Table 3.

Different Methods for Surface Titanium Modification That were Used for Bisphosphonates Fixation

Bisphosphonate	Method for BP immobilization on titanium surface	Qualitative/Quantitative analysis for BPs fixation	Experimental trial	BP release quantification	Most important contributions	References
Pamidronate	Ca ion-implanted titanium and hydroxyapatite coating	X-ray photoelectron spectroscopy (qualitative)	In vitro	-	They achieved incorporating the Pamidronate into the Ca-coated implant: it was not toxic for osteoblastic cells and for inhibiting the adherence of P. gingivalis, which is important for dental applications.	159
	Ca ion-implanted titanium	X-ray photoelectron spectroscopy (qualitative)	In vivo	-	The incorporation of BP into the surface of a Ca-coated Ti implant accelerates new bone formation around the implant in comparison with Ti and Ca-Ti implants	60
	Hydroxyapatite coating on titanium	-	In vivo	-	The molecular precursor used for implant coating allows that Ca coating of any shape can be deposited. The incorporation of BP into the implant showed a better bone formation than untreated Ti and apatite-Ti.	160
	Co-precipitation directly onto the Ti surface and Hydroxyapatite coating	X-ray photoelectron spectroscopy (qualitative)	In vitro	Alternating ionic current (AIC) conductivity measurements, during 24 h.	For BP incorporation into the implant, co-precipitation and fast loading methods were used, showing the simplicity of both methods. The Pamidrotante present on the surface of the fast-loaded HA coatings was strongly bound, which makes a slower release.	161
Zoledronate	Hydroxyapatite coating on titanium	Determination of the phosphorous content: Ames method (quantitative)	In vivo	-	The local delivery of BP incorporated on calcium phosphate-coated Ti allowed for an increase in the mechanical fixation of an orthopedic implant. Bone volume fraction is dependent on the ZOL content of the coating: implants (volume: 35.3 mm3) containing 8.5 μg ZOL induced the highest mechanical stability.	131
	Poly(D,L-lactide)-BP coating	-	In vitro	-	ZOL incorporated (from 10 to 50 μM) in a poly(D,L-lactide) coating of a Ti implant inhibited osteoclast formation and reduced their resorption activity.	162
	Hydroxyapatite coating on titanium	Determination of the phosphorous content: Ames method, 31P NMR (quantitative)	In vivo	-	The incorporation of ZOL (2.1 μg ZOL/35.3 mm3 implant) on HA-coated implants improved its fixation, which was confirmed by the increase of periprosthetic bone density.	158
	Hydroxyapatite coating on titanium	-	In vivo	In vitro release of ZOL in buffer media during 21 days, quantified by HPLC.	HA-coated Ti implants were loaded with ZOL and bFGF. The in vitro release test showed that the amounts of ZOL and bFGF released from implants treated with ZOL + bFGF were low during the first days. The maximal amount of new bone ingrowth into HA-coated implants was found in the rats treated with both agents. The use of ZOL and bFGF effectively increased trabecular microarchitecture parameters to a greater degree than the use of ZOL or bFGF alone.	163
Zoledronate Pamidronate Ibandronate	Hydroxyapatite coating on titanium	-	In vivo	In vitro release of BPs for 21 days, quantified by HPLC using an UV detector.	Three different HA-coated Ti implants were made (ZOL-implant; PAM-implant; Ibandronate-implant). Immobilized BPs had positive effects on implant fixation in osteoporotic bone, promoting peri-implant bone formation and improving its mechanical properties. The release rate of BPs in the first few days was slightly different, but three BPs were still detectable during 21 days, which was a key period for the early bone formation and, thus, more important for peri-implant bone formation and implant-bone osseointegration. The three BPs used in this study have different levels of efficacy, with a rank order of ZOL > Ibandronate > PAM.	164