Osteoporosis

Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing individuals to an increased fracture risk. 

Categories of osteoporosis include (1) postmenopausal osteoporosis, (2) age-related osteoporosis, and (3) secondary osteoporosis. 

Bone loss occurs when bone resorption exceeds bone formation, usually from high bone turnover when the number and/or depth of bone resorption sites greatly exceed the rate and ability of osteoblasts to form new bone. 

In addition to reduced bone mineral density (BMD), bone quality and structural integrity are impaired because of the increased quantity of immature bone that is not yet adequately mineralized. 

Age-related osteoporosis occurs mainly because of hormone, calcium, and vitamin D deficiencies leading to accelerated bone turnover and reduced osteoblast formation. 

Osteoporosis is defined as a generalized decrease in bone mass (osteopenia) that affects bone matrix and mineral content equally, giving rise to fractures of vertebral bodies with bone pain, kyphosis, and shortening of the torso. Fractures of the hip and the distal radius are also commoa The underlying process is a disequilibrium between bone formation by osteoblasts and bone resorption by osteoclasts. 

Qassification Idiopathic osteoporosis type 1, occurring in postmenopausal females type 11, occurring in senescent males and females ( 70 y). Secondary osteoporosis associated with primary disorders such as Cushing s disease, or induced by drugs, e.g chronic therapy with glucocorticoids or heparin. In these forms, the cause can be eliminated. 

Postmenopausal osteoporosis represents a period of accelerated loss of bone mass. The lower the preexisting bone mass, the earlier the clinical signs become manifest. 

Risk factors are premature menopause, physical inactivity, cigarette smoking, alcohol abuse, low body weight, and calcium-poor diet 

Prophylaxis Administration of estrogen can protect against postmenopausal loss of bone mass. Frequently, conjugated estrogens are used (p. 254). 

In hypocalcemia, the parathyroid increases its secretion of parathormone, resulting in enhanced liberation of Ca2+. Calcitonin transfers active osteoclasts into a resting state. Calcitonin given therapeutically relieves pain associated with neoplastic bone metastases and vertebral body collapse. Estrogens diminish bone resorption by (a) inhibiting activation of osteoclasts by osteoblasts and (b) promoting apoptosis of osteoclasts. 

Idiopathic osteoporosis cannot be prevented by prophylactic therapy, but its development can be delayed. This requires a healthy lifestyle with plenty of physical exercise (sports, hiking), daily intake of calcium (lOOOmg/day Ca2+) and of vitamin D (1000 IU/day). The same principle holds for postmenopausal osteoporosis. Hormone Luellmann, Color Atlas of Pharmacology All rights reserved. Usage subject to terms 

If osteoporosis has become clinically manifest, attempts can be made at improving the condition by means of drugs, or at least slowing down further deterioration. Besides administration of calcium and vitamin D, the following options are available. 

Bisphosphonates (N-containing) structurally mimic endogenous pyrophosphate (see formulae), and like the latter are incorporated into the mineral substance of bone. During phagocytosis of the bone matrix, they are taken up by osteoclasts. There, the N-containing bisphosphonates inhibit prenyla-tion of G-proteins and thus damage the cells. Accordingly, osteoclast activity levels are lowered by alendronate and risedronate, while osteoclast apoptosis is promoted. The result is a reduction in bone resorption and a decreased risk of bone fractures. 

Osteoporosis is a condition involving loss of bone mineral and matrix in elderly people, and may affect 40% of women and 12% of men as they age. The loss of bone mineral is associated with inappropriate calcification of other tissues, especially arteries and the kidneys. This may be more dangerous than the loss of bone, in that the majority of deaths among women suffering from osteoporosis are from cardiovascular disease. 

Unlike osteomalacia, there is no defect of bone mineralization in osteoporosis. The lower density of the bone renders it more susceptible to fracture, whereas in osteomalacia the incompletely mineralized bone matrix is liable to deformation rather than fracture. 

Type 1 osteoporosis, also known as postmenopausal osteoporosis, involves loss of trabecular bone in the vertebrae, leading to crush fracture with minimal trauma. It is essentially a condition affecting postmenopausal women, with a femaleimale ratio of 10 1. Type 11 osteoporosis (senile osteoporosis) is osteoporotic hip fracture. It shows only a 2 1 excess of females over males and a geometric increase in incidence with increasing age. The two types of osteoporosis are not exclusive, and type 1 patients are more susceptible to hip fracture, whereas many hip fracture patients have asymptomatic vertebral crush fractures. 

A lifetime low intake of calcium is a risk factor, and there is some evidence that a moderately high Intake of calcium during early life, while the skeleton is being formed, is protective. Postmenopausal hormone replacement therapy is beneficial in reducing the rate of bone loss. 

Osteoporosis (OP) is a chronic bone disease in which the bones become brittle and break more easily. It develops primarily as a con- 

Cross-sectional analyses are supportive of a protective relationship between soy intake and bone health (Messina et al. 2004) for example, modest association were shown in Chinese early PMW women, but only if more than 4 years post-menopause (Ho et al. 2003). A prospective study found that PRE-M women with higher SI intakes had a slower rate of bone loss (measured by bone mineral density (BMD) (average follow-up 38.1 months) (Ho et al. 2001). An inverse association between risk of bone fracture, perhaps a more accurate indicator of OP risk, and SP intake was reported in a cohort of 24,403 Chinese PMW the highest intakes associated with a 48% reduction in risk during early menopause, and a 29% reduction in late menopause compared to the lowest intakes (Zhang et al 2005). 

Biomarkers of bone turnover (serum osteocalcin, urinary DPD, serum BAP, etc.), typically included in studies with 3-6 month intervention duration, are also inconsistent in their response to soy product interventions these studies are described in more detail elsewhere (Coxam 2008). Meta-analyses of these trials revealed a moderate decrease in the bone resorption marker, urinary DPD, n = 887) but there were no effects on serum BAP or serum osteocalcin (Taku et al. 2010b). Intervention studies that include fracture as an outcome variable would be the optimum route for making conclusive assessments of the efficacy of SI in the prevention of OP, but very large numbers of participants would be required to achieve adequate statistical power. In the absence of data of this quality, the only recommendation is that including SF in the diet will not adversely affect bone health and might yield skeletal benefits in the long term. 

Systemic osteoporosis is a disease characterized by a lowered bone mass per unit volume of skeleton that results from faulty calcification. In fact, as much as 50% of the bone mass may be lost before the diagnosis of osteoporosis becomes obvious. It is therefore not surprising that attempts are made to quantitate the bone mass on biopsy material for the purpose of securing the early diagnosis of osteoporosis. In osteoporosis there are no known alterations in the mineral composition of the bone, but a slight reduction in the Ca/ 

PO4 ratio proportional to the demineralization has been reported. A patient is arbitrarily classified as osteoporotic when the specific gravity of the bone drops from 1.075 (normal bone) to 1.050. 

In areas of osteoporosis, the calcified bone is progressively replaced by the softer components of the skeleton (fibrous tissue, fat, and marrow). The pathogenesis of osteoporosis has not been established and therefore an adequate classification is not available. Cases of osteoporosis are grouped in two main categories those patients in whom osteoporosis results from endocrine or vitamin imbalance, and the idiopathic cases of osteoporosis, which cannot be traced to a well-established pathogenesis [26-28]. 

If radiological pictures of the bone of an osteoporotic individual are compared with those of normal bone, it becomes obvious that the density of the diseased bone is considerably decreased, but the structure of the bone is not changed, and in fact the trabecular appearance may even be exaggerated, as if the outline and the fine structure of the bone had been drawn out with a thick dark pencil. As osteoporosis pro- 

Bone demineralization leads to increased fragility of the bone. A typical deformation occurs in the thinned vertebrae where the nucleus pulposus depresses the softened bone giving a biconcave appearance to the vertebral body. Small herniations in bone of adjacent cartilage occur and are responsible for a deformation known as Schmorl s nodules. 

The search for suitable animal models for the study of osteoporosis receives its impetus from the protracted periods of time required to monitor the effect of experimental variables on the progress of the disease in humans and the invasive techniques required. Research on animal models also has been fueled by the increasing proportion of aged persons in the population. 

Finally hold in mind that falls are frequent in old age and can lead to severe consequences, including sufferings both for the individual and the next of kin. Also the cost for the society of falls and fractures are considerable. Falls increase with the use of fall-risk-increasing drugs and polypharmacy and can be prevented by a multifactor approach including reassessing the medications used by older people. 

Osteoporosis is a world wide problem with consequences for both the individual affected and society as a whole. Osteoporosis affects an estimated 75 million people in Europe, USA and Japan. The estimated cost for the treatment of osteoporosis in the world is 18.3 billion dollars a year. Hip, vertebrae and wrist are the most frequent sites for osteoporotic fractures. Due to the increase in the population over 60 years of age this scenario is about to escalate and regarding one of the most serious fractures, the hip fracture, an increase with more than 200% is likely to occur. Today, approximately 1.6 million hip fractures happen yearly in the world and, in the nearest forty to fifty years, this number can increase to about 5 million. The risk of hip fractures is highest in Norway, Iceland, Sweden, Denmark and the United States (NIH 2000). 

Osteoporosis is in many ways a silent disease and osteoporotic fractures occurs mainly in women, the ratio being 1.6 females to 1 male. There are many risk factors that have been identified as increasing the development of osteoporosis and age, sex and life styles factors are some (Box 5.13) 

There are no symptoms of the poor bone quality until a fracture occurs. When a person has reached the age of 80 the bone quality has in most cases deteriorated to the extent to put her/him at high risk of developing a fracture. Osteoporosis occurs 

The definition of osteoporosis is (NIH 2000) A systemic skeletal disease characterized by low bone mass and micro architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture . 

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Hydrocortisone and Prednisolone. Following the discovery of the antiinflammatory actions of cortisone (1) and cortisol (2), there was a need not only to develop highly efficient routes to the corticoids, but to discover novel stmctures with fewer side effects than those of the corticoids, eg, sodium and water retention, reduced carbohydrate tolerance (steroid diabetes), osteoporosis, and depressed host defense. 

Human growth hormone, used as a human pharmaceutical, is approved for only one indication in the United States, treatment of growth failure owing to hGH deficiency, a condition known as pituitary dwarfism. However, clinical trials are under way to test its efficacy in Turner s syndrome, bums, wound healing, cachexia, osteoporosis, constitutional growth delay, aging, malnutrition, and obesity. 

Other Calcium Disorders. In addition to hypocalcemia, tremors, osteoporosis, and muscle spasms (tetary), calcium deficiency can lead to rickets, osteomalacia, and possibly heart disease. These, as well as Paget s disease, can also result from faulty utilization of calcium. Calcium excess can lead to excess secretion of calcitonin, possible calcification of soft tissues, and kidney stones when combined with magnesium deficiency. 

Phosphorus Disorders. Phosphoms nutrient deficiency can lead to rickets, osteomalacia, and osteoporosis, whereas an excess can produce hypocalcemia. Faulty utilisation of phosphoms results in rickets, osteomalacia, osteoporosis, and Paget s disease, and renal or vitamin D-resistant rickets. 

Unfortunately steroids merely suppress the inflammation while the underlying cause of the disease remains. Another serious concern about steroids is that of toxicity. The abmpt withdrawal of glucocorticoid steroids results in acute adrenal insufficiency. Long term use may induce osteoporosis, peptidic ulcers, the retention of fluid, or an increased susceptibiUty to infections. Because of these problems, steroids are rarely the first line of treatment for any inflammatory condition, and their use in rheumatoid arthritis begins after more conservative therapies have failed. 

Ascorbic acid also forms soluble chelate complexes with iron (142—145). It seems ascorbic acid has no effect on high iron levels found in people with iron overload (146). It is well known, in fact, that ascorbic acid in the presence of iron can exhibit either prooxidant or antioxidant effects, depending on the concentration used (147). The combination of citric acid and ascorbic acid may enhance the iron load in aging populations. Iron overload may be the most important common etiologic factor in the development of heart disease, cancer, diabetes, osteoporosis, arthritis, and possibly other disorders. The synergistic combination of citric acid and ascorbic acid needs further study, particularly because the iron overload produced may be correctable (147). 

Clinical stresses which interfere with vitamin metabohsm, can result in calcium deficiency leading to osteomalacia and osteoporosis (secondary vitamin D deficiency). These stresses include intestinal malabsorption (lack of bile salts) stomach bypass surgery obstmctive jaundice alcoholism Hver or kidney failure decreasing hydroxylation of vitamin to active forms inborn error of metabohsm and use of anticonverdiants that may lead to increased requirement. 

In the treatment of diseases where the metaboUtes are not being deUvered to the system, synthetic metaboUtes or active analogues have been successfully adrninistered. Vitamin metaboUtes have been successfully used for treatment of milk fever ia catde, turkey leg weakness, plaque psoriasis, and osteoporosis and renal osteodystrophy ia humans. Many of these clinical studies are outlined ia References 6, 16, 40, 51, and 141. The vitamin D receptor complex is a member of the gene superfamily of transcriptional activators, and 1,25 dihydroxy vitamin D is thus supportive of selective cell differentiation. In addition to mineral homeostasis mediated ia the iatestiae, kidney, and bone, the metaboUte acts on the immune system, P-ceUs of the pancreas (iasulin secretion), cerebellum, and hypothalamus. 

H. M. Frost, Bone Dynamics in Osteoporosis and Osteomalacia Surgery Monograph Series, Charles C. Thomas, Pubhsher, Springfield, HI., 1966. 

Despite the limitations imposed by the physiology of the skin, several marketed controUed release transdermal dmg dehvery systems are available in the United States for example, scopolamine [51-34-3] for the treatment of motion sickness, nitroglycerin [55-63-0] for angina, estradiol [50-28-2] for the rehef of postmenopausal symptoms and osteoporosis, clonidine [4205-90-7] for the treatment of hypertension, fentanyl [437-38-7] as an analgesic, and nicotine [54-11-5] as an aid to smoking cessation. These systems are designed to dehver dmg for periods of one to seven days. 

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