Table 9.

Summary of the studies on bone drug delivery examined in this review.

System	Applications	Advantages/Disadvantages	References
Beads	OS	Carrier of low molecular weight drugs Best results with alginate/chitosan association Time-dependent, but burst and inconsistent release profile Non-biodegradable, need to be surgical removed	[44,45,120]
Cements	Bone regeneration Bone metastases Osteoporosis Osteomyelitis OS	Ability to harden in vivo and to form bond with bone, low temperature setting reaction, excellent bioactivity, osteoconductivity Low strength, lack of full injectability, slow resorption rate, limited amount of incorporated drug, heterogeneity of drug repartition	[50,51,83,94,95,100,101,102,103,104,105,121,122,123,124,125,161,162]
Ceramics	Osteomyelitis	Simple preparation, modifiable size and structure, desirable stability under physiological conditions, low toxicity, good biocompatibility High cost, low encapsulation, uncontrollable dose	[2,52,53,133,137]
Conjugates	Bone metastases Osteoporosis	Good aqueous solubility, stability and controlled delivery Better oral bioavailability, tumor targeting, reduced toxicity for lipid-drug conjugates	[48,49,77,79,80]
Dendrimers	Bone metastases	Drug/oligonucleotides easily encapsulated Monodisperse size, good water solubility Modifiable surface Markable cytotoxicity for cationic surface end groups	[47,73,75]
EVs	OS	Cargo of cellular content, drugs and biomolecules	[38,39,84,85,86]
Gel	Osteoporosis	Controlled and continuous drug release High therapeutic effects, capable of auto-forming in situ	[58,116]
Hydrogels	Bone regeneration	Sol-gel transitions due to body temperature or pH variations Possibility to be tailored for a better geometry, degradation rate and release profile Development of a hydrophilic environment suitable for new bone growth, fast setting time Suitable for dental and orthopedic applications	[142,148,149,150,151,152,153,154,155,156]
Implants	Osteoporosis	Biocompatibility, prolonged drug release, tailored biodegradation kinetics Suitable for cardiovascular, neuroprosthetic and orthopedic purpose Required surgical procedures with some side effects like bleeding, infections or nerve injuries (for dental implants) High production costs and the possible presence of degradation fragments which impair new grown bone	[62,106,107,108,119]
Liposomes	Bone metastases OS	Good biocompatibility and loading properties Possible prolonged/targeted drug delivery	[40,71,72,90,91]
Matrices	Osteoporosis	Improved patient compliance, treatment efficiency, reduced costs, possibility to reduce drug administrated Probability of dose dumping, poor in vitro/in vivo correlations	[59,118]
Nanocapsules	Osteoporosis	Protective coating which delays compounds release, high reproducibility, broad range of application	[60,115]
Nanocrystals	Bone regeneration	Suitable for intravenously injection, slowly blood dissolution, improved biodistribution Opsonization could prolong circulating time, promote tumor accumulation, improve targeting efficiency	[55,163]
Nanodiamonds	Osteoporosis	Large surface area, easiness surface functionalization, suitable as photoluminescent probes Negligible cytotoxicity, high biocompatibility	[54,114]
Nanohybrids	OS	Capable to incapsulate drug with low water solubility, possible tool for non-invasive tumor targeting Good biocompatibility and biodegradability	[56,57,97]
Nanoplatforms	Bone metastases Osteomyelitis	Biocompatible and biodegradable Tunable size, changeable membrane permeability, possible bound with targeting ligand, capable to load hydrophilic/lipophilic drugs Responsive to pH, ionic strength, temperature	[30,31,64,81,82,143]
NPs	Bone regeneration Bone metastases Osteoporosis Osteomyelitis OS	High soluble, bioavailable Possible surface coating or functionalization to improve stability and bone targeting	[32,43,46,65,66,67,68,69,70,87,88,89,110,111,126,127,128,129,130,131,132,157,158]
Scaffolds	Bone regeneration Osteomyelitis	Biocompatible templates, promote attachment and growth of bone cells, induce osteogenesis Possible drug carriers	[61,63,96,138,139,140,141,144,145,146,147,164]
Spheres and microspheres	Bone regeneration Osteoporosis Osteomyelitis OS	Reduced side effects and improved efficiency of cytotoxic anticancer drugs Alternative routes: ophthalmic, topical, nasal, intramuscular Good choice for low/high molecular weight drugs, DNA fragments, peptides, proteins	[41,42,92,93,112,117,159,160]