## 4 Treating Bone Diseases: Evidence from Bone Imaging and Analysis  
### Pharmaceutical Drugs  
Common pharmacological interventions for bone diseases, especially osteoporosis, include bisphosphonates and strontium ranelate. Bisphosphonates encompass a number of pharmaceutical drugs such as alendronate (sold under the trade names Fosamax, Binosto), risedronate (Atelvia, Actonel), and zoledronate (Reclast). Nitrogen-containing bisphosphonates are particularly preferred for treating [PERSON]'s disease of the bone [163]. As an inhibitor of osteoclast activity, bisphosphonates minimize bone resorption and suppress bone turnover. While they can indeed stabilize bone loss in osteopororotic and OI patients, improve BMD, and decrease porosity [164; 136], there are systemic drug-induced side effects such as severe musculoskeletal pain or stroke. One well-known long-term complication of bisphosphonate use is osteonecrosis, particularly in the jaw [48]. Moreover, defects in the ultrastructure of diseased bone can either remain undealt with or emerge unintentionally following bisphosphonate treatments. There is evidence that bisphosphonates such as tiludronate can improve bone mineralization to a level similar to healthy bone [165]. However, the bisphosphonate-induced mineralization can be uncontrolled and heterogeneous in nature [166]. Moreover, ovariectomized osteopororotic rats treated with tiludronate showed a significant \(\sim\)30% increase in crystal thickness, at dosing concentrations of both 35 and 160 mg kg\({}^{-1}\), despite that no initial difference was observed in crystal thickness between sham and osteopororotic bone [165]. Similar studies have shown that different bisphosphonates can indeed induce different morphological changes in apatite nanocrystallites [167]. Effects of bisphosphonate treatment on collagen at the molecular and fibrillar levels remain to be further investigated, likely leaving the disorganized collagenous matrix unaltered. These ultrastructural defects can lead to even more compromised mechanical performance of the bone, including reduced fracture toughness when compared to the untreated pathological state [49; 168].  
Approved by the European Medicines Agency, strontium ranelate is another antiresource drug. In vitro investigations have demonstrated that strontium ranelate promotes osteoblast differentiation and proliferation whilst inhibiting osteocl activities, promoting new bone formation [169; 170]. Improvements on the whole-bone level included increased bone mass and micro-architecture [171]. At the nanoscale, apatite minerals of bone remained relatively unchanged with respect to crystal thickness, morphology, orientation, and mineral crystallinity [172; 173]. Divalent strontium ions Sr\({}^{2+}\), with a high binding affinity for hydroxyapatite, were believed to incorporate into the crystal lattice of the neo-bone, only affecting the lattice parameters and carbonate substitutions in the apatite mineral [173; 174; 175]. Regarding the collagen phase, no apparent improvements were seen in the arrangement and organization of the collagen fibers when examining, using TEM, the bones of ovariectomized osteopororotic rats following strontium ranelate treatment [176]. Rat bone strength improved significantly compared to the untreated conditions but not to the level of healthy controls [176]. On the other hand, the toughness of bone did not ameliorate even compared to the untreated osteopororotic bone [176]. For patient specimens, the nanomechanical properties of bone, including compressive modulus and hardness, showed no apparent improvements [175]. Despite their extensive clinical use, both bisphosphonates and strontium ranelate fail to address the nanoscale defects in pathological bone. There thus exists a need for alternative treatment options, precisely targeting ultrastructural changes such as defective collagen structure whilst minimizing adverse side effects.