Effect of low-dose prednisone (with calcium and calcitriol supplementation) on calcium and bone metabolism in healthy volunteers.

The administration of moderate to high doses of corticosteroids is associated with bone loss. This probably results from the uncoupling of bone formation (decreased) and bone resorption (unchanged or increased). We examined the effect of low-dose (10 mg/day) prednisone (LDP) and the possible mitigating effects of calcium and 1.25 (OH)2 vitamin D (calcitriol) on calcium and bone metabolism in eight healthy, young male volunteers. The study consisted of four observation periods: in the first period, LDP was prescribed during 1 week; in the second, third and fourth periods, calcium (500 mg/day), calcitriol (0.5 micrograms b.i.d.) and calcium in combination with calcitriol, respectively, were added to LDP. Bone formation was measured by means of serum osteocalcin, carboxy-terminal propeptide of type 1 procollagen (P1CP) and alkaline phosphatase, bone resorption by means of urinary excretion of calcium, hydroxyproline, (free and total) pyridinoline, (free and total) deoxypyridinoline and serum carboxy-terminal cross-linked telopeptide of type 1 collagen (1CTP). Dietary calcium and sodium intake were maintained at a stable level during the entire study period. Treatment with LDP led to a decrease in osteocalcin, P1CP and alkaline phosphatase (all P < 0.01). Urinary excretion of pyridinolines, hydroxyproline and serum 1CTP did not increase, but remained unchanged or slightly reduced (P < 0.05), depending on the time of measurement and the marker of bone resorption. Parathyroid hormone (PTH) (insignificantly) increased during LDP (+19%) and LDP plus calcium (+14%), but decreased during supplementation with calcitriol (-16%) and calcium/calcitriol (-44%; P < 0.01). Urinary excretion of calcium increased during treatment with LDP and calcitriol (P < 0.05) and calcium/calcitriol (P < 0.05). It is concluded that LDP has a negative effect on bone metabolism, since bone formation decreased while bone resorption remained unchanged or decreased slightly. The increase in PTH during LDP could be prevented by calcitriol combined with calcium supplementation.

Comparison of urinary bone resorption markers in women of 40-70 years; day-to-day and long-term variation in individual subjects.

OBJECTIVES: Bone resorption can be judged using biochemical markers in urine and blood. Our aim was to study the patterns of markers in the postmenopausal period. METHODS: The urinary excretion of bone resorption markers was tested using different assays. The study was undertaken to determine the day-to-day and the long-term variation, over 8 years, of these markers in individual women. RESULTS: Over a period of 2 weeks, the median of the day-to-day variation of the pyridinium crosslink markers varied between 12 and 23%, the median value of the long-term variation over 8 years between 10 and 21%, for the telopeptide markers median day-to-day variation was 18 and 20% and the long-term variation was 17 and 19%. The correlations between the different crosslink markers varied between 0.63 and 0.92, depending on the kind of the crosslink and on the method of determination. The two telopeptide markers showed an excellent correlation with r of 0.95. The excretion of all bone resorption markers varied with postmenopausal age, some differences were found between the crosslink and the telopeptide excretions with age, in women more than 20 years postmenopausal the telopeptides decrease whereas the crosslinks show an increase. CONCLUSIONS: This study shows that crosslinks and telopeptides give similar information on the rate of bone resorption: an increase during the first 5 years and a slight decrease in the next 5 years after menopause, discrepancies were found after 10 or more postmenopausal years.

Is addition of sodium fluoride to cyclical etidronate beneficial in the treatment of corticosteroid induced osteoporosis?

OBJECTIVE: To investigate whether administration of sodium fluoride (NaF) in addition to cyclical etidronate has a positive effect on bone mineral density (BMD) in patients with established osteoporosis during continued treatment with corticosteroids. PATIENTS AND METHODS: 47 patients who were receiving treatment with corticosteroids were included in a two year randomised, double blind, placebo controlled trial. Established osteoporosis was defined as a history of a peripheral fracture or a vertebral deformity, or both, on a radiograph. All patients were treated with cyclical etidronate, calcium, and either NaF (25 twice daily) or placebo. Vitamin D was supplemented in the case of a low serum 25 (OH) vitamin D concentration. BMD of the lumbar spine and hips was measured at baseline and at 6, 12, 18, and 24 months. RESULTS: After two years of treatment, the BMD of the lumbar spine in the etidronate/NaF group had increased by +9.3% (95% confidence intervals (CI): +2.3% to +16.2%, p < 0.01), while the BMD in the etidronate/placebo group was unchanged: +0.3% (95% CI: -2.2% to +2.8%). The difference in the change in BMD between groups was +8.9% (95% CI: +1.9% to +16.0%, p < 0.01). For the hips, no significant changes in BMD were observed in the etidronate/NaF group after two years: -2.5% (95% CI: -6.8% to +1.8%); in the etidronate/placebo group BMD had significantly decreased: -4.0% (95% CI: -6.6% to -1.4%; p < 0.01). The difference between the groups was not significant: +1.5% (95% CI: -3.4% to +6.4%). No significant differences in number of vertebral deformities and peripheral fractures were observed between the two groups. CONCLUSION: The effect of combination treatment with NaF and etidronate on the BMD of the lumbar spine in corticosteroid treated patients with established osteoporosis is superior to that of etidronate alone.

Effect of sodium fluoride on the prevention of corticosteroid-induced osteoporosis.

To investigate whether sodium fluoride (NaF) is able to prevent bone loss in patients treated with corticosteroids (Cs), we performed a randomized double-masked, placebo-controlled trial with 44 Cs-treated patients without established osteoporosis, defined as the absence of previous peripheral fractures and vertebral deformities on radiographs. The effects of NaF (25 mg twice daily) and placebo on the bone mineral density (BMD) of the lumbar spine and hips were compared at baseline and at 6, 12, 18 and 24 months. After 2 years, the BMD of the lumbar spine had decreased in the placebo group by 3.0% (95% CI: -4.9% to -1.0%; p < 0.01); in the NaF group there was a statistically insignificant increase in BMD of 2.2% (95% CI: -0.8% to +5.3%). The difference in the changes in BMD between the two groups was +5.2% (95% CI: +1.8% to +8.6%; p < 0.01). In the hips, BMD had decreased after 2 years in both groups: in the placebo group by -3.0% (95% CI: -5.0% to -1.0%; p < 0.05) and in the NaF group by 3.8% (95% CI: -6.1% to -1.5%; p < 0.01). The difference in the changes in BMD between the two groups was not significant: +0.8% (95% CI: -2.1% to +3.8%). Three vertebral deformities were observed in the placebo group and one in the NaF group (insignificant difference), while no peripheral fractures occurred during the study period. It is concluded that in Cs-treated patients without established osteoporosis NaF prevents bone loss in the lumbar spine but does not have a positive effect on the BMD of the hips.

Changes in (markers of) bone metabolism during high dose corticosteroid pulse treatment in patients with rheumatoid arthritis.

OBJECTIVE: To examine the effect of high dose corticosteroid pulse treatment (three times 200 mg dexamethasone intravenously in eight days) on calcium and bone metabolism in 17 consecutive patients with active rheumatoid arthritis (RA). METHODS: Bone formation was quantified by measurement of serum alkaline phosphatase, osteocalcin, and carboxyterminal propeptide of type I procollagen (pro-I-CPP) concentrations. Bone resorption was measured by urinary excretion of calcium, hydroxyproline, (free and total) deoxypyridinoline (Dpyr), (free and total) pyridinoline (Pyr), and serum concentrations of the carboxyterminal cross linked telopeptide of type I collagen (I-CTP). Disease activity of RA was measured by erythrocyte sedimentation rate, C reactive protein, and Ritchie and Thompson joint scores. RESULTS: Disease activity was initially high, and decreased during corticosteroid pulse treatment and the following five weeks. Osteocalcin, alkaline phosphatase, and pro-I-CPP concentrations were initially within normal limits, while I-CTP, Dpyr, and Pyr were increased. Osteocalcin and pro-I-CPP concentrations decreased (p < 0.01) during corticosteroid pulse treatment, but rapidly returned to baseline after the treatment. No changes were observed in alkaline phosphatase and urinary excretion of calcium and hydroxyproline. Bone resorption measured by serum I-CTP and urinary excretion of Pyr and Dpyr was unchanged or decreased (p < 0.05-0.01), depending on the time of measurement and the parameter measured. CONCLUSIONS: In these patients with active RA, bone resorption was increased, while bone formation was within normal limits. During high dose corticosteroid pulse treatment, bone formation was only transiently decreased, while markers of bone resorption were unchanged or decreased. Because corticosteroid pulse treatment has only a short term negative effect on bone formation, and because it probably reduces bone resorption, at least partly as a result of the decreased disease activity, the effect of corticosteroid pulse treatment on bone may be assumed to be relatively mild.

Determination of pyridinoline and deoxypyridinoline in urine, with special attention to retaining their stability.

Urinary excretion of the pyridinium crosslinks pyridinoline (Pyr) and deoxypyridinoline (Dpyr) is used as a biochemical marker of bone resorption. The present study was undertaken to determine the long-term stability of these compounds in stored urine, using the HPLC method. Systematic investigation of their chemical stability in urine demonstrated that both the free and conjugated forms of Pyr and Dpyr are extremely stable: No significant changes were observed after 6 weeks at -20 degrees C storage (e.g., free Pyr 9.6 +/- 1.2 mumol/mol creatinine (before) and 10.6 +/- 3.2 (after); free Dpyr 2.3 +/- 0.2 mumol/mol creatinine (before) and 2.5 +/- 1.2 (after)). These results predict stability of urines stored for 10-20 years at -20 degrees C in the dark. Also, freezing and thawing as many as 10 times had no effect on the concentrations of the crosslinks. Study of the stability of the excretion pattern in healthy women showed substantially higher variations in excretions of free and total Dpyr (18% and 13%, respectively) than of Pyr (10% for both forms).