Immediate Fall of Bone Formation and Transient Increase of Bone Resorption in the Course of High-Dose, Short-Term Glucocorticoid Therapy in Young Patients with Multiple Sclerosis

Abstract

Glucocorticoid (GC)-induced osteoporosis is the leading form of secondary osteoporosis. Bone loss can be rapid. However, longitudinal studies at the very beginning of treatment are scarce. Patients relapsing from multiple sclerosis are treated with high-dose, short-term iv GCs. A number of them are young, without concomitant disease affecting bone and with no substantial impairment of mobility. Such patients were selected for the present study. Thirteen patients suffering from multiple sclerosis [11 females, two males; age 32 +/- 2 yr (mean +/- se)] and receiving iv methylprednisolone 15 mg/kg daily for 10 d completed the study. We measured serum osteocalcin (OC), aminoterminal propeptide of type I collagen (PINP), bone isoform of alkaline phosphatase (bALP), carboxyterminal telopeptide of type I collagen (CTX), and urinary calcium/creatinine ratio (uCa/Cr) during the 10-d cycle and 3 months later. Dual-energy x-ray absorptiometry and calcaneal quantitative ultrasonometry were performed before and 6 months after therapy. We found an immediate, impressive fall of OC and PINP (-80 +/- 3 and -54 +/- 5% at d 2, respectively), which persisted throughout the whole treatment period (P < 0.0001 for both markers). bALP levels showed only a modest decrease at d 6 (-19 +/- 7%, P < 0.05), with subsequent return to baseline in d 7-10. After 3 months, OC, PINP, and bALP levels rose to +51 +/- 22, +37 +/- 16 (not significant), and +61 +/- 17% (P < 0.01) with respect to baseline, respectively. uCa/Cr and CTX showed a progressive, marked increase during treatment, peaking at d 7-9 (+92 +/- 44 and +149 +/- 63%, respectively), with subsequent decrement at d 10 (P < 0.01 and P < 0.05, respectively) despite continuing GC administration. After 3 months, uCa/Cr and CTX levels were also higher than baseline. No change in quantitative ultrasonometry parameters and bone mineral density was observed 6 months after therapy. In conclusion, high-dose, short-term iv GC regimens cause an immediate and persistent decrease in bone formation and a rapid and transient increase of bone resorption. Our data also support the concept that discontinuation of such regimens is followed by a high bone turnover phase.

Glucocorticoids maintain human osteoclasts in the active mode of their resorption cycle

“…Accordingly, novel skeletonization and meshing algorithms are being performed on 3D images of the excavations produced in the presence of GCs in this study, and so far, they predict lower stiffness and increased fracture risk despite unchanged total resorbed area. (46) Furthermore, the serum levels of CTX are increased in GC-treated patients, (5,6) as are also the levels of CTX in the present pit assay in the presence of GCs. However, as stressed in the introduction, GC-induced osteoporosis is multifactorial (2,8) and also may result from increased OC survival and differentiation (9)(10)(11)13,15,16) and may be due both to direct effects and mediation by other cell types.…”

“…(10,17,18) One would expect that besides survival and differentiation, the resorptive activity of existing OCs is also stimulated by GCs because of the very early increase in bone-resorption markers induced by GCs in patients. (5,6) However, we are not aware of any mechanistic OC culture study supporting this view. Instead, primary OCs isolated from rat bones eroded the surfaces of bone slices less extensively in the presence of high-dose GC.…”

“…In addition, bone-resorption markers increase immediately in patients receiving intravenous GCs, and the maximum increase in serum cross-linked C-telopeptide (CTX) was already reached 24 hours after the very first infusion. (5,6) In bone explants the levels of specific markers of osteoclasts (OCs), the bone-resorbing cells, also increase significantly already after 3 hours of exposure to GCs. (7) These observations clearly indicate an immediate effect of GCs on OCs.…”

Bone health in ambulatory individuals with multiple sclerosis: Impact of physical activity, glucocorticoid use, and body composition

“…The severity of bone loss depends on dose and duration of treatment [12]. High doses of glucocorticoids, such as those typically used in treatment of MS exacerbations, have been shown to increase bone resorption and decrease bone formation [14][15]. Research suggests that the use of glucocorticoids is a predictor of bone loss in individuals with MS [2,7]; however, most studies do not assess the effect of long-term use of glucocorticoids on BMD in those with MS [9,[15][16].…”

“…High doses of glucocorticoids, such as those typically used in treatment of MS exacerbations, have been shown to increase bone resorption and decrease bone formation [14][15]. Research suggests that the use of glucocorticoids is a predictor of bone loss in individuals with MS [2,7]; however, most studies do not assess the effect of long-term use of glucocorticoids on BMD in those with MS [9,[15][16]. The association between long-term glucocorticoid use and BMD is still somewhat unclear because only one study has reported long-term effects and reported no association of high dose methylprednisolone on BMD in MS patients [17].…”