alphacalcidol and group B (control; n = 20) was given 500 mg calcium daily for three years. There were no significant differences in age and steroid doses between groups. Serum calcium (Ca), osteocalcin (OC), collagen I C-terminal propeptide (PICP), parathyroid hormone (PTH), and urinary calcium and deoxypyridinoline crosslink excretion (DPD) were measured before corticosteroid administration, and before alphacalcidol or calcium treatment as well as 6 weeks, 6 months, and 1, 2, and 3 years later. Bone mineral density (BMD) was examined before treatment and 6 months, 1, 2, and 3 years later by DEXA and SPA. OC and PICP decreased significantly after 4 weeks on steroid in both groups and increased in group A but not in group B after 6 weeks of

Introduction The association between endogenous corticosteroid excess and osteoporosis was first reported by Cushing in 1932 (1). Parallel with the widespread use of corticosteroid treatments, the deleterious effect of these drugs on bone has been documented. The bone loss stimulated

treatment with alphacalcidol and remained unchanged for 3 years. Serum PTH increased in both groups after 4 weeks of glucocorticoid treatment and was reduced in group A, but not in group B, after 6 weeks on alphacalcidol. Serum Ca, urinary Ca, and DPD did not change significantly in either group during the study period. Lumbar spine and femoral neck BMD were significantly reduced in group B after 6 months and 1 year, respectively, and continued to decrease during the study, while no significant change in group A was observed. BMD of the radius did not change in either group for 2 years but there was a significant reduction by the third year in group B. Based on these results, alphacalcidol treatment appears to be effective in preventing glucocorticoid-induced bone loss in these patients by reducing secondary hyperparathyroidism and stimulating bone formation. Key words Alphacalcidol ± corticosteroid ± osteoporosis

by corticosteroids leads to increased fragility of bone and finally to fractures. The incidence of corticosteroid-induced osteoporosis is estimated to be between 30±50% among patients receiving this type of treatment (2). Bone loss is primarily stimulated by steroids in the spine and the femoral neck which are composed of mainly trabecular bone with higher metabolic turnover (3).

P. Lakatos et al. Prevention of corticosteroid-induced osteoporosis by alfacalcidol

Corticosteroids exert their effect on bone tissue via two major mechanisms. They stimulate renal calcium excretion and inhibit intestinal calcium absorption, opposing the effects of vitamin D, thus, leading to secondary hyperparathyroidism (4). Corticosteroids also directly inhibit osteoblasts and thus reduce bone formation (5). This effect is presumably mediated by an inhibitory effect of corticosteroids on the local production of growth factors anabolic for bone (5). During the last few decades, several attempts were made to prevent or treat corticosteroid-induced osteoporosis; however, different treatment modalities yielded conflicting results. Alfacalcidol (1-a-hydroxycholecalciferol) has been shown to enhance intestinal calcium absorption (6), as well as to inhibit the synthesis and release of parathyroid hormone (7, 8). Serum 25-hydroxyvitamin D levels of patients on chronic corticosteroid therapy have been reported to be lower than normal (9). On the other hand, BB alleles of vitamin D receptor gene which is thought to be associated with low bone mass appears to be more frequent in patients who develop corticosteroid-induced osteoporosis (10). Based on these data, we postulated that alfacalcidol may be able to reduce corticosteroid-induced bone loss.

Subjects and materials We studied 41 women (age: 32±52 yrs) who have been recently diagnosed with systemic lupus erythematodes, multiple sclerosis, rheumatoid arthritis or asthma bronchiale. The patients did not have any other diseases or take medication known to influence calcium or bone metabolism. Renal stone formation in the history was an exclusion criterion. Patients were randomly divided into two groups after 4 weeks of steroid (5±25 mg prednisone/day) treatment. Group A (n = 21) received 0.25± 1.0 lg (mean: 0.54 Ô 0.03 lg) alfacalcidol (Alpha-D3, Teva Pharma) daily, while Group B (n = 20) was administered 500 mg calcium (Calcium-Sandoz, Novartis) every day for 3 years. Steroid treatment was continuous in both groups for the 3 years of follow-up. There was no significant difference between the mean age (A= 43.8 yrs, B = 44.1 yrs) and corticosteroid dosage (A= 14.7 Ô 1.1 mg/day, B = 14.9 Ô 1.3 mg/day prednisone, cumulated dose for A: 15 920 Ô 872 mg for B: 16 137 Ô 798 mg), as well as in body weight, height, calcium intake, and renal function of the two groups. Informed consent was obtained from all subjects enrolled in the study. Patients were followed for 3 years. Serum calcium, osteocalcin (OC), procollagen I, carboxyterminal peptide (PICP), parathyroid hormone (PTH), urinary calcium and deoxypyridinoline crosslink (DPD) excretion were determined at the start of steroid (±4 weeks) and

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alfacalcidol or calcium (0 timepoint) treatment, as well as 6 weeks, 6 months, 1, 2, and 3 years later. Serum and urinary calcium concentrations were measured by atomic absorption spectrometry. Serum calcium levels were corrected for serum albumin. Urinary calcium excretion was estimated by calculating calcium/creatinine ratio from the first morning void. OC, PICP, and DPD were assessed by commercial ELISA assays (Metra Biosystems, Santa Clara, CA, USA). Intact PTH was tested by IRMA method (Bio-Rad, Hercules, CA, USA). Bone mineral density (BMD) of the lumbar spine (L 2±4), femoral neck, and radius midshaft was measured by DEXA (Lunar DPX-L, Lunar Corp. Madison, WI, USA) and SPA (NK-365, Gamma Ltd., Budapest, Hungary), respectively, at the beginning of the study, as well as after 6 months, 1, 2, and 3 years of alfacalcidol or calcium therapy. Data were expressed as mean Ô SEM and analyzed by ANOVA and subsequent Fisher's least significant difference multiple-comparison test.

Results OC and PICP showed a significant decrease in both groups after the first 4 weeks of corticosteroid treatment followed by a significant increase in group A after 6 weeks of alfacalcidol administration (Fig. 1 a and b). OC and PICP did not increase in group B. OC and PICP levels observed at 6 weeks remained unchanged in both groups during the rest of the follow-up period. Serum and urinary calcium as well as DPD were within the normal range at the beginning of the study, and did not change during the 3 years. PTH levels increased in both groups significantly after the first 4 weeks of steroid therapy (Fig. 1 c). In group A, PTH was reduced to the initial level after 6 weeks on alfacalcidol while it remained elevated in group B. Lumbar and femoral BMD decreased in group B after 6 months (Fig. 2 a and b). This reduction was 5.8% in the lumbar spine and 3.6% in the femoral neck after 3 years. No statistically significant reduction was seen in group A. The BMD of the radius showed no change during the first year; however it showed a 3.2% reduction by the end of the third year (Fig. 2 c). Two clinically significant bone fractures in group B and 1 in group A were observed. Both alfacalcidol and calcium treatments were welltolerated by the patients. One patient in group A was excluded in the third year due to renal stone formation.

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Zeitschrift fuÈr Rheumatologie, Band 59, Suppl 1 (2000) ° Steinkopff Verlag 2000

Fig. 1 A) Changes in serum osteocalcin of patients on corticosteroids treated with alfacalcidol (squares) or calcium (triangles) for 3 years. Data represent mean Ô SEM. *** = p < 0.001 vs. `±4 weeks'; +++ = p < 0.01 vs. `0'; # = p

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