Influence of the bisphosphonates alendronate, risedronate and zoledronic acid on the setting reaction of a hydroxyapatite-forming calcium phosphate cement

Calcium phosphate cements (CPCs) are established as bone substitutes. Bisphosphonates (BPs) are applied for treatment of osteoporosis. Local BP delivery directly at the bone defect site, enhancing bone regeneration, could be achieved by adding BPs directly to CPCs. However, previous studies showed a strong retarding effect of BPs on cement setting. This is negative for clinical application, where proper setting kinetics are essential. Here, a hydroxyapatite-forming CPC with composition of “Biocement D” was modified with 0.5 and 1 wt.% of either alendronate (AL), risedronate (RIS) or zoledronic acid (ZOL). A highly concentrated Na 2 HPO 4 /NaH 2 PO 4 aqueous mixing liquid was used to counteract the retarding effect of the BPs. The setting reaction was thoroughly studied by isothermal calorimetry, in-situ X-ray diffraction (XRD) and Imeter measurements (automated Gillmore needle). The set cements were characterized in terms of their mineralogical phase composition, compressive strength and crystal morphology. All three BPs strongly retarded cement setting. Especially dissolution of the starting compounds was significantly retarded, while no retardation of the initial HA formation was observed. The amount of HA formed was increased by BP addition. Changes of the lattice parameters of hexagonal HA between 1 d and 3 d, combined with other observations like concurrent calcite dissolution, strongly suggested an increase in carbonate content within the HA phase during setting. Compressive strength after 7 d was negatively affected by RIS, while AL had only minor and ZOL no negative effect. Despite the strong retarding effects of the BPs, cement setting within reasonable times is achievable by application of a highly concentrated phosphate solution as accelerator.