Factores que determinan la duración de la respuesta al tratamiento con tiludronato en una cohorte de pacientes con enfermedad de Paget / Factors determining duration of response to tiludronate in a cohort of patients with Paget's disease

Fundamento: Investigar la influencia de los factores que determinan la duración de la respuesta al tiludronato en la enfermedad de Paget. Pacientes y métodos: Se ha seguido a intervalos regulares, desde abril de 1993 hasta mayo de 2003, a todos los pacientes (n = 26) incluidos en un ensayo clínico sobre eficacia y bioequivalencia del tiludronato en la enfermedad de Paget. Cada paciente tomó 400 mg/día por vía oral durante 90 ñ 6 días. Diecisiete (65 por ciento) eran varones y 9 (35 por ciento) mujeres, y la media de edad ñ desviación estándar (DE) era 60,3 ñ 9,8 años. La evolución de la probabilidad de recaída bioquímica se investigó mediante la prueba de Kaplan-Meier. Para determinar qué variables predicen mejor la duración de la respuesta, y en qué medida, se realizó análisis de modelos de riesgo proporcional (regresión de Cox).Resultados: Sólo uno de los 26 pacientes incluidos en el ensayo clínico presentó resistencia inicial al tratamiento con tiludronato. De los restantes, en 19 se normalizaron las cifras de fosfatasa alcalina y 6 tuvieron una respuesta superior al 50 por ciento de los valores basales, aunque no alcanzaron la remisión completa. Nueve de los 19 pacientes en que se normalizaron las cifras de fosfatasa alcalina han permanecido durante los 10 años de seguimiento libres de recaída, por lo que no han precisado de nuevos ciclos. Los 16 restantes han presentado recaída, y han recibido uno o varios ciclos posteriores, con una media ñ DE de 1,43 ñ 0,68 ciclos por paciente. No se observaron efectos secundarios importantes ni alteraciones analíticas relevantes que indicaran toxicidad en los 49 ciclos administrados. El tiempo medio hasta la primera recaída fue de 53,5 meses y de 36 meses hasta la segunda. El porcentaje máximo de reducción de fosfatasa alcalina (media ñ DE) tras el segundo ciclo fue del 55,3 ñ 12,9 por ciento. Los pacientes con recaída muestran una mayor extensión de las lesiones óseas (11,68 ñ 7,4 frente a 5,33 ñ 0,7; p = 0,003) y una fosfatasa alcalina más elevada (1.446 ñ 810 frente a 849 ñ 255; p = 0,01). La concentración basal de fosfatasa alcalina y las concentraciones mínima y máxima de tiludronato al mes de comenzar el tratamiento son las que predicen con mayor fiabilidad la probabilidad de recaída. Conclusiones: El tiludronato suprime de manera eficaz a largo plazo la actividad bioquímica de la enfermedad de Paget. La concentración mínima o valle de tiludronato en plasma es el mejor predictor de la duración de la respuesta (AU)

[Factors that determine intensity of response to treatment with tiludronate in Paget's disease]. / Factores que determinan la intensidad de la respuesta al tratamiento con tiludronato en la enfermedad de Paget.

OBJECTIVE: To investigate the influence of both clinical and pharmacokinetic factors as determinants of response to tiludronate in Paget's bone disease (PBD). PATIENTS AND METHODS: Twenty six PBD patients with serum alkaline phosphatase (SAP) levels at least twice the normal upper limit were enrolled. The sample included 17 (65%) men and 9 (35%) women whose mean age (SD) was 60.3 (9.8) (range: 38-76). Each patient received 400 mg/day of tiludronate, per os, for 90 (6) days. The SAP variations were considered as the main parameter of response. Plasma concentrations of tiludronate were assayed using the HPLC method with UV detection; the maximum and minimum (Cmin) concentration, as well as the area under a concentration-time curve were calculated. Multivariate regression analysis was performed to assess the influence on tiludronate effect. RESULTS: Mean (SD) percent reduction of SAP from the initial values ranged from 30.5 (13.9) at the end of the first month of drug intake to a nadir of 76.1 (8.8) achieved 6 months after the treatment was stopped. Serum SAP activity fell to normal range in 7 (27%) patients at the end of the therapy period, in 17 (65%) three months later, and in 18 (69%) one year thereafter. One year after the treatment ended only one patient had evidence of relapse. Final multivariate regression model showed that the percent reduction of SAP increases by 11.9 percent points per Cmin tiludronate unit and by 0.006 points per basal SAP unit, and decreases by 0.52 per year of age. Out of 13 patients with bone pain, 9 (69%) experienced relief within the second and third months of treatment. No clinical or laboratory severe side effects were seen and only five patients (19%) had mild adverse events. CONCLUSIONS: These results confirm that tiludronate leads to a marked suppression of PDB clinical and biochemical activity. Cmin of tiludronate in plasma is the best predictor of biochemical response.

Cattle, pets, and Paget's disease of bone.

To identify animal-related factors associated with Paget's disease of bone (osteitis deformans), we conducted a case-control study in two geographical areas of Spain characterized by different socioeconomic profiles. The analysis presented here is based on 149 cases and 150 controls, frequency matched by sex, age, study area, and place of residence in youth (urban/rural). From a logistic regression analysis, we found that contact with bovine cattle [odds ratio (OR) = 2.14; 95% confidence interval (CI) = 1.16-3.94], consumption of meat traceable to sick livestock (OR = 2.70; 95% CI = 0.98-7.43), and frequent consumption during youth of brains (OR = 1.77; 95% CI = 1.05-2.98) and other viscera increased the risk for Paget's disease of bone. Contact with bovine cattle and consumption during youth of bovid viscera exhibited a dose-response effect as regards length of exposure and frequency of consumption, respectively. A life-style shared with dogs showed itself to be differentially linked to the disease in one study area. Overall, our results support the hypothesis that various animal species are carriers of etiologic agents of Paget's disease of bone.

Frequency and characteristics of familial aggregation of Paget's disease of bone.

The cause of Paget's disease of bone (PDB) is unknown. In an attempt to ascertain the proportion of familial cases and evaluate the influence of genetic factors on the occurrence of the disease, a study was undertaken based on 35 PDB patients from our Unit. Their families were investigated, with the participation of a total of 128 first-degree relatives. Fourteen (40%) of these 35 index cases had at least one other first-degree relative affected with PDB and were defined as "familial." The remaining 21 (60%) were considered "sporadic." The frequency of males in the familial cases (79%) was significantly higher than among the sporadics (29%; p < or = 0.01). Mean age at diagnosis (63.1 +/- 12.6 vs. 71.3 +/- 8.7; p < or = 0.02), proportion of polyostotic cases (85.7% vs. 52.4%, p < or = 0.05), and mean number of involved bones per patient (4.36 +/- 2.50 vs. 2.33 +/- 1.93, p < or = 0.01) differ significantly in the familial and sporadic groups. The disease appears to be transmitted via both paternal and maternal sides, and pedigree analysis suggested an autosomal dominant inheritance or multifactorial mechanism. Apart from green-and-blue eye color, which was clearly associated with familial grouping (OR 6.25, 95% CI 1.15-37.16, p < or = 0.01), crude analysis on several genetically based traits and environmental variables revealed no other significant differences between the groups. The adjusted odds ratio estimated for green-and-blue eye color was 2.92 (95% CI 0.38-22.74).(ABSTRACT TRUNCATED AT 250 WORDS)