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Page 8 of 21 Mu et al. Microstructures 2023;3:2023030 https://dx.doi.org/10.20517/microstructures.2023.05

deficiency of calcium and vitamin D can result in a reduction in Ca that leads to impaired bone
mineralization and a higher proportion of organic matrix compared to inorganic mineral content, which
[105]
contributes to reduced mechanical strength and increased fracture risk .

Besides, certain genetic disorders can induce abnormal bone development, such as osteogenesis imperfecta,
a condition characterized by fragile bones due to the mutation in genes responsible for collagen production
that leads to aberrant collagen production, and hypophosphatasia, an inherited disorder that results from a
deficiency in alkaline phosphatase, which is essential for proper bone mineralization [106,108] .

Hypermineralization
Hypermineralization, characterized by abnormally high bone mineral density (BMD), is associated with
[104]
hereditary and nonhereditary disorders . For example, in hereditary disorders, such as osteopetrosis and
osteosclerosis, a dramatic decrease in osteoclast number or osteoclast activity and increased bone mass and
density were observed. At the crystal level, low remodeling activities alter the crystal size/shape and increase
the amount of highly mineralized bone tissues, leading to decreased toughness of bone tissues and thus
increasing the risk of fracture . Skeletal fluorosis is another nonhereditary disorder associated with
[104]
excessive ingestion of F. The accumulation of F results in abnormal bone deposition and adsorption. At the
crystal level, the hydroxyl group in HAp is substituted by F, resulting in an increased crystallinity, crystal
[109]
size, and elastic modulus .
Other abnormal mineralization patterns
Osteoporosis, one of the most prevalent pathological abnormal mineralization conditions, is mainly related
to menopause and aging [104,110,111] . Osteoporosis is diagnosed based on low BMD and leads to reduced bone
mass and deterioration in bone micro-architecture, which further increases the susceptibility to fracture .
[110]
In osteoporosis, bone resorption exceeds bone formation, resulting in altered mineralization properties,
including mineral content, composition, and crystal size, which leads to reduced fracture resistance . It
[110]
has been reported that the bone tissue Ca/P ratio was reduced in osteoporosis patients and the imbalance
increased the defect in the HAp network, thus resulting in a less rigid HAp crystal structure and further
contributing to the increased fracture susceptibility in osteoporotic bones . Meanwhile, the uneven
[112]
distribution of minerals in the bone matrix is observed in some pathological conditions, such as Paget’s
disease, which is a chronic disorder that the normal bone remodeling process is disrupted, leading to
abnormally shaped, enlarged, and weakened bones that are more susceptible to fractures and deformities.

The presence of whitlockite in osteocyte lacunae (micropetrosis) is associated with pathological conditions,
as it is primarily found in the pathological mineralization of various soft tissues, dental calculus, and
occasionally in enamel and dentine . Notably, Mg-whitlockite [Ca Mg (HPO ) (PO ) ] has been detected
[113]
4 2
4 12
18
2
in post-apoptotic osteocyte lacunae in human alveolar bone, but this unusual mineral has not been found in
the extracellular matrix of mammalian bone under normal conditions . The notion that Mg-whitlockite is
[113]
a significant constituent of bone minerals remains unsubstantiated, and it is considered a pathological
biomineral . Therefore, contrary to some claims, biomaterials containing Mg-whitlockite do not represent
[114]
a bioinspired or biomimetic approach to bone repair .
[113]
Joint
Cartilage calcification that has been observed in the hip and knee is pathological in almost all osteoarthritis
[115]
(OA) patients . The deposition of calcium pyrophosphate dihydrate (CPPD) has been found in patients
suffering from acute attacks of pseudogout in the joints [116-118] . Other CaPs have also been found in synovial
fluids, synovium, and cartilage of OA patients, such as carbonate HAp, tricalcium phosphate (TCP), and