Monday, September 19

Osteoporosis

Osteoporosis, porous bones",  meaning "bone" and πόρος/poros meaning "pore") is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density (BMD) is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered. Osteoporosis is defined by the World Health Organization (WHO) as a bone mineral density that is 2.5 standard deviations or more below the mean peak bone mass (average of young, healthy adults) as measured by DXA; the term "established osteoporosis" includes the presence of a fragility fracture. The disease may be classified as primary type 1, primary type 2, or secondary. The form of osteoporosis most common in women after menopause is referred to as primary type 1 or postmenopausal osteoporosis. Primary type 2 osteoporosis or senile osteoporosis occurs after age 75 and is seen in both females and males at a ratio of 2:1. Finally, secondary osteoporosis may arise at any age and affects men and women equally. This form of osteoporosis results from chronic predisposing medical problems or disease, or prolonged use of medications such as glucocorticoids, when the disease is called steroid- or glucocorticoid-induced osteoporosis (SIOP or GIOP).
Osteoporosis risks can be reduced with lifestyle changes and sometimes medication; in people with osteoporosis, treatment may involve both. Lifestyle change includes diet and 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.



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.


Fractures

Fractures are the most dangerous aspect of osteoporosis. Debilitating acute and chronic pain in the elderly is often attributed to fractures from osteoporosis and can lead to further disability and early mortality. The fractures from osteoporosis may also be asymptomatic. 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. Recognised calculators include FRAX and Dubbo.


Falls risk

The increased risk of falling associated with aging leads to fractures of the wrist, spine and hip. The risk of falling, in turn, is increased by impaired eyesight due to any cause (e.g. glaucoma, macular degeneration), balance disorder, movement disorders (e.g. Parkinson's disease), dementia, and sarcopenia (age-related loss of skeletal muscle). Collapse (transient loss of postural tone with or without loss of consciousness) leads to a significant risk of falls; causes of syncope are manifold but may include cardiac arrhythmias (irregular heart beat), vasovagal syncope, orthostatic hypotension (abnormal drop in blood pressure on standing up) and seizures. Removal of obstacles and loose carpets in the living environment may substantially reduce falls. Those with previous falls, as well as those with a gait or balance disorder, are most at risk.


Risk factors

Risk factors for osteoporotic fracture can be split between non-modifiable and (potentially) modifiable. In addition, there are specific diseases and disorders in which osteoporosis is a recognized complication. Medication use is theoretically modifiable, although in many cases the use of medication that increases osteoporosis risk is unavoidable. Caffeine is not a risk factor for osteoporosis.


Nonmodifiable

The most important risk factors for osteoporosis are advanced age (in both men and women) and female gender; estrogen deficiency following menopause or oophorectomy 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. A small stature is also a non-modifiable risk factor associated with the development of osteoporosis.


Potentially modifiable

Excess alcohol—small amounts of alcohol are probably beneficial. Bone density increases with increasing alcohol intake. However chronic heavy drinking (alcohol intake greater than 3 units/day) probably increases fracture risk despite any beneficial effects on bone density.
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. A positive association exists between serum 1,25-dihydroxycholecalciferol levels and bone mineral density, while PTH is negatively associated with bone mineral density.
Tobacco smoking—tobacco smoking inhibits the activity of osteoblasts, and is an independent risk factor for osteoporosis. Smoking also results in increased breakdown of exogenous estrogen, lower body weight and earlier menopause, all of which contribute to lower bone mineral density.
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, boron, iron, fluoride, copper, vitamins A, K, E and C (and D where skin exposure to sunlight provides an inadequate supply). Excess sodium is a risk factor. High blood acidity may be diet-related, and is a known antagonist of bone.Some have identified low protein intake as associated with lower peak bone mass during adolescence and lower bone mineral density in elderly populations.Conversely, some have identified low protein intake as a positive factor, protein is among the causes of dietary acidity. Imbalance of omega 6 to omega 3 polyunsaturated fats is yet another identified risk factor.
High protein diet—Research has found an association between diets high in animal protein and increased urinary calcium loss from the bones.
Underweight/inactive—bone remodeling occurs in response to physical stress, and weight bearing exercise can increase peak bone mass achieved in adolescence. In adults, physical activity helps maintain bone mass, and can increase it by 1 or 2%.[citation needed] Conversely, physical inactivity can lead to significant bone loss. (Incidence of osteoporosis is lower in overweight people.)
Excess physical activity—excessive exercise can lead to constant damage to the bones which can cause exhaustion of the structures as described above. There are numerous examples of marathon runners who developed severe osteoporosis later in life. In women, heavy exercise can lead to decreased estrogen levels, which predisposes to osteoporosis. In addition, intensive training without proper compensatory increased nutrition increases the risk.
Heavy metals—a strong association between cadmium, lead and bone disease has been established. Low level exposure to cadmium is associated with an increased loss of bone mineral density readily in both genders, leading to pain and increased risk of fractures, especially in the elderly and in females. Higher cadmium exposure results in osteomalacia (softening of the bone).
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.


Diseases and disorders

Many diseases and disorders have been associated with osteoporosis. For some, the underlying mechanism influencing the bone metabolism is straight-forward, whereas for others the causes are multiple or unknown.
In general, immobilization causes bone loss (following the 'use it or lose it' rule). For example, localized osteoporosis can occur after prolonged immobilization of a fractured limb in a cast. This is also more common in active patients with a high bone turn-over (for example, athletes). Other examples include bone loss during space flight or in people who are bedridden or who use wheelchairs for various reasons.
Hypogonadal states can cause secondary osteoporosis. These include Turner syndrome, Klinefelter syndrome, Kallmann syndrome, anorexia nervosa, andropause, hypothalamic amenorrhea or hyperprolactinemia. In females, the effect of hypogonadism is mediated by estrogen deficiency. It can appear as early menopause (<45 years) or from prolonged premenopausal amenorrhea (>1 year). A bilateral oophorectomy (surgical removal of the ovaries) or a premature ovarian failure cause deficient estrogen production. In males, testosterone deficiency is the cause (for example, andropause or after surgical removal of the testes).
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 and malabsorption can lead to osteoporosis. Nutritional and gastrointestinal disorders that can predispose to osteoporosis include coeliac disease, Crohn's disease, lactose intolerance, surgery (after gastrectomy, intestinal bypass surgery or bowel resection) and severe liver disease (especially primary biliary cirrhosis). Patients with bulimia can also develop osteoporosis. Those with an otherwise adequate calcium intake can develop osteoporosis due to the inability to absorb calcium and/or vitamin D. Other micro-nutrients such as vitamin K or vitamin B12 deficiency may also contribute.
Patients with rheumatologic disorders like rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus and polyarticular juvenile idiopathic arthritis are at increased risk of osteoporosis, either as part of their disease or because of other risk factors (notably corticosteroid therapy). Systemic diseases such as amyloidosis and sarcoidosis can also lead to 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,hemochromatosis,hypophosphatasia, glycogen storage diseases, homocystinuria, Ehlers–Danlos syndrome,porphyria, Menkes' syndrome, epidermolysis bullosa and Gaucher's disease.
People with scoliosis of unknown cause also have a higher risk of osteoporosis. Bone loss can be a feature of complex regional pain syndrome. It is also more frequent in people with Parkinson's disease and chronic obstructive pulmonary disease.



Medication
Certain medications have been associated with an increase in osteoporosis risk; only steroids and anticonvulsants are classically associated, but evidence is emerging with regard to other drugs.
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 - these probably accelerate the metabolism of vitamin D.
L-Thyroxine over-replacement may contribute to osteoporosis, in a similar fashion as thyrotoxicosis does. This can be relevant in subclinical hypothyroidism.
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, inhibitors of PPARγ, have been linked with an increased risk of osteoporosis and fracture.
Chronic lithium therapy has been associated with osteoporosis.


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 process takes place in bone multicellular units (BMUs) as first described by Frost in 1963. Bone is resorbed by osteoclast cells (which derive from the bone marrow), after which new bone is deposited by osteoblast cells.
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.[9] 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-bearing bones. The amount of estrogen needed to suppress this process is lower than that normally needed to stimulate the uterus and breast gland. The α-form of the estrogen receptor appears to be the most important in regulating bone turnover. In addition to estrogen, calcium metabolism plays a significant role in bone turnover, and deficiency of calcium and vitamin D leads to impaired bone deposition; in addition, the parathyroid glands react to low calcium levels by secreting parathyroid hormone (parathormone, PTH), which increases bone resorption to ensure sufficient calcium in the blood. The role of calcitonin, a hormone generated by the thyroid that increases bone deposition, is less clear and probably not as significant as that of PTH.
The activation of osteoclasts is regulated by various molecular signals, of which RANKL (receptor activator for nuclear factor κB ligand) is one of best studied. This molecule is produced by osteoblasts and other cells (e.g. lymphocytes), and stimulates RANK (receptor activator of nuclear factor κB). Osteoprotegerin (OPG) binds RANKL before it has an opportunity to bind to RANK, and hence suppresses its ability to increase bone resorption. RANKL, RANK and OPG are closely related to tumor necrosis factor and its receptors. The role of the wnt signalling pathway is recognized but less well understood. Local production of eicosanoids and interleukins is thought to participate in the regulation of bone turnover, and excess or reduced production of these mediators may underlie the development of osteoporosis.
Trabecular bone (or cancellous 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.[citation needed] Around the ages of 30-35, cancellous or trabecular bone loss begins. Women may lose as much as 50%, while men lose about 30%.


Diagnosis
A scanner used to measure bone density with Dual energy X-ray absorptiometry.
The diagnosis of osteoporosis can be made using conventional radiography and by measuring the bone mineral density (BMD). The most popular method of measuring BMD 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. 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.


Conventional radiography
Conventional radiography is useful, both by itself and in conjunction with CT or MRI, for detecting complications of osteopenia (reduced bone mass; pre-osteoporosis), such as fractures; for differential diagnosis of osteopenia; or for follow-up examinations in specific clinical settings, such as soft tissue calcifications, secondary hyperparathyroidism, or osteomalacia in renal osteodystrophy. However, radiography is relatively insensitive to detection of early disease and requires a substantial amount of bone loss (about 30%) to be apparent on x-ray images.
The main radiographic features of generalized osteoporosis are cortical thinning and increased radiolucency. Frequent complications of osteoporosis are vertebral fractures for which spinal radiography can help considerably in diagnosis and follow-up. Vertebral height measurements can objectively be made using plain-film x-rays by using several methods such as height loss together with area reduction, particularly when looking at vertical deformity in T4-L4, or by determining a spinal fracture index that takes into account the number of vertebrae involved. Involvement of multiple vertebral bodies leads to kyphosis of the thoracic spine, obvious to the clinician as "dowager's hump."


Clinical decision rule

A number of clinical decision rules have been created to predict the risk of osteoporotic fractures. The QFracture score was developed in 2009 and is based on age, BMI, smoking status, alcohol use, rheumatoid arthritis, cardiovascular disease, type 2 diabetes, asthma, use of tricyclic antidepressants or corticosteroids, liver disease, and a history of falls in men. In women hormone replacement therapy, parental history of osteoporosis, gastrointestinal malabsorption, and menopausal symptoms are also taken into account. A website is available to help apply this score.



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
When there has also been an osteoporotic fracture (also termed "low trauma-fracture" or "fragility fracture"), defined as one that occurs as a result of a fall from a standing height, the term "severe or established" osteoporosis is used.
The International Society for Clinical Densitometry takes the position that a diagnosis of osteoporosis in men under 50 years of age should not be made on the basis of densitometric criteria alone. It also states that for pre-menopausal women, Z-scores (comparison with age group rather than peak bone mass) rather than T-scores should be used, and that the diagnosis of osteoporosis in such women also should not be made on the basis of densitometric criteria alone.


Biomarkers

Chemical biomarkers are a useful tool in detecting bone degradation. The enzyme cathepsin K breaks down type-I collagen protein, an important constituent in bones. Prepared antibodies can recognize the resulting fragment, called a neoepitope, as a way to diagnose osteoporosis. Increased urinary excretion of C-telopeptides, a type-I collagen breakdown product, also serves as a biomarker for osteoporosis.


Other measuring tools

Quantitative computer tomography differs from DXA in that it gives separate estimates of BMD for trabecular and cortical bone and reports precise volumetric mineral density in mg/cm3 rather than BMD's relative Z score. Among QCT's advantages: it can be performed at axial and peripheral sites, is sensitive to change over time, can analyze a region of any size or shape, excludes irrelevant tissue such as fat, muscle, and air, and does not require knowledge of the patient's subpopulation in order to create a clinical score (e.g. the Z-score of all females of a certain age). Among QCT's disadvantages: it requires a high radiation dose, CT scanners are large and expensive, and because its practice has been less standardized than BMD, its results are more operator-dependent. Peripheral QCT has been introduced to improve upon the limitations of DXA and QCT.
Quantitative ultrasound has many advantages in assessing osteoporosis. The modality is small, no ionizing radiation is involved, measurements can be made quickly and easily, and the cost of the device is low compared with DXA and QCT devices. The calcaneus is the most common skeletal site for quantitative ultrasound assessment because it has a high percentage of trabecular bone that is replaced more often than cortical bone, providing early evidence of metabolic change. Also, the calcaneus is fairly flat and parallel, reducing repositioning errors. The method can be applied to children, neonates, and preterm infants, just as well as to adults. Once microimaging tools to examine specific aspects of bone quality are developed, it is expected that quantitative ultrasound will be increasingly used in clinical practice.

Screening

The U.S. Preventive Services Task Force (USPSTF) recommended in 2011 that all women 65 years of age or older should be screened with bone densitometry. They recommend screening women of any age with increased risk factors that puts them at risk equivalent to a 65 year old without additional risk factors. The most significant risk factors is lower body weight (weight < 70 kg), with less evidence for history of 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.
The USPSTF concludes that the harm versus benefit of screening for osteoporosis in men of any age is unknown. Others have however claimed that screening may be cost effective in those 80 to 85 years of age.


Prevention

Methods to prevent osteoporosis include changes of lifestyle. However, there are medications that can be used for prevention as well. As a different concept there are osteoporosis ortheses which help to prevent spine fractures and support the building up of muscles. Fall prevention can help prevent osteoporosis complications.


Lifestyle

Lifestyle prevention of osteoporosis is in many aspects inversions from potentially modifiable risk factors. As tobacco smoking and unsafe alcohol intake have been linked with osteoporosis, smoking cessation and moderation of alcohol intake are commonly recommended in the prevention of osteoporosis. Many other risk factors, some modifiable and others non modifiable such as genetic may be involved in osteoporosis.
Achieving a higher peak bone mass through exercise and proper nutrition during adolescence is important for the prevention of osteoporosis. Exercise and nutrition throughout the rest of the life delays bone degeneration. Jogging, walking, or stair climbing at 70-90% of maximum effort three times per week, along with 1,500 mg of calcium per day, increased bone density of the lumbar (lower) spine by 5% over nine months. Individuals already diagnosed with osteopenia or osteoporosis should discuss their exercise program with their physician to avoid fractures.

Nutrition

Proper nutrition includes a diet sufficient in calcium and vitamin D. People at risk for osteoporosis (e.g. steroid use) are generally treated with vitamin D and calcium supplements and often with bisphosphonates. Vitamin D supplementation alone does not prevent fractures, and needs to be combined with calcium. Calcium supplements come in two forms: calcium carbonate and calcium citrate. Due to its lower cost, calcium carbonate is often the first choice, however it needs to be taken with food to maximize absorption. Calcium citrate is more expensive, but it is better absorbed than calcium carbonate and can be taken without food. In addition, patients who are taking proton pump inhibitors or H2 blockers do not absorb calcium carbonate well; calcium citrate is the supplement of choice in this population. In renal disease, more active forms of Vitamin D such as cholecalciferol or (1,25-dihydroxycholecalciferol or calcitriol which is the main biologically active form of vitamin D) is used, as the kidney cannot adequately generate calcitriol from calcidiol (25-hydroxycholecalciferol) which is the storage form of vitamin D.In vitamin D assays, vitamin D2 (ergocalitrol) is not accurately measured, therefore vitamin D3 (cholecalciferol) is recommended for supplementation.
High dietary protein intake increases calcium excretion in urine and has been linked to increased risk of fractures in research studies. Other investigations have shown that protein is required for calcium absorption, but that excessive protein consumption inhibits this process. No interventional trials have been performed on dietary protein in the prevention and treatment of osteoporosis.


Medication

Just as for treatment, bisphosphonate can be used in cases of very high risk. Other medicines prescribed for prevention of osteoporosis include raloxifene, a selective estrogen receptor modulator (SERM).
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.


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 an important aspect of treatment. A major problem is gaining long-term adherence to therapy from patients with osteoporosis. Fifty percent of patients do not take their medications and most discontinue within 1 year.

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