inheritance of OPG, RANK, estrogen receptors are also important as 60 percent to 80 percent of the variation in bone density is genetically determined. Aging contributes to the development of osteoporosis by decreasing replicative activity of osteoprogenitor cells, decreasing the synthetic activity of osteoblasts, and decreasing the biological activity of matrix-bound growth factors. Females in menopause are more likely to develop this disease because this condition is associated with decreased serum estrogen, increased levels of IL-1, IL-6, and TNF levels, increased expression of RANK, RANKL, and increased osteoclastic activity. This disease can be relatively controlled if the patient is encouraged to exercise regularly as well as have a good diet rich in calcium and vitamin D. Smoking is also thought to have a major contributory effect, so cessation of smoking can also prevent aggravation of disease.
Paget’s Disease
Paget’s disease (osteitis deformans) is a primary disease caused by osteoclastic dysfunction. It usually begins in late adulthood and becomes progressively more common thereafter. It can be divided into three phases: (1) initial osteolytic stage, (2) a mixed osteoclastic-osteoblastic stage, and (3) a burnt-out quiescent osteosclerotic stage. The cause of Paget’s disease remains uncertain but evidence suggests both genetic and environmental factors being contributory. The risk of developing this disorder is approximately seven times greater in first-degree relatives of affected individuals. Mutations involving the SQSTM1 gene are found in approximately 40 to 50 percent of the cases of familial disease. The SQSTM1 mutations enhance NF-kB activation of RANK signaling, leading to increased osteoclast activity and an increased susceptibility to the disease. Mutations in the RANKL and RANK/OPG genes have also been linked to genetic conditions that resemble clinical features of Paget’s disease. The cases are usually mild and are discovered accidentally. The axial skeleton is involved in up to 80 percent of the cases, and although no bone is immune, involvement of the ribs, fibula, and small bones of the hands and feet is unusual.
Infection: Osteomyelitis
Osteomyelitis indicates inflammation of the bone and marrow and may arise as a complication of any systemic infection. Most of the time, it manifests as a primary solitary focus of disease with all types of organisms (viruses, bacteria, parasites, fungi) producing the disease. Pyogenic osteomyelitis is always caused by bacteria and the organism can reach the bone by hematogeneous spread, extension from a contiguous site, and by direct implantation. Staphylococcus aureus is responsible for the majority of the cases in which an organism is recovered.
Other organisms commonly associated are Escherichia coli, pseudomonas, and Klebisella in patients with genitourinary tract infections and IV drug abusers and Haemophilus influenzae and group B streptococci in neonatal patients. The location of the infection within the bone is influenced by the osseous vascular circulation, which varies with age. The metaphyseal vessels penetrate the growth plate in neonates and localization of the organism in the metaphysis in children is common. In adults, the organisms are commonly isolated from epiphysis and subchondral regions.
Tuberculous osteomyelitis is prevalent in underdeveloped nations and the resurgence of this condition in the developed areas is occurring due to immigrants. The organism is usually blood borne and originates from a focus of acute visceral disease during the final stages of primary infection. Direct extension and spread via draining lymphatics may also occur. Immunosuppressed individuals frequently have multifocal bone involvement. The spine followed by the knees and hips are the most common sites of skeletal involvement. This type of osteomyelitis tends to be more destructive and resistant to control than the pyogenic type. A number of complications can arise from this condition, namely, permanent compression fractures, neurologic defects secondary to spinal cord or nerve compression, tuberculous arthritis, sinus tract formation, and amyloidosis.
Osteogenesis Imperfecta
Osteogenesis imperfecta, or brittle bone disease, is a type 1 collagen disease caused by deficiencies in the synthesis of collagen. It is the most common inherited connective tissue disorder and primarily affects the bone and other tissues rich in collagen (eyes, ears, joints). It is usually an autosomal dominant mutation in the genes that encode the a-1 and a-2 chains of collagen. The genotype-phenotype relationship of the condition depends on the location of the mutation in the protein. Mutations causing a decrease in the amount of normal collagen are associated with mild skeletal abnormalities. More severe forms have polypeptide chains that cannot be arranged in the triple helix. Clinically, four major subtypes exist that vary in severity. Type 1 is compatible with life and has a decreased synthesis of pro-a1(1) chain and abnormal chains. This type is associated with postnatal fractures, skeletal fragility, hearing impairment, and joint laxity. Type 2 is lethal perinataly and the collagen defect is abnormally short pro-a1(1) chain or unstable triple helix. Death in utero or within days of birth, skeletal deformity with excessive fragility, and blue sclera are the major clinical features. Type 3 is progressive and is associated with growth retardation multiple fractures, dentinogenesis imperfecta, and progressive kyphoscoliosis. Finally, type 4 is associated with short pro-a2(1) chain defect and unstable triple helix and the major features include postnatal fractures, short stature, and moderate skeletal fragility.
Rickets
Rickets is a defective mineralization of bones before epiphyseal closure in humans due to deficiency of or impaired metabolism of vitamin D, phosphorus, or calcium. It is a disease of the growing bone and is unique to children and young adults. The primary cause is a vitamin D deficiency, but rarely, a dietary deficiency of calcium or phosphorus can also cause rickets. In a vitamin D deficiency state, hypocalcemia development leads to the production and secretion of excessive parathyroid hormone. This, in turn, causes a greater renal phosphorus loss. The excessive parathyroid hormone causes the decreased calcium levels to rise to normal values and the ALP, which is produced due to the overactive osteoblast cells, leaks into the ECF, causing elevation to very high levels. Also, recent studies have shown a correlation with increased fibroblast growth factor 23 and the development of rickets. Rickets leads to skeletal deformity and short stature. In females, pelvic distortion from rickets can cause problems with childbirth. Respiratory failure is a severe consequence. Thickening of the skull, frontal bossing, greenstick fractures, rickety myopathy, tetany, uncalcified osteoid at the metaphases, and weight-bearing deformities are all common clinical features.
Osteomalacia
Osteomalacia is the softening of bones caused by defective bone mineralization secondary to low levels of vitamin D, phosphorus, or calcium. Hyperparathyroidism causing hypercalcemia is contributory. This disease is the counterpart of rickets specific to adults. Causes can include a low dietary intake of the vitamin and minerals, not enough exposure to sunlight, malabsorption syndromes, and health conditions such as cancer, disorders of metabolism, kidney failure, and liver disease. The clinical features include aches and pains (symmetrical, non-radiating, sensitivity), muscle weakness, less rigid bones, and weight-bearing pathologies. Major biochemical findings include low serum calcium, low urinary calcium, low serum phosphate, and high ALP levels.
Bone-Forming Tumors
Bone tumors are diverse in their gross and microscopic features and vary in their natural history. Benign lesions greatly outnumber their malignant counterparts and occur mainly within the first three decades of life, whereas in the elderly, a bone tumor is more likely to be malignant. There is production of bone by neoplastic cells and the tumor bone is usually deposited as woven trabeculae and is mineralized. Bone tumors affect all ages and arise in virtually every bone, but most develop in the first several decades of life. Tumors have affinity to develop in the long bones of the extremities.
However, specific types of tumors target certain bones and age groups. The specific cause of bone tumors is unknown. However, genetic abnormalities play a significant role. For example, sarcomas occur in patients with hereditary retinoblastoma cancer, which linked to mutations in the genes coding for p53 and RB. Other bone neoplasms are also associated with conditions such as Paget’s disease, radiation, and metal prostheses. However, these types of neoplasms account for only a small number of tumors. Clinically,