After intravenous administration, however, if the plasma peak levels are higher, these levels are transient and short-lived. LCZ696 Similarly to what is observed after oral administration, serum levels rapidly decrease due to their rapid adsorption on the surface of bone (±50%). The rest is cleared by both glomerular filtration and proximal tubular secretion (± the remaining 50%) [117]. The retention time in the skeleton is extremely long and depends on the individual bone affinity of the various BPs. Part of the released BPs from the skeleton can be re-uptaken, and part is eliminated in the urine. Even if

their terminal half-life is long, plasma levels remain very low. However, small amounts have been

GDC-0941 nmr detected in body fluids up to 8 years after stopping the drug [118, 119]. This justified some warning regarding the use of BPs in premenopausal women of child bearing age. Even if there has been no demonstrated adverse foetal events in humans, large controlled studies are lacking to confirm their widespread safe use [120]. Some caution to restrict the use BPs to severe condition is still justified. Bisphosphonate and acute phase reaction After the first intravenous administration of a nitrogen-containing bisphosphonate (n-BP) (e.g. disodium pamidronate, zoledronic acid, ibandronate), about 25% of patients experienced flu-like symptoms, consisting of transient and self-limited fever, myalgias and/or arthralgias for 2 to 3 days. Acute phase reaction (APR) has been associated with the release of serum inflammatory cytokines Branched chain aminotransferase such as tumour necrosis factor (TNFα) and IL-6, but not IL-1 [121]. The origin of these pro-inflammatory agents was homed on monocytes and/or

macrophages [122] but also in human peripheral blood γδ T cells, which could constitute the trigger for activation of the former cells [123]. The APRs were absent or at least strongly attenuated with subsequent infusions with n-BPs. The APR has also been observed after high-dose oral monthly ibandronate [124]. The post-infusion syndrome can be reduced by acetaminophen [125]. It has been learn more suggested that the co-administration of statins could prevent this reaction [123, 126], but this preventative effect does not seem to be systematic [127]. On the contrary, concomitant glucocorticoid (GC) therapy did not alleviate it [128]. Depletion in 25(OH)D could constitute a factor favouring the occurrence of APR after n-BPs infusion in n-BP-naive patients, but this remains to be confirmed [129]. Bisphosphonate and musculoskeletal pain Some cases of prolonged musculoskeletal pain have been reported [130] in up to 20% to 25% of patients on alendronate and risedronate, as well as zoledronic acid [128, 131]. The majority of patients experienced gradual relief of pain after discontinuation of the drug.