osteoprosis

Osteoporosis
is a disease of bone that leads to an increased risk of fracture. In osteoporosis the bone mineral density (BMD) is reduced, bone microarchitecture is disrupted, and the amount and variety of proteins in bone is altered. Osteoporosis is defined by the World Health Organization (WHO) in women as a bone mineral density 2.5 standard deviations below peak bone mass (20-year-old healthy female average) as measured by DXA; the term "established osteoporosis" includes the presence of a fragility fracture
Osteoporosis is most common in women after menopause, when it is called postmenopausal osteoporosis, but may also develop in men, and may occur in anyone in the presence of particular hormonal disorders and other chronic diseases or as a result of medications, specifically glucocorticoids, when the disease is called steroid- or glucocorticoid-induced osteoporosis (SIOP or GIOP). Given its influence in the risk of fragility fracture, osteoporosis may significantly affect life expectancy and quality of life.
Osteoporosis can be prevented with lifestyle changes and sometimes medication; in people with osteoporosis, treatment may involve both. Lifestyle change includes exercise and preventing falls; medication includes calcium, vitamin D, bisphosphonates and several others. Fall-prevention advice includes exercise to tone deambulatory muscles, proprioception-improvement exercises; equilibrium therapies may be included. Exercise with its anabolic effect, may at the same time stop or reverse osteoporosis. Osteoporosis is a component of the frailty syndrome.
Pathogenesis
The underlying mechanism in all cases of osteoporosis is an imbalance between bone resorption and bone formation. In normal bone, there is constant matrix remodeling of bone; up to 10% of all bone mass may be undergoing remodeling at any point in time
The three main mechanisms by which osteoporosis develops are an inadequate peak bone mass (the skeleton develops insufficient mass and strength during growth), excessive bone resorption and inadequate formation of new bone during remodeling. An interplay of these three mechanisms underlies the development of fragile bone tissue
Hormonal factors strongly determine the rate of bone resorption; lack of estrogen (e.g. as a result of menopause) increases bone resorption as well as decreasing the deposition of new bone that normally takes place in weight-
Trabecular bone is the sponge-like bone in the ends of long bones and vertebrae. Cortical bone is the hard outer shell of bones and the middle of long bones. Because osteoblasts and osteoclasts inhabit the surface of bones, trabecular bone is more active, more subject to bone turnover, to remodeling. Not only is bone density decreased, but the microarchitecture of bone is disrupted. The weaker spicules of trabecular bone break ("microcracks"), and are replaced by weaker bone. Common osteoporotic fracture sites, the wrist, the hip and the spine, have a relatively high trabecular bone to cortical bone ratio. These areas rely on trabecular bone for strength, and therefore the intense remodeling causes these areas to degenerate most when the remodeling is imbalanced

Signs and symptoms
Osteoporosis itself has no specific symptoms; its main consequence is the increased risk of bone fractures. Osteoporotic fractures are those that occur in situations where healthy people would not normally break a bone; they are therefore regarded as fragility fractures. Typical fragility fractures occur in the vertebral column, rib, hip and wrist
The symptoms of a vertebral collapse ("compression fracture") are sudden back pain, often with radiculopathic pain (shooting pain due to nerve root compression) and rarely with spinal cord compression or cauda equina syndrome. Multiple vertebral fractures lead to a stooped posture, loss of height, and chronic pain with resultant reduction in mobility.
Fractures of the long bones acutely impair mobility and may require surgery. Hip fracture, in particular, usually requires prompt surgery, as there are serious risks associated with a hip fracture, such as deep vein thrombosis and a pulmonary embolism, and increased mortality.
Fracture Risk Calculators assess the risk of fracture based upon several criteria, including BMD, age, smoking, alcohol usage, weight, and gender.
Risk factors
Nonmodifiable
The most important risk factors for osteoporosis are advanced age (in both men and women) and female sex; estrogen deficiency following menopause is correlated with a rapid reduction in bone mineral density, while in men a decrease in testosterone levels has a comparable (but less pronounced) effect. While osteoporosis occurs in people from all ethnic groups, European or Asian ancestry predisposes for osteoporosis. Those with a family history of fracture or osteoporosis are at an increased risk; the heritability of the fracture as well as low bone mineral density are relatively high, ranging from 25 to 80 percent. There are at least 30 genes associated with the development of osteoporosis. Those who have already had a fracture are at least twice as likely to have another fracture compared to someone of the same age and sex
Potentially modifiable
chronic heavy drinking (alcohol intake greater than 3 units/day), especially at a younger age,
Vitamin D deficiency- low circulating Vitamin D is common among the elderly worldwide. Mild vitamin D insufficiency is associated with increased Parathyroid Hormone (PTH) production. PTH increases bone resorption, leading to bone loss
Tobacco smoking - tobacco smoking inhibits the activity of osteoblasts, and is an independent risk factor for osteoporosis
Malnutrition - nutrition has an important and complex role in maintenance of good bone. Identified risk factors include low dietary calcium and/or phosphorus, magnesium, zinc
Underweight/inactive - bone remodeling occurs in response to physical stress
Excess physical activity - excessive exercise can lead to constant damages to the bones which can cause exhaustion of the structures as described above
Heavy metals - a strong association between cadmium, lead and bone disease has been established
Soft drinks - some studies indicate that soft drinks (many of which contain phosphoric acid) may increase risk of osteoporosis Others suggest soft drinks may displace calcium-containing drinks from the diet rather than directly causing osteoporosis
Caffeine – contrary to popular belief, there is no evidence linking caffeine to osteoporosis
Diseases and disorders
In general, immobilization causes bone loss
Hypogonadal states can cause secondary osteoporosis
Endocrine disorders that can induce bone loss include Cushing s syndrome[], hyperparathyroidism[], thyrotoxicosis[], hypothyroidism, diabetes mellitus type 1 and 2, acromegaly and adrenal insufficiency. In pregnancy and lactation, there can be a reversible bone loss
Malnutrition, parenteral nutrition[12] and malabsorption can lead to osteoporosis
Patients with rheumatologic disorders like rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus and polyarticular juvenile idiopathic arthritis are at increased risk of osteoporosis
Renal insufficiency can lead to osteodystrophy
Hematologic disorders linked to osteoporosis are multiple myeloma and other monoclonal gammopathies, lymphoma and leukemia, mastocytosis[, hemophilia, sickle-cell disease and thalassemia
Several inherited disorders have been linked to osteoporosis. These include osteogenesis imperfecta, Marfan syndrome



Medication
Steroid-induced osteoporosis (SIOP) arises due to use of glucocorticoids - analogous to Cushing s syndrome and involving mainly the axial skeleton. The synthetic glucocorticoid prescription drug prednisone is a main candidate after prolonged intake. Some professional guidelines recommend prophylaxis in patients who take the equivalent of more than 30 mg hydrocortisone (7.5 mg of prednisolone), especially when this is in excess of three months.] Alternate day use may not prevent this complication
Barbiturates, phenytoin and some other enzyme-inducing antiepileptics
L-Thyroxine over-replacement may contribute to osteoporosis, in a similar fashion as thyrotoxicosis does
Several drugs induce hypogonadism, for example aromatase inhibitors used in breast cancer, methotrexate and other anti-metabolite drugs, depot progesterone and gonadotropin-releasing hormone agonists.
Anticoagulants - long-term use of heparin is associated with a decrease in bone density, and warfarin (and related coumarins) have been linked with an increased risk in osteoporotic fracture in long-term use
Proton pump inhibitors - these drugs inhibit the production of stomach acid; it is thought that this interferes with calcium absorption.[] Chronic phosphate binding may also occur with aluminium-containing antacids
Thiazolidinediones (used for diabetes) - rosiglitazone and possibly pioglitazone
Diagnosis
The diagnosis of osteoporosis is made on measuring the bone mineral density (BMD). The most popular method is dual energy X-ray absorptiometry (DXA or DEXA). In addition to the detection of abnormal BMD, the diagnosis of osteoporosis requires investigations into potentially modifiable underlying causes; this may be done with blood tests and X-rays. Depending on the likelihood of an underlying problem, investigations for cancer with metastasis to the bone, multiple myeloma, Cushing s disease and other above mentioned causes may be performed
Dual energy X-ray absorptiometry
Dual energy X-ray absorptiometry (DXA, formerly DEXA) is considered the gold standard for the diagnosis of osteoporosis. Osteoporosis is diagnosed when the bone mineral density is less than or equal to 2.5 standard deviations below that of a young adult reference population. This is translated as a T-score. The World Health Organization has established the following diagnostic guidelines:
• T-score -1.0 or greater is "normal"
• T-score between -1.0 and -2.5 is "low bone mass" (or "osteopenia")
• T-score -2.5 or below is osteoporosis
Screening
The U.S. Preventive Services Task Force (USPSTF) recommended in 2002 that all women 65 years of age or older should be screened with bone densitometry. The Task Force recommends screening only those women ages 60 to 64 years of age who are at increased risk. The best risk factor for indicating increased risk is lower body weight (weight < 70 kg), with less evidence for smoking or family history. There was insufficient evidence to make recommendations about the optimal intervals for repeated screening and the appropriate age to stop screening. Clinical prediction rules are available to guide selection of women ages 60–64 for screening. The Osteoporosis Risk Assessment Instrument (ORAI) may be the most sensitive strategy[
Regarding the screening of men, a cost-analysis study suggests that screening may be "cost-effective for men with a self-reported prior fracture beginning at age 65 years and for men 80 years and older with no prior fracture
Treatment
There are several medications used to treat osteoporosis, depending on gender. Medications themselves can be classified as antiresorptive or bone anabolic agents. Antiresorptive agents work primarily by reducing bone resorption, while bone anabolic agents build bone rather than inhibit resorption. Lifestyle changes are also an aspect of treatment
Antiresorptive agents
• Bisphosphonates
Bisphosphonates are the main pharmacological measures for treatment. However, newer drugs have appeared in the 1990s, such as teriparatide and strontium ranelate.
In confirmed osteoporosis, bisphosphonate drugs are the first-line treatment in women. The most often prescribed bisphosphonates are presently sodium alendronate (Fosamax) 10 mg a day or 70 mg once a week, risedronate (Actonel) 5 mg a day or 35 mg once a week and or ibandronate (Boniva) once a month
• Oral bisphosphonates are relatively poorly absorbed, and must therefore be taken on an empty stomach, with no food or drink to follow for the next 30 minutes. They are associated with inflammation of the esophagusEstrogen analogs
Estrogen replacement therapy remains a good treatment for prevention of osteoporosis but, at this time, is not recommended unless there are other indications for its use as well. There is uncertainty and controversy about whether estrogen should be recommended in women in the first decade after the menopause.
In hypogonadal men testosterone has been shown to give improvement in bone quantity and quality, but, as of 2008, there are no studies of the effects on fractures or in men with a normal testosterone level.
• Raloxifene
Selective Estrogen Receptor Modulators (SERMs) are a class of medications that act on the estrogen receptors throughout the body in a selective manner. Normally, bone mineral density (BMD) is tightly regulated by a balance between osteoblast and osteoclast activity in the trabecular bone.
• Calcitonin
Calcitonin works by directly inhibiting osteoclast activity via the calcitonin receptor.Calcitonin receptors have been identified on the surface of osteoclasts. Calcitonin directly induces inhibition of osteoclastic bone resorption by affecting actin cytoskeleton which is needed for the osteoclastic activity
Bone anabolic agents
• Teriparatide
Recently, teriparatide (Forteo, recombinant parathyroid hormone residues 1–34) has been shown to be effective in osteoporosis. It acts like parathyroid hormone and stimulates osteoblasts, thus increasing their activity
• Sodium fluoride
Sodium fluoride treatment in patients with osteoporosis has been shown to cause skeletal changes such as pronounced bone density with increased number and thickness of trabeculae, cortical thickening, and partial obliteration of the medullary space
Other agents
• RANKL inhibitors
Denosumab is a fully human monoclonal antibody that mimics the activity of osteoprotegerin

..Oral strontium ranelate is an alternative oral treatment, belonging to a class of drugs called "dual action bone agents" (DABAs) by its manufacturer. It has proven efficacy, especially in the prevention of vertebral fracture. In laboratory experiments, strontium ranelate was noted to stimulate the proliferation of osteoblasts, as well as inhibiting the proliferation of osteoclasts.
Nutrition
• Calcium
Calcium is required to support bone growth, bone healing and maintain bone strength and is one aspect of treatment for osteoporosis. Recommendations for calcium intake vary depending country and age; for individuals at higher risk of osteoporosis (after fifty years of age) the amount recommended by US health agencies is 1,200 mg per day. Calcium supplements can be used to increase dietary intake, and absorption is optimized through taking in several small (500 mg or less) doses throughout the day
• Vitamin D
Several studies have shown that a high intake of vitamin D reduces fractures in the elderly, The Women s Health Initiative found that though calcium plus vitamin D did increase bone density by 1% but it did not affect hip fracture. It did increase formation of kidney stones by 17%.This study has been criticised for using an inadequate dose of vitamin D (400 U) and for allowing the control arm to take supplemental vitamin D.
Exercise
Multiple studies have shown that aerobics, weight bearing, and resistance exercises can all maintain or increase BMD in postmenopausal women
Prognosis
Hip fractures per 1000 patient-years
WHO category Age 50-64 Age > 64 Overall
Normal 5.3 9.4 6.6
Osteopenia
11.4 19.6 15.7
Osteoporosis 22.4 46.6 40.6
Although osteoporosis patients have an increased mortality rate due to the complications of fracture, most patients die with the disease rather than of it.
Hip fractures can lead to decreased mobility and an additional risk of numerous complications (such as deep venous thrombosis and/or pulmonary embolism, pneumonia). The 6-month mortality rate following hip fracture is approximately 13.5%, and a substantial proportion (almost 13%) of people who have suffered a hip fracture need total assistance to mobilize after a hip fracture
Epidemiology
Osteoporosis is a major public health threat which afflicts 55% of Americans aged 50 and above. Of these, approximately 80% are women