Angels Martinez-Ferrer

Lithocholic acid downregulates vitamin D effects in human osteoblasts.

Eur J Clin Invest 2010; 40 (1): 25–34

Effects of bilirubin and sera from jaundiced patients on osteoblasts: Contribution to the development of osteoporosis in liver diseases†

Low bone formation is considered to be the main feature in osteoporosis associated with cholestatic and end‐stage liver diseases, although the consequences of retained substances in chronic cholestasis on bone cells have scarcely been studied. Therefore, we analyzed the effects of bilirubin and serum from jaundiced patients on viability, differentiation, mineralization, and gene expression in the cells involved in bone formation. The experiments were performed in human primary osteoblasts and SAOS‐2 human osteosarcoma cells. Unconjugated bilirubin or serum from jaundiced patients resulted in a dose‐dependent decrease in osteoblast viability. Concentrations of bilirubin or jaundiced serum without effects on cell survival significantly diminished osteoblast differentiation. Mineralization was significantly reduced by exposure to 50 μM bilirubin at all time points (from −32% to −55%) and jaundiced sera resulted in a significant decrease on cell mineralization as well. Furthermore, bilirubin down‐regulated RUNX2 (runt‐related transcription factor 2) gene expression, a basic osteogenic factor involved in osteoblast differentiation, and serum from jaundiced patients significantly up‐regulated the RANKL/OPG (receptor activator of nuclear factor‐κB ligand/osteoprotegerin) gene expression ratio, a system closely involved in osteoblast‐induced osteoclastogenesis. Conclusion: Besides decreased cell viability, unconjugated bilirubin and serum from jaundiced patients led to defective consequences on osteoblasts. Moreover, jaundiced serum up‐regulates the system involved in osteoblast‐induced osteoclastogenesis. These results support the deleterious consequences of increased bilirubin in advanced chronic cholestasis and in end‐stage liver diseases, resulting in disturbed bone formation related to osteoblast dysfunction. (HEPATOLOGY 2011)

Prolonged bisphosphonate release after treatment in women with osteoporosis. Relationship with bone turnover

Bisphosphonates (BP), especially alendronate and risedronate, are the drugs most commonly used for osteoporosis treatment, being incorporated into the skeleton where they inhibit bone resorption and are thereafter slowly released during bone turnover. However, there are few data on the release of BP in patients who have received treatment with these drugs for osteoporosis. This information is essential for evaluating the possibility of BP cyclic therapy in these patients and for controlling their long-term presence in bone tissue. This study evaluated the urinary excretion of alendronate and risedronate in patients treated with these drugs for osteoporosis and analysed its relationship with bone turnover, time of previous drug exposure and time of treatment discontinuation. We included 43 women (aged 65±9.4 years) previously treated with alendronate (36) or risedronate (7) during a mean of 51±3 and 53±3 months, respectively, who had not been treated with other antiosteoporotic treatment and with a median time of discontinuation of 13.5 and 14 months, respectively. Both BP were detected in 24-hour urine by HPLC. In addition, bone formation (PINP) and resorption (NTx) markers were analysed. Both BP were also determined in a control group of women during treatment. Alendronate was detected in 41% of women previously treated with this drug whereas no patient previously treated with risedronate showed detectable urinary values. All control patients showed detectable values of both BP. In patients with detectable alendronate levels, the time of drug cessation was shorter than in patients with undetectable values (12 [6-19] versus 31 [7-72] months, p<0.001). Alendronate was not detected in any patient 19 months after treatment cessation. Alendronate levels were inversely related to time of treatment discontinuation (r=-0.403, p=0.01) and the latter was directly related to NTx (r=0.394, p=0.02). No relationship was observed with age, length of drug exposure, renal function or weight. In conclusion, contrary to risedronate, which was not detected in patients after cessation of treatment, alendronate was frequently detected in women previously treated with this agent up to 19 months after discontinuation of therapy. The relationship between alendronate levels and both bone resorption and time of treatment cessation further indicates a residual effect of this drug in bone, despite treatment discontinuation.

Eficacia de la vertebroplastia en fracturas vertebrales crónicas sintomáticas debidas a osteoporosis. Estudio de 5 pacientes

BACKGROUND AND OBJECTIVE Percutaneous vertebroplasty (PVP) has been successfully used in the treatment of pain related to osteoporotic vertebral fractures refractory to medical therapy, especially in the treatment of acute factures. However, the effectiveness of this therapeutic approach in the treatment of painful chronic vertebral fractures is less clear. PATIENTS AND METHODS In this report we evaluate the short and long-term effectiveness in pain relief of PVP in a group of 5 patients with pain related to chronic osteoporotic vertebral fractures without bone marrow edema (BME) on magnetic resonance imaging (MRI). All patients were followed during one year, assessing analgesic use, pain evolution (on a 10-point visual analog scale [VAS]), new vertebral fractures and other clinical complications. Seven procedures were performed in the 5 patients. RESULTS All patients reported substantial improvement in back pain 2 weeks after the procedure, with a mean decrease of 53% in the VAS. However, one year after PVP most patients (4 out 5) worsened, achieving similar VAS scores to those obtained at baseline. No additional vertebral fractures or other clinical complications were observed. CONCLUSION The present cases suggest that the long-term effectiveness of PVP in the treatment of painful chronic vertebral fractures without BME on MRI is scarce.

1306 URSODEOXYCHOLIC ACID NEUTRALIZES THE NOXIOUS EFFECTS OF LITHOCHOLIC ACID AND BILIRUBIN ON OSTEOBLASTS

did not differ between the two groups. ALT response was inversely correlated with HA, BDL and F score, while ALP response was inversely correlated with BDL score. In addition, positive anti-gp210 antibodies was significantly associated with poor response of both ALT and ALP. Conclusions: Positive anti-gp210 antibodies is a significant risk factor for poor biochemical response to UDCA treatment in Japanese patients with PBC.