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Biomarkers of bone turnover after a short period of steroid therapy in elderly men.

An excess of glucocorticoids is the third most common cause of bone loss after postmenopausal and senile osteoporosis. The iatrogenic form of glucocorticoid-induced osteoporosis, which is more frequent than Cushing syndrome, has uncertain cellular and molecular bases. The lack of consistent information concerning the pathophysiology of corticosteroid-related bone loss is attributable to several coexisting factors, e.g., the heterogeneity of the underlying disease, that may themselves influence skeletal loss, dosage, and duration of treatment (1, 2).

A well-known action of steroids on bone is decreased bone formation. There are no consistent findings concerning bone resorption in glucocorticoid-induced osteoporosis. The aim of this study was to evaluate the impact of a short period of steroid therapy on the serum concentrations of bone biomarkers in elderly men.

We studied 14 elderly men (mean age [+ or -] SD, 66.1 [+ or -] 6.4 years; range, 57-76 years), admitted to our hospital from October 1998 to June 1999, who were suffering from various medical pathologies requiring systemic steroid therapy. Four patients were suffering from pulmonary diseases, four from immunologic, two from cerebral, and four from neoplastic diseases without bone metastases. None of these patients was bedridden. The patients were studied while undergoing treatment, which lasted no more than 30 days (mean [+ or -] SD, 9.1 [+ or -] 9.6 days), with a cumulative dose of 10-1250 mg of prednisone (mean prednisone equivalent, 338 [+ or -] 382 mg) or its equivalent. The patients were compared with 14 hospitalized patients of similar age (67.9 [+ or -] 6.7 years) without any history of bone illness who were not taking drugs known to affect bone tissue. The mean period of hospitalization was similar for patients and controls at the time of investigation. Informed consent was obtained from patients and controls to perform this investigation.

Metabolic tests included a blood sample, collected in the morning between 0800 and 1000, to evaluate serum biomarkers of bone turnover.

Bone resorption was assessed by measuring tartrate-resistant acid phosphatase activity (TRAP) and the C-terminal telopeptides of type I collagen ([beta]CTx; Osteometer Biotech A/S), whereas bone formation was assessed by measuring serum osteocalcin (BGP; N-tact Osteo SP; Incstar Co.) and bone-specific alkaline phosphatase (ALP; Alkphase B; Metra Biosystem Inc.). Serum TRAP was assayed by a spectrophotometric assay used in our laboratory (3). Serum [beta]CTx was measured by a two-site ELISA based on two highly specific monoclonal antibodies against the amino acid sequence AHD-[beta]-GGR, where the aspartic acid residue (D) is [beta]-isomerized (4). The detection limit, defined as the concentration corresponding to 2 SD above the mean of 15 determinations of the zero calibrator, was 75 pmol/L. We assessed imprecision (as CV) by measuring three serum samples in eight consecutive analytical runs (5%) and each of the three samples in the same analytical run (9.8%). Serum bone ALP was assayed by an immunoenzymatic assay and serum BGP by an immunoradiometric assay used in our laboratory. The details of these two methods are reported elsewhere (5, 6).

We found no difference between patients and controls for mean serum TRAP (10.5 [+ or -] 2.4 vs 10.6 [+ or -] 2.3 U/L), whereas mean serum [beta]CTx was significantly higher in steroid-treated patients compared with controls (5194 [+ or -] 2617 vs 1491 [+ or -] 774 pmol/L; P <0.001; Fig. 1). Bone ALP was similar between the two groups (17.1 [+ or -] 4.5 vs 18.1 [+ or -] 3.6 U/L), whereas we found a statistically significant difference for serum BGP (1.4 [+ or -] 1.1 vs 5.1 [+ or -] 1.4 /,g/L; P <0.001; Fig. 1). Finally, serum BGP was inversely correlated with the cumulative dose of steroids (r = -0.56; P <0.05).

During glucocorticoid treatment, there is biphasic bone loss with a rapid initial loss of ~12% during the first few months, followed by a slower phase of ~2-5% annually (1). The effect of glucocorticoids on bone consists of reduced bone formation with decreased wall thickness of the trabeculae, a strong indication of the decreased output of osteoblasts (7, 8). In agreement with these data, our study showed a decrease in serum BGP that was correlated with the cumulative dose of steroids. Recent studies have provided evidence that the decreased bone formation may be attributable to a suppressive effect of glucocorticoids on osteoblastogenesis as well as promotion of apoptosis of osteoblasts and osteocytes. This suppressive effect could explain the efficacy of bisphosphonates in preventing bone fractures because of their potent antiapoptotic effects on osteoblasts and osteocytes in vitro and in vivo (9, 10).

The effect of glucocorticoids on bone resorption is unknown. Some histomorphometric studies have shown an increased number of osteoclasts, whereas other studies have not confirmed this finding and more recent ones have shown that the number of osteoclasts is reduced (8). Because of the molecular and cellular linkage between osteoblastogenesis and osteoclastogenesis, the suppressive effect of glucocorticoids on the first process implies a similar effect on the second (1). Nevertheless, after administration of glucocorticoids to mice, the number of osteoclasts in a bone section doubles, although osteoclastogenesis in ex vivo marrow cultures is significantly decreased. The sudden death of osteoblasts by apoptosis of existing basic multicellular units and the prolonged life span of existing osteoclasts would lead to a relative increase in resorption and finally to bone loss (11). In agreement with these data, our study demonstrated an increase in serum [beta]CTx during steroid therapy.

[FIGURE 1 OMITTED]

Some studies have demonstrated that the risk of fractures, particularly those of the vertebral body and proximal femur, is increased during oral corticosteroid treatment and is directly related to the daily dose of oral corticosteroids. The risk of fractures increases rapidly at the beginning of oral steroid therapy, but reverses sharply toward baseline values after discontinuation of therapy. However, bone density does not predict the magnitude of the risk of fractures. In fact, vertebral fractures occur in corticosteroid users at higher bone densities compared with involutional osteoporosis. It would be necessary to implement preventive therapy before rapid bone loss occurs, without taking into account bone mineral density (11, 12). According to our results, the markers of bone turnover could help to identify high-risk patients; furthermore, given the rapidity of the changes observed, it would be important to monitor these markers at close intervals.

An important underlying fact is that the changes in markers are not uniform because bone ALP and TRAP concentrations are unchanged. Glucocorticoids could act in different phases of bone turnover, as expressed by different markers. In fact, bone ALP and BGP are bone formation markers, but the first is produced in the early phase of osteoblastogenesis, whereas BGP is produced during bone mineralization. TRAP and [beta]CTx are two bone resorption markers: serum TRAP is a cytochemical marker useful for identification of the number of osteoclasts (3), whereas [beta]CTx is produced by osteoclasts during resorption of the matrix.

In conclusion, our study indicates that a short period of steroid therapy in elderly men is associated with alterations in markers of bone turnover. In particular, in the early phase of therapy, glucocorticoids cause a reduction in bone formation, as shown by the decrease in BGP, and an increase in bone resorption, as shown by the increase in [beta]CTx, which represent the pathophysiologic bases leading to bone loss. Prospective studies would therefore be needed to determine whether such perturbations of skeletal remodeling and biomarkers persist on a long-term bases.

References

(1.) Manolagas SC, Weinstein RS. New developments in the pathogenesis and treatment of steroid-induced osteoporosis. J Bone Miner Res 1999;14: 1061-6.

(2.) Pearce G, Tabensky AD, Delmas PD, Gordon Baker HW, Seeman E. Corticosteroid-induced bone loss in men. J Clin Endocrinol Metab 1998;83: 801-6.

(3.) Ballanti P, Minisola S, Pacitti MT, Scarnecchia L, Rosso R, Mazzuoli GF, Bonucci E. Tartrate-resistant acid phosphate activity as osteoclastic marker: sensitivity of cytochemical assessment and serum assay in comparison with standardized osteoclast histomorphometry. Osteoporos Int 1997;7:39-43.

(4.) Rosenquist C, Fledelius C, Christgau S, Pedersen BJ, Bonde M, Qvist P, Christiansen C. Serum CrossLaps one step ELISA. First application of monoclonal antibodies for measurement in serum of bone-related degradation products from C-terminal telopeptides of type I collagen. Clin Chem 1998;44:2281-9.

(5.) Minisola S, Pacitti MT, Romagnoli E, Rosso R, Carnevale V, Caravella P, et al. Clinical validation of new immunoradiometric assay for intact human osteocalcin. Calcif Tissue Int 1999;64:365-9.

(6.) Romagnoli E, Minisola G, Carnevale V, Scillitani A, Frusciante V, Aliberti G, Minisola S. Assessment of serum total and bone alkaline phosphatase in clinical practice. Clin Chem Lab Med 1998;36:163-8.

(7.) Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. J Clin Invest 1998;102:274-82.

(8.) Dempster DW. Bone histomorphometry in glucocorticoid-induced osteoporosis. J Bone Miner Res 1989;4:137-41.

(9.) Saag KG, Emkey R, Schnitzer TJ, Brown JP, Hawkins F, Goemaere S, et al. Alendronate for the prevention and treatment of glucocorticoid induced osteoporosis. N Engl J Med 1998;339:292-9.

(10.) Reid DM, Hughes RA, Laan RFIM, Sacco-Gibson NA, Wenderoth DH, Adami S, et al. Safety of daily risedronate in the treatment steroid-induced osteoporosis in men and women: a randomized trial. J Bone Miner Res 2000;15:1006-13.

(11.) Manolagas SC. Corticosteroids and fractures: a close encounter of the third cell kind. J Bone Miner Res 2000;15:1001-5.

(12.) Van Staa TP, Leufkens HGM, Abenhaim L, Zhang B, Cooper C. Use of oral corticosteroids and risk of fractures. J Bone Miner Res 2000;15:993-1000.

Federica Paglia, [1] Simona Dionisi, [1] Simona De Geronimo, [1] Rossana Rosso, [1] Elisabetta Romagnoli, [2] Natalia Raejentroph, [1] Alessandro Ragno, [1] Massimiliano Celi, [1] Jessica Pepe, [1] Emilio D'Erasmo, [1] and Salvatore Minisola [1] * ([1] Dipartimento di Scienze Cliniche, Universita di Roma "La Sapienza", 00161 Rome, Italy; [2] Ospedale "Casa Sollievo della Sofferenza" IRCCS, San Giovanni 71013 Rotondo (FG), Italy; address correspondence to this author at: Department of Clinical Sciences, Policlinico Umberto I, Viale del Policlinico 155, 00161 Rome, Italy; fax 39-06-68803566, e-mail salvatore.minisola@uniromal.it)
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Title Annotation:Technical Briefs
Author:Paglia, Federica; Dionisi, Simona; De Geronimo, Simona; Rosso, Rossana; Romagnoli, Elisabetta; Raeje
Publication:Clinical Chemistry
Date:Jul 1, 2001
Words:1684
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