Osteoporosis reference

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 non-collagenous 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.[1] 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 on the risk of fragility fracture, osteoporosis may significantly affect life expectancy and quality of life.

Osteoporosis can be prevented with lifestyle advice and sometimes medication, and in people with osteoporosis treatment may involve lifestyle advice, preventing falls and medication (calcium, vitamin D, bisphosphonates and several others).

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.

[edit] Fractures

The symptoms of a vertebral collapse ("compression fracture") are sudden back pain, often with radiculopathic pain (shooting pain due to nerve 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.[2]

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.

[edit] 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.[3]

[edit] 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.

[edit] 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 BMD, 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.[4] 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.[5] 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.[6]

[edit] Potentially modifiable

* Excess alcohol - small amounts of alcohol do not increase osteoporosis risk and may even be beneficial, but chronic heavy drinking(Alcohol intake greater than 2 units/day),[7] especially at a younger age, increases risk significantly.[8]
* Vitamin D deficiency[9] - low circulating Vitamin D is common among the elderly worldwide.[10] Mild vitamin D insufficiency is associated with increased Parathyroid Hormone (PTH) production. [10] PTH increases bone reabsorption, 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.[10]
* Tobacco smoking - tobacco smoking inhibits the activity of osteoblasts, and is an independent risk factor for osteoporosis.[7][11] Smoking also results in increased breakdown of exogenous estrogen, lower body weight and earlier menopause, all of which contribute to lower bone mineral density.[10]
* Low body mass index - being overweight protects against osteoporosis, either by increasing load or through the hormone leptin.[12]
* Malnutrition - low dietary calcium intake, low dietary intake of vitamins K and C[9] Also low protein intake is associated with lower peak bone mass during adolescence and lower bone mineral density in elderly populations.[10]
* Physical inactivity - bone remodeling occurs in response to physical stress. Weight bearing exercise can increase peak bone mass achieved in adolescence.[10] 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.[10]
* Excess physical activity - excessive exercise can lead to constant damages 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. Intensive training is often associated with low body mass index.[citation needed]
* 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).[13]
* Soft drinks - some studies indicate that soft drinks (many of which contain phosphoric acid) may increase risk of osteoporosis;[14] Others suggest soft drinks may displace calcium-containing drinks from the diet rather than directly causing osteoporosis.[15]

[edit] Diseases and disorders

Many diseases and disorders have been associated with osteoporosis.[16] 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 wheelchair-bound for various reasons.
* Hypogonadal states can cause secondary osteoporosis. These include Turner syndrome, Klinefelter syndrome, Kallmann syndrome, anorexia nervosa, andropause[17], hypothalamic amenorrhea or hyperprolactinemia[17]. 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[10], hyperparathyroidism[10], thyrotoxicosis[10], hypothyroidism, diabetes mellitus type 1 and 2,[18] acromegaly and adrenal insufficiency. In pregnancy and lactation, there can be a reversible bone loss. [16]
* Malnutrition, parenteral nutrition[10] and malabsorption can lead to osteoporosis. Nutritional and gastrointestinal disorders that can predispose to osteoporosis include coeliac disease[10], Crohn's disease, lactose intolerance, surgery[17] (after gastrectomy, intestinal bypass surgery or bowel resection) and severe liver disease (especially primary biliary cirrhosis)[17]. Patients with bulemia 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[17], ankylosing spondylitis[17], 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[17] and other monoclonal gammopathies,[18] lymphoma and leukemia, mastocytosis[17], hemophilia, sickle-cell disease and thalassemia.
* Several inherited disorders have been linked to osteoporosis. These include osteogenesis imperfecta[17], Marfan syndrome[17], hemochromatosis[10], hypophosphatasia, glycogen storage diseases, homocystinuria[17], Ehlers-Danlos syndrome[17], 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.

[edit] 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.[19] Alternate day use may not prevent this complication.[20]
* Barbiturates, phenytoin and some other enzyme-inducing antiepileptics - these probably accelerate the metabolism of vitamin D. [21]
* L-Thyroxine over-replacement may contribute to osteoporosis, in a similar fashion as thyrotoxicosis does.[16] 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,[22] and warfarin (and related coumarins) have been linked with an increased risk in osteoporotic fracture in long-term use.[23]
* Proton pump inhibitors - these drugs inhibit the production of stomach acid; it is thought that this interferes with calcium absorption.[24] Chronic phosphate binding may also occur with aluminum-containing antacids.[16]
* Thiazolidinediones (used for diabetes) - rosiglitazone and possibly pioglitazone, inhibitors of PPARγ, have been linked with an increased risk of osteoporosis and fracture.[25]
* Chronic lithium therapy has been associated with osteoporosis.[16]

[edit] Diagnosis
A scanner used to measure bone density with dual energy X-ray absorptiometry.
A scanner used to measure bone density with dual energy X-ray absorptiometry.

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.

[edit] 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:[1][10]

* 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.[1]

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.[26]

[edit] 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.[27] 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[28]

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".[29] Also cost-effective is the screening of adult men from middle age on to detect any significant decrease in testosterone levels, say, below 300.

[edit] 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.[30] Bone is resorbed by osteoclast cells (which derive from the bone marrow), after which new bone is deposited by osteoblast cells. [5]

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.[5] 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.[5] 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.[5]

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.[5]

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.[citation needed]

[edit] Treatment

There are several alternatives of medication to treat osteoporosis, depending on gender, though lifestyle changes are also very frequently an aspect of treatment.