Metabolic Bone Disease Metabolic bone disease is a general disease of metabolism affect the entire skeleton in which every

bone is involved. Biopsy of any bone in the body should reflect these metabolic alterations to some extent. Very few metabolic disorders (e.g., fluorosis, vitamin A toxicity) may increase bone density, a vast majority of metabolic bone diseases are clinical problems resulting in decreased bone density. The result may be bones with decreased organic matrix with normal mineralization (e.g., osteoporosis), bones with decreased mineral content without a significant decrease in organic matrix (e.g., osteomalacia), or bones with both diminished organic matrix and decreased mineral content (e.g., renal osteodystrophy). Osteoporosis Osteoporosis is the most common metabolic disease of bone. It is a systemic skeletal disorder characterized by decreased organic bone matrix and microarchitectural deterioration of bone tissue, with a subsequent increase in bone fragility and susceptibility to fracture. Bone density is expressed as low bone mineral density as measured by dual-energy x-ray absorptiometry (DEXA) in which the mineral is normal in structure and content. Total bone mass is decreased in osteoporosis primarily because of a decrease in bone collagen. Bone mass and strength are related to volumetric density, bone size, microarchitecture, and intrinsic tissue quality. These factors are likely to change during bone growth and bone loss, with selective modifications according to the skeletal site. Postmenopausal white and Asian women who are thin or small and have a positive family history are at greatest risk. Other risk factors include cigarette smoking, alcohol abuse, a sedentary lifestyle, and consumption of too little calcium. Strong evidence indicates that genetic and lifestyle factors are important determinants of peak bone mass. As bone becomes less dense, it becomes more radiolucent; this appearance may be due to decreased collagen and/or decreased mineral. Osteopenia in radiographic term is a state in which bone becomes less dense, more radiolucent, decreased collagen and/or decreased mineral. Compact bone resorption is an endosteal event, bone becomes more osteoporotic, and more hollow. Hollowing is compensated by intramembranous ossification on the cortical surface. As long as the bone forms a continuous ring, the strength and stiffness of a long bone is directly proportional to the distance from the center of the medullary cavity to the outside of the cortex. When the medullary cavity enlarges by endosteal osteoclasis, the diameter of the cortex also enlarges resulting to increase in the radius from medullary midpoint to outer cortex which is also directly proportional to the strength of the intact bone resulting in a small increase in appositional bone compensation for a relatively large loss of endosteal bonebiomechanically. Cancellous or trabecular bone is affected earlier due to less mass and its architecture. Cancellous bone is arranged in thin, highly perforated, vertically oriented parallel plates braced laterally by even thinner horizontal struts. Only 25% of the cancellous bone compartment is bone by volume; the remaining intertrabecular spaces are filled with fat and marrow. Compared with the cortex, the surface/volume ratio in the cancellous bone is very high, giving all bone cells free access to the delicate surfaces of the trabeculae; so cancellous bone is resorbed more rapidly than cortical bone. Progression of osteoclastic resorption at an equal rate in all parts of cancellous bone, result to earlier loss of bone mass of the horizontal struts due to the less bone mass compared to vertical plates. Resorption of these horizontal braces contributes proportionately more to the morbidity of osteoporosis than the diffuse loss of bone mass. As these struts disappear, the vertical trabeculae form longer and longer vertical line segments that are subject to progressively increased bending forces resulting to increase in susceptibility to fatigue fracture. Pain, skeletal deformities, and fractures are common sequalae. Osteoporosis may be divided etiologically into primary and secondary types. In primary osteoporosis, there are typical complex associations and patient ages, but the exact cause of bone loss in not known. The most common type of primary osteoporosis is postmenopausal osteoporosis, which occurs in the setting of hormonal decrease,

has its maximal loss of bone mass in the first menopausal decade, and seems to be associated with increased osteoclastic activity. It is manifest mainly as a loss of cancellous bone. It is similar to Idiopathic Juvenile osteoporosis that occurs in peripubertal period associated with increased osteoclastic activity. Senile osteoporosis manifests a decade or more later than the postmenopausal variety and is associated with a decline in osteoblast number proportionate to the demand for their activity; it affects mainly compact bone. Unlike the postmenopausal and senile varieties, Idiopathic juvenile osteoporosis is usually selflimited, and the skeleton may regain much of its bone mass. In secondary osteoporosis, there is a known reason for the loss of bone mass, which may sometimes be preventable or even reversed. Etiologies include hyperparathyroidism and other endocrinopathies, spaceoccupying marrow lesions causing increased pressure in the marrow cavity, calcium deficiency, malabsorption, administration of steroids or heparin, and immobilization. Certain connective tissue disorders such as osteogenesis imperfecta, Marfan syndrome, and Ehlers-Danlos syndrome also result in structural or functional osteoporosis. Current treatment efforts are aimed at preventing resorption or stimulating new bone production. Current antiresorptive treatments include estrogens, selective estrogen receptor modulators (SERMs), vitamin D, calcitonin, and bisphosphonates, and the only anabolic agent is parathyroid hormone. Of these modalities, a more rapid effect is noted with antiresorptive medications; anabolic medications require a longer time to produce a measurable effect. Osteomalacia and Rickets They are disorders of calcification. Osteomalacia is a failure to mineralize newly formed organic matrix (osteoid) in the mature skeleton. The bones gradually become softer as the ratio of osteoid to mineralized bone increases over time. Weakness, skeletal pain and deformities, and fractures as the disease progresses. Generalized decrease in skeletal radiodensity in roentgenographic examination is revealed. Rickets is a disease of children. It is an osteomalacia that occurs before cessation of growth and closure of epiphyseal plate. Deformities of the bone are accentuated as a compensatory overgrowth of epiphyseal cartilage, wide bands of which remain unmineralized and unresorbed. In severe cases, decresed overgrowth evident swelling of the costochondral junctions of the ribs (rachitic rosary), a protuberant sternum, costodiaphragmatic depression (harissons sulcus), delayed closure of the anterior fontanelle with frontal bossing, and visibly widened metaphyses of long bones. Optimal mineralization requires (1) an adequate supply of calcium and phosphate ions from the extracellular fluid, (2) an appropriate pH (7.6), (3) bone matrix of normal chemical composition and rate of synthesis, and (4) control of inhibitors of mineralization. The major categories of diseases that produce osteomalacia or rickets are vitamin D deficiency states, phosphate depletion, systemic acidosis, and inhibitors of mineralization. Vitamin D deficiency is particularly important in childhood and may be caused by inadequate dietary intake, intestinal malabsorption, diminished synthesis of active metabolites, increased catabolism, or peripheral resistance to vitamin D action. Dietary deficiency is very uncommon in the United States because of the widespread use of fortified milk and bread and vitamin supplements. When vitamin D deficiency occurs in adults, it is usually a consequence of malabsorption. Because vitamin D is a fat soluble vitamin, its absorption is impaired in celiac disease (nontropical sprue), biliary and pancreatic disease, or steatorrhea from other causes. Systemic resistance to vitamin D can be of major importance in the osteomalacia that accompanies chronic renal disease. On the other hand, hereditary resistance to 1,25(OH)2D3, often called vitamin Ddependent rickets type II, is a rare disorder caused by a variety of defects in the vitamin D receptor.

Renal Osteodystrophy Refers to the spectrum of bone abnormalities that occur in patients with end-stage renal disease (ESRD), predominantly osteitis fibrosa cystica, osteomalacia, or a combination of the two. Osteitis fibrosa cystica is characterized by increased bone turnover due to secondary hyperparathyroidism, a consequence of decreased levels of 1,25(OH)2D3 and ionized calcium. Osteomalacia is characterized by poor mineralization of bone resulting in the accumulation of surface osteoid (unmineralized bone). Osteoclasts cannot penetrate (resorb) these osteoid surfaces because they are attracted only to mineralized surfaces. Thus, osteoclasts dig cutting cones through the few remaining mineralized surfaces into the mineralized cores of old trabeculae. This phenomenon is histologically referred to as tunneling resorption because of the manner in which osteoclasts gain access to mineralized bone. The defective mineralization process in osteomalacia of ESRD patients can be attributed to low serum calcium levels, the accumulation of aluminum in bone, or other as yet unexplained factors. Renal failure patients who are treated orally with aluminum-containing phosphate binders to control hyperphosphatemia, or who undergo hemodialysis using aluminum-containing dialysates, can experience osteomalacia because aluminum ion can interfere with normal hydroxyapatite lattice formation. Undecalcified bone biopsies stained for aluminum can distinguish between this and the more usual types of osteomalacia. Pagets Disease Pagets disease of bone (osteitis deformans) is a chronic disorder of bone that may be unifocal or multifocal. It is not a true metabolic disease in which uninvolved bones are normal, although it resembles a metabolic disease because involved bones are structurally and functionally abnormal. The cause of Pagets disease is currently unknown; however, it has been suspected to be of viral origin because paramyxovirus-like particles have been identified in the nuclei of osteoclasts from affected bone. A family history of the disorder is sometimes identified. Regardless of its origin, the disease displays uncoupling of osteoclast and osteoblast function with osteoclastic activity predominating early in the disease and osteoblastic activity predominating late in the disease. The osteoclasts are often large and bizarre, with 50 or more nuclei; trabecular scalloping with multiple Howships lacunae, paratrabecular fibrosis, and marrow hypervascularity may occur. The early histologic picture resembles osteitis fibrosa of hyperparathyroidism. As osteoblastic new bone production takes place, Howships lacunae are filled in by irregular patches of mature and immature bone; the outlines of the original delimitations of osteoclast resorption are preserved as irregularly disposed reversal cement lines, and the resulting bone comes to resemble a tile mosaic. This results in structurally weak bone that is prone to both deformities and fractures. Patients with extensive bone lesions who have underlying heart disease may develop high output cardiac failure as a complication. Approximately 1% of patients eventually develop bone sarcomas, usually with osteosarcomatous differentiation. Laboratory findings are of some interest. Although serum calcium and inorganic phosphorus concentrations are typically normal, they may occasionally become elevated. Serum calcium levels may, in fact, become very elevated if an extensive area of Pagets disease is immobilized. Once osteoblast activity begins, serum alkaline phosphatase increases and may be used to follow the activity of the bone-synthesizing phase of the disease. Alkaline phosphatase levels rise further if a patient with Pagets disease d evelops osteosarcoma. Urinary excretion of calcium and phosphorus is normal or increased, whereas excretion of hydroxyproline is usually significantly increased. Pagets disease frequently responds both clinically and pathologically to therapeutic administration of calcitonin. Transudate vs Exudate Classical teaching stressed that exudates and transudates can be distinguished on the basis of total protein concentrations above (exudates) or below (transudates) 3.0 g/dL. However, using total protein alone misclassifies both exudates and transudates by about 30%. It is now well accepted that test combinations increase sensitivity

(any positive parameter indicates an exudate), improve accuracy, and serve as the basis for the well-established Light criteria. Laboratory Criteria for Pleural Fluid Exudate Pleural fluid/serum protein ratio Pleural fluid/serum LD ratio Pleural fluid LD Pleural fluid cholesterol Pleural fluid/serum cholesterol ratio Serum-pleural fluid albumin gradient Pleural fluid/serum bilirubin ratio

0.50 0.60 2/3 upper limit of normal serum LD >45mg/dL 0.30 1.2g/dL 0.60

Accordingly, an exudate meets one or more of the following criteria: (1) Pleural fluid/serum protein ratio greater than 0.5; (2) pleural fluid/serum LD ratio greater than 0.6; and (3) pleural fluid LD level greater than two thirds of the serum upper limit of normal. The sensitivity and specificity are about 98% and 80%, respectively. Lights Criteria Pleural fluid/serum protein ratio Pleural fluid/serum LD ratio Pleural fluid LD

0.50 0.60 2/3 upper limit of normal serum LD