Bisphosphonate (olpadronate) retention and its determinants in Paget's disease of bone

Abstract

Bisphosphonates (BPs) are the treatment of choice for Paget's disease of bone. They concentrate selectively in the skeleton at active sites and suppress osteoclastic bone resorption. Understanding the pharmacokinetics and pharmacodynamics can lead to improvements in the management of patients. Because of the specific pharmacology of BPs, the amount of BP delivered to the skeleton is likely to determine its effect. This amount can be estimated by measuring the whole body retention (WBR) of the BP [1]. In the present study BP WBR was investigated in 75 patients with active Paget's disease of bone, and PK/PD relationships were explored. The BP WBR (WBR=dose BP−amount excreted in urine) was investigated during 5 days of intravenous treatment with olpadronate 8 mg day−1. Relationships between WBR, body weight, renal function and pretreatment disease activity (serum alkaline phosphatase (sAP), urinary hydroxyproline and urinary cross-linked N-telopeptides of type 1 collagen, both corrected for renal function (uOHP/Cr, uNTx/Cr)) were investigated. The relationships between change in biochemical parameters of bone metabolism (to day 5 of treatment and to nadir) and pretreatment disease activity and WBR corrected for body weight (WBR/BW) were investigated (Pearson correlation test). Statistical significance was regarded as P<0.05. The mean WBR during the 5 day treatment period was 47 ± 14% of the dose administered (range 13% to 91%). The WBR and WBR/BW were significantly related to renal function (r=−0.43 and −0.56, respectively). Correlation with the activity of the disease was examined after logarithmic transformation of the bone turnover data. All pretreatment biochemical parameters of bone turnover measured were significantly correlated with WBR and WBR/BW of olpadronate (r=0.50, 0.61 and 0.57, respectively for WBR/BW), even after adjustment for renal function. The decreases in biochemical parameters of bone turnover were significantly related to the pretreatment values of these parameters (e.g. r=0.96 for the change of sAP from pretreatment to nadir and 0.99 for uNTx/Cr). They were also significantly related to olpadronate WBR/BW (e.g. r=0.57 (uOHP/Cr), r=0.50 (uNTx/Cr) and r=0.35 (uSAP) for the change to nadir). The decrease in bone turnover by intravenous olpadronate in patients with Paget's disease of bone strongly depends on the pretreatment rate of bone turnover. This may be explained, at least partially, by the amount of BP delivered to the skeleton, which is related to renal function and rate of bone turnover. This is the first clinical study on PK/PD relationships of a BP, where the specific pharmacology of BPs is taken into account. Future studies and more longitudinally obtained data can help in better understanding the PK/PD properties of BPs in patients with Paget's disease of bone.