**4.1 Disease-associated bone deterioration**

**Paget disease of bone (PDB):** It is a chronic bone disease, considered as the second-most common bone disease after osteoporosis. It is defined as a skeletal growth disorder, leading to bone pain, deformities, deafness, and fractures usually found in the pelvis, spine, femur, and skull [31]. PDB is most common among men than women, and by 50 years of age, the preponderance of being affected by the disease reaches 1 to 5% [32]. The real cause of PDB appearance is not well known. However, many researchers have found a causal relationship between PDB and mutation of the gene encoding sequestosome 1 SQSTM1/p62 that plays an important role in bone-resorbing cell differentiation, activity, and survival [31]. Given this disruption of bone-resorbing cell functioning, the whole bone remodeling process is perturbed, leading to fragile bones and disorganized bone architecture. Otherwise, this disruption causes increased BMD in areas affected by PDB, whether in cortical or trabecular compartments [33].

**Osteogenesis imperfecta (OI):** Also known as brittle bone disease, OI is a group of rare bone diseases characterized by heterogeneous disturbance of the cognitive tissue. All these diseases are associated with bone mass diminution, increased bone fragility, bone disfigurement, and bone formation insufficiency [34]. OI etiology differs from one disease to another as it depends mainly on the onsets and intensity of each one. Genetic, phenotypic, and functional classifications have been adopted to find out the new causative mutation of OI onset [35]. The most-known OI diseases are X-linked hyposphantaemia, characterized by a mutation of phosphate-regulating endopeptidase that affects vitamin D concentration in the body and consequently bone quality; hypoparathyroidism, characterized by low levels of parathyroid hormone (PTH) that regulates calcium homeostasis; and hypophosphatasia, resulting from the mutation of a responsible gene encoding alkaline phosphatase. The dysregulation of the enzyme disrupts its function to prompt adequate mineralization at an appropriate time in bone tissue. In terms of BMD, OI has been found to be associated with low BMD and also with high BMD in patients with a pathogenic variant of COL1A2, as recently proved by [36].

**Myeloma disease (MM):** It is a clonal plasma cell proliferative disorder that affects bones by causing bone pain, fractures, and hypercalcemia. It is ranked as the second most-frequent hematological malignancy, with a percentage of 10% [37, 38] in elderly population. This blood cancer is characterized by renal impairment (creatinine >2 mg/dL), hypercalcemia (calcium >11 mg/dL), anemia (hemoglobin <10 mg/dL), the infiltration of clonal plasma with ≥ 60% of the bone marrow, and end organ damage such as lytic lesions in the bone [39, 40]. Because of MM cancer, bone-resorbing cell differentiation is stimulated, and bone-forming cell functioning is suppressed [31]. Due to calcium levels perturbation in blood and bone in addition to bone marrow infiltration, the BMD value is affected.

**Breast cancer (BC):** It consists of a group of biologically and molecularly heterogeneous diseases that originate from the breast and manifests particularly in the mammary glands. It is the most common type of cancer affecting women worldwide [41]. Whether in its primary state or after metastasizing into the bone, BC affects bones. In a recent research study [42], authors have mimicked bone adaptation during the breast cancer premetastatic state by analyzing the effect of the tumor conditioned media (TCM) of the breast cancer cell line MDA-MB-231 on mice bone. Based on their experiments, they found that TCM injection into mice induced an increase of bone formation characterized by increased bone mineral apposition and altered bone quality such as high mineralization rate, less bone matrix with more carbonate substitution, and disoriented deposition of minerals. Those findings could explain the results of [43] that found a higher BMD in women newly diagnosed with breast cancer. Otherwise, metastatic BC causes osteolytic lesions due to their stimulation of bone-resorbing cell functioning and repression of the forming cell functioning. The tumor cell and bone cell interactions cause a decrease in bone mass, which leads to less bone mineral density in the matrix [44].

**Prostate cancer (PC):** This disease consists of a cancer that starts in the gland cells of the prostate. The prostate is a small glandular organ where the seminal fluid is produced. PC has a tendency to spread in surrounding organs such as rectum and seminal vesicles and also to distant organs such as bones through lymphatic and hematogenous routes [45]. Its characterization is tightly related to androgenic hormone signaling such as testosterone [46]. As well as estrogen, testosterone plays an important role in bone remodeling regulation. By its exposure in men with PC, it acts on the bone remodeling process directly or indirectly via aromatization to estradiol, leading to enhanced bone formation and repressed resorption [47]. Probably, because of testosterone increased action, PC patients frequently develop osteoblastic lesions [48]. However, PC is still a risk factor for osteoporosis development, leading to decrease BMD value as shown in the retrospective study of Kwon et al. [49].

**Lung cancer (LC):** This cancer refers to tumors originating in the lung, which is a spongy organ located in the chest. It is caused due to genetic mutations and disruption in protein synthesis resulting generally from individual cigarette smoking. Those DNA mutations disrupt cells' cycle and promote carcinogenesis [50]. In addition to lung complications, patients with this type of carcinoma develop skeletal complications and fractures. In the work of [51] studying the effect of lung cancer cells on bone cells in mice, authors have found that lung tumor cells secrete inhibitory factors that act on bone-reforming cells and inhibit their mineralization, which induce bone loss and decreased BMD.

**Cushing disease:** It is an endocrine disorder characterized by a hypersecretion of the adrenocorticotropic hormone (ACTH) by the anterior pituitary, leading to an excessive production of cortisol by the adrenal glands [52]. As well as the abovementioned diseases, Cushing disease is linked with bone degradation. Different factors contribute to bone loss and decreased BMD in patients with Cushing syndrome, including a direct effect of the high secreted glucocorticoids on bone cells, enhanced bone resorption, impaired bone formation, and limited calcium absorption [53].

**Hypogonadism:** It refers to a failure in the gonads' functioning activity. The gonads are testes for men and ovaries for women; both are the principle organs producing sexual hormones such like testosterone, estrogen, and progesterone and gametes, notably eggs and sperm [54]. This disease could arise from Klinefelter syndrome, Kallman syndrome, pituitary disorders, cancer treatment, obesity, aging, and stress [55]. Given that hypogonadism is related to a failure in sexual hormone synthesis, it is also associated with reduction of BMD, especially if sex steroid deficiency occurs at a young age [56]. For males, for example, a low testosterone level is the main cause of low BMD and increased bone fracture risk for patients with primary and secondary hypogonadism [57].
