## 3 Bone Pathologies: Alterations to Bone Ultrastruct and Mechanics
### Rickets and Osteomalacia  
Rickets and osteomalacia are two closely linked bone disorders, where the diseased bone is abnormally soft due to hypomineralized bone matrix. Because of this, the ultrastructural features of the collagen fibrils have been less studied compared to the mineral phase of bone in these pathological conditions. Both hypophosphatemia (i.e., having low concentrations of phosphate in the blood) and vitamin D deficiency can lead to racmitic and osteomalacic bone, yet these two causes can present different disease characteristics at the nanometric level.  
Rickets arising from a deficiency in phosphates are called hypophosphatemic rickets, synonymous with X-linked hypophosphatemia (XLH) or vitamin-D-resistant rickets. In hypophosphatemic-rickets-affected bone, sometimes denoted _Hyp_ bone, there is a decreased average degree of mineralization. [PERSON] et al. revealed that this incomplete mineralization was heterogeneous, detecting a 21% reduction in extrafibrillar mineralization but negligible changes in the intrafibrillar mineral content using qBEI [160]. Additionally, the distribution pattern of the bone mineral also appeared more variable compared to healthy WT bone [160]. During bone development, the mineralization process was found to have terminated prematurely in _Hyp_ bone, where FIB-SEM images showed a greater amount of smaller mineral ellipsoids in the affected bone matrix [27]. These mineral ellipsoids were believed to mature into the cross-fibrillar minerals seen in healthy adult bone. As a result of this premature arrest in mineralization during bone growth, a greater variability in mineral size was measured and defective mineral packing and mineralization patterns were seen in the FIB-SEM images of hypophosphatemic-rickets-affected bone [27]. On a microstructural level, abnormal patchy mineralization of the collagen bundles was also captured using SEM [160]. The patchy appearance of the mineralized bone in hypophosphatemic rickets pathology likely resembles bone tissues with osteogenesis imperfectca or Paget's disease, mentioned previously, as well as in osteomalacia [161]. Since there was an overall decreased amount of high-stiffness bone mineral, a significant 70% reduction in fibril-level stiffness--i.e., a softening of bone--was measured under both tension and compression [160; 162]. As such, a common nanostructural mechanism becomes evident: both lower stiffness and greater fibril extensibility are observed in hypomineralized collagen of bone at the fibrillar level. This also holds true for osteoporoptic bone [137].  
In the rickets or osteomalacia-like disease phenotype induced by severe vitamin D deficiency, the BMDD shifts to higher Ca values, reminiscent of aged bone tissue [119]. This is different from bone with hypophosphatemic rickets with a hypomineralized bone matrix.  
Specifically, the osteocyte lacunae in vitamin-D-deficient bone were hypermineralized [119]. It is thus apparent that in both hypophosphatemic and vitamin-D deficiency-induced crickets, the changes in bone mineralization proved to be spatially heterogeneous. Bone from individuals with vitamin D deficiencies also presented decreased fracture toughness. In situ fracture testing of hydrated WT and diseased bone in an ESEM showed that the deformation pathways during fracture were dissimilar and that there was an absence of normal toughening mechanisms in bone with vitamin-D deficiency [119].