Osteoporosis

Osteoporosis ("porous bones", from Greek: ὀστέον/osteon 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—Many studies have associated smoking with decreased bone health, but the mechanisms are unclear. It has been proposed tobacco smoking inhibits the activity of osteoblasts, and is an independent risk factor for osteoporosis. Another is that smoking 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.  However, the relevance of this observation to bone density is unclear, since higher protein diets tend to increase absorption of calcium from the diet and are associated with higher bone density. Indeed, it has recently been argued that low protein diets cause poor bone health.
 * 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%.  Conversely, physical inactivity can lead to significant bone loss. (Incidence of osteoporosis is lower in overweight people.)
 * Endurance training— In female endurance athletes, large volumes of training can lead to decreased bone density and an increased risk of osteoporosis. This effect might be caused by intense training suppressing menstruation, producing amenorrhea, and it is part of the female athlete triad. However, for male athletes the situation is less clear and although some studies have reported that low bone density in elite male endurance athletes, others have instead seen increased leg bone density.
 * 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. 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. 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


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, can be calculated from existing CT scans without a separate radiation dose, 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 compared to DXA, 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.

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 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.


 * A 2007 manufacturer-supported study suggested that in patients who had suffered a low-impact hip fracture, annual infusion of 5 mg zoledronic acid reduced risk of any fracture by 35% (from 13.9 to 8.6%), vertebral fracture risk from 3.8% to 1.7% and non-vertebral fracture risk from 10.7% to 7.6%. This study also found a mortality benefit: after 1.9 years, 9.6% of the study group (as opposed to 13.3% of the control group) had died of any cause, indicating a mortality benefit of 28%. There are currently no studies which examine the efficacy or side-effects of zoledronic acid past the three-year period.


 * 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 esophagus (esophagitis) and are therefore sometimes poorly tolerated; weekly or monthly administration (depending on the preparation) decreases likelihood of esophagitis, and is now standard. Although intermittent dosing with the intravenous formulations such as zolendronate (zoledronic acid) avoids oral tolerance problems, these agents are implicated at higher rates in a rare but severe bone disease called osteonecrosis of the jaw. For this reason, oral bisphosphonate therapy is probably to be preferred, and doctors now recommend that any needed remedial dental work be done before treatment begins.


 * Estrogen 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. Estrogen has a major role in regulation of the bone formation-resorption equilibrium, as it stimulates osteoblast activity. Some SERMs such as raloxifene, act on the bone by slowing bone resorption by the osteoclasts. Raloxifene has the added advantage of reducing the risk of invasive breast cancer. SERMs have been proven effective in clinical trials.


 * '''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. It is used mostly for patients with established osteoporosis (who have already fractured), have particularly low BMD or several risk factors for fracture or cannot tolerate the oral bisphosphonates. It is given as a daily injection with the use of a pen-type injection device. In some countries, Teriparatide is licensed to be used for treatment only if bisphosphonates have failed or are contraindicated. (In the US, this restriction has not been imposed by the FDA.) Patients with previous radiation therapy, or Paget's disease, or young patients, should avoid this medication.


 * Calcium salts
 * Calcium salts come as water insoluble and soluble formulations. Calcium carbonate is the primary water insoluble drug, while calcium citrate, lactate, and gluconate are water soluble. Calcium carbonate's absorption is improved in acidic conditions, while the water soluble salts are relatively unaffected by acidic conditions.


 * 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. It binds to RANKL, thereby preventing RANKL from interacting with RANK and reducing its bone resorption. It was approved for use in the treatment of osteoporosis by the European Commission on May 28, 2010 and by the United States Food and Drug Administration on June 2, 2010.


 * Strontium ranelate
 * 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.


 * Strontium ranelate is taken as a 2 g oral suspension daily, and is licenced for the treatment of osteoporosis to prevent vertebral and hip fracture. Strontium ranelate has side effect benefits over the bisphosphonates, as it does not cause any form of upper GI side effect, which is the most common cause for medication withdrawal in osteoporosis. In studies a small increase in the risk of venous thromboembolism was noted, the cause for which has not been determined. This suggests it may be less suitable in patients at risk for thrombosis for different reasons.  The uptake of (heavier) strontium in place of calcium into bone matrix results in a substantial and disproportionate increase in bone mineral density as measured on DXA scanning, making further followup of bone density by this method harder to interpret for strontium treated patients. A correction algorithm has been devised.


 * Although strontium ranelate is effective, it is not approved for use in the United States yet. However, strontium citrate is available in the US from several well-known vitamin manufacturers. Most researchers believe that strontium is safe and effective no matter what form it is used. The ranelate form is simply a device invented by the Servier company of France so that they could patent their version of strontium.


 * Strontium, no matter what the form, must be water-soluble and ionized in the stomach acid. Strontium is then protein-bound for transport from the intestinal tract into the blood stream. Unlike drugs like sodium alendronate (Fosamax), strontium doesn't inhibit bone recycling and, in fact, may produce stronger bones. Studies have shown that after five years alendronate may even cause bone loss, while strontium continues to build bone during lifetime use.


 * Strontium must not be taken with food or calcium-containing preparations as calcium competes with strontium during uptake. However, it is essential that calcium, magnesium, and vitamin D in therapeutic amounts must be taken daily, but not at the same time as strontium. Strontium should be taken on an empty stomach at night.

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. The role of calcium in preventing and treating osteoporosis is unclear &mdash; some populations with extremely low calcium intake also have extremely low rates of bone fracture, and others with high rates of calcium intake through milk and milk products have higher rates of bone fracture.  Other factors, such as protein, salt and vitamin D intake, exercise and exposure to sunlight, can all influence bone mineralization, making calcium intake one factor among many in the development of osteoporosis. In the report of WHO (World Health Organization) in 2007, because calcium is consumed by an acid load with food, it influences osteoporosis.


 * A meta-analysis of randomized controlled trials involving calcium and calcium plus vitamin D supported the use of high levels of calcium (1,200 mg or more) and vitamin D (800 IU or more), though outcomes varied depending on which measure was used to assess bone health (rates of fracture versus rates of bone loss). The meta-analysis, along with another study, also supported much better outcomes for patients with high compliance to the treatment protocol. In contrast, despite earlier reports in improved high density lipoprotein (HDL, "good cholesterol") in calcium supplementation, a possible increase in the rate of myocardial infarction (heart attack) was found in a study in New Zealand in which 1471 women participated. If confirmed, this would indicate that calcium supplementation in women otherwise at low risk of fracture may cause more harm than good.


 * 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.


 * Calcium and vitamin D are currently recommended for the primary prevention of osteoporosis and the primary and secondary prevention of osteoporotic fractures. However, calcium and vitamin D may reduce fracture risk by only 16%. This study followed 2532 community-dwelling residents (median age, 73 years; 59.8% female) over 3 years who supplemented with 400 IU vitamin D3 and 1000 mg calcium as calcium carbonate daily.


 * Vitamin K
 * In osteoporosis research, vitamin K has been extensively studied for its ability to stimulate collagen production, promote bone health and decrease fracture risk. Vitamin K is a category that includes vitamin K1 and vitamin K2. Vitamin K1 (phylloquinone) is found in green leafy vegetables. Vitamin K2 itself is a category that contains various forms of vitamin K2, including menaquinone-4 (menatetrenone, MK4) and menaquinone-7 (MK7). Among the vitamin K analogues, the form most researched for osteoporosis treatment and fracture reduction is MK4. MK4 is produced via conversion of K1 in the body, in the testes, pancreas and arterial walls. MK7 is instead not produced in humans, but converted from vitamin K1 in the intestines by bacteria.


 * MK4 and MK7 are both found in the United States in dietary supplements for bone health. The US FDA has not approved any form of vitamin K for the prevention or treatment of osteoporosis. With respect to osteoporosis, MK7 has never been shown to reduce fractures. However, MK4 has been shown to reduce fractures in clinical trials and has been approved for the prevention and treatment of osteoporosis by the Ministry of Health in Japan since 1995. In Japan MK4 is used in the amount of 45 mg daily for the prevention and treatment of osteoporosis. As an approved medication in Japan it has been extensively studied and shown to decrease fractures in clinical trials up to 87% independent of the number of falls sustained. In clinical trials MK4 (45 mg daily) prevented bone loss and/or fractures caused by corticosteroids (e.g., prednisone, dexamethasone, prednisolone),     anorexia nervosa,  cirrhosis of the liver, postmenopausal osteoporosis,    disuse from stroke, Alzheimer’s disease, Parkinson disease, primary biliary cirrhosis and leuprolide treatment (for prostate cancer).


 * Pathological fractures is a serious problem resulting from skeletal unloading in handicapped children. Sugiyama et al. published a case report of an institutionalized, bedridden 8-year-old girl with Arnold-Chiari malformation with low BMD whose BMD increased with MK4 treatment. MK4 also inhibited phenytoin-induced bone loss in rats; prevented and increased bone formation in neurectomized rats, an animal model for immobilization osteoporosis; prevented and increased bone formation in orchidectomized (castrated) rats, an animal model for secondary osteoporosis caused by testosterone deficiency;  and improved healing time and bone quality in experimentally induced osteotomy in rats alone and in the presence of glucocorticoids. And MK4 therapy has been cited as a potential strategy for drug-induced bone loss.


 * The safety of MK4 in the doses used to treat and prevent osteoporosis (45 mg daily) and in even higher amounts have been shown in multiple studies. In two human studies, people using 45 mg per day of vitamin K2 (as MK4) and even up to 135 mg/day (45 mg three times daily) of MK4, showed no increase blood clot risk. Even doses in rats as high as 250 mg/kg body weight did not alter the tendency for blood-clot formation to occur. MK4 appears safe except in people taking the blood clotting medication Coumadin (warfarin). Since warfarin, which was originally used as a rat poison, decreases blood clot risk by interrupting the vitamin K-dependent clotting factors, taking vitamin K in any amount interferes with the actions of warfarin and can increase blood clot risk.

Exercise

 * Multiple studies have shown that aerobics, weight bearing, and resistance exercises can all maintain or increase BMD in postmenopausal women. Many researchers have attempted to pinpoint which types of exercise are most effective at improving BMD and other metrics of bone quality, however results have varied. The BEST (Bone-Estrogen Strength Training) Project at the University of Arizona identified six specific weight training exercises that yielded the largest improvements in BMD; this project suggests squat, military press, lat pulldown, leg press, back extension, and seated row, with three weight training sessions a week of two sets of each exercise, alternating between moderate (6-8 reps at 70% of 1-rep max) and heavy (4-6 reps at 80% of 1-rep max).  One year of regular jumping exercises appears to increase the BMD and moment of inertia of the proximal tibia in normal postmenopausal women.  Treadmill walking, gymnastic training, stepping, jumping, endurance, and strength exercises all resulted in significant increases of L2-L4 BMD in osteopenic postmenopausal women.    Strength training elicited improvements specifically in distal radius and hip BMD. Exercise combined with other pharmacological treatments such as hormone replacement therapy (HRT) has been shown to increases BMD more than HRT alone.


 * Additional benefits for osteoporotic patients other than BMD increase include improvements in balance, gait, and a reduction in risk of falls.

Prognosis
Although osteoporosis patients have an increased mortality rate due to the complications of fracture, it is rarely lethal.

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.

Vertebral fractures, while having a smaller impact on mortality, can lead to severe chronic pain of neurogenic origin, which can be hard to control, as well as deformity. Though rare, multiple vertebral fractures can lead to such severe hunch back (kyphosis) that the resulting pressure on internal organs can impair one's ability to breathe.

Apart from risk of death and other complications, osteoporotic fractures are associated with a reduced health-related quality of life.

Epidemiology
Osteoporosis is a major public health threat which afflicts 55% of Americans aged 50 and above. Of these, approximately 80% are women. It is estimated that 1 in 3 women and 1 in 12 men over the age of 50 worldwide have osteoporosis. It is responsible for millions of fractures annually, mostly involving the lumbar vertebrae, hip, and wrist. Fragility fractures of ribs are also common in men.

Hip fractures
Hip fractures are responsible for the most serious consequences of osteoporosis. In the United States, more than 250,000 hip fractures annually are attributable to osteoporosis. It is estimated that a 50-year-old white woman has a 17.5% lifetime risk of fracture of the proximal femur. The incidence of hip fractures increases each decade from the sixth through the ninth for both women and men for all populations. The highest incidence is found among men and women ages 80 or older.

Vertebral fractures
Between 35-50% of all women over 50 had at least one vertebral fracture. In the United States, 700,000 vertebral fractures occur annually, but only about a third are recognized. In a series of 9704 of women aged 68.8 on average studied for 15 years, 324 had already suffered a vertebral fracture at entry into the study; 18.2% developed a vertebral fracture, but that risk rose to 41.4% in women who had a previous vertebral fracture.

Wrist
In the United States, 250,000 wrist fractures annually are attributable to osteoporosis. Wrist fractures are the third most common type of osteoporotic fractures. The lifetime risk of sustaining a Colles' fracture is about 16% for white women. By the time women reach age 70, about 20% have had at least one wrist fracture.

Rib Fractures
Fragility fractures of the ribs are common in men as young as age thirty-five on. These are often overlooked as signs of osteoporosis as these men are often physically active and suffer the fracture in the course of physical activity. An example would be as a result of falling while water skiing or jet skiing. However, a quick test of the individual's testosterone level following the diagnosis of the fracture will readily reveal whether that individual might be at risk.

History
The link between age-related reductions in bone density and fracture risk goes back at least to Astley Cooper, and the term "osteoporosis" and recognition of its pathological appearance is generally attributed to the French pathologist Jean Lobstein. The American endocrinologist Fuller Albright linked osteoporosis with the postmenopausal state. Bisphosponates, which revolutionized the treatment of osteoporosis, were discovered in the 1960s.

Awareness
Various organizations have been established to raise awareness on osteoporosis.

The National Osteoporosis Society, established in 1986, is a United Kingdom charity dedicated to improving the diagnosis, prevention and treatment of osteoporosis.

The National Osteoporosis Foundation (headquartered in Washington, D.C., US) seeks to prevent osteoporosis and related fractures, to promote lifelong bone health, to help improve the lives of those affected by osteoporosis and to find a cure through programs of awareness, advocacy, public and health professional education and research.

The International Osteoporosis Foundation (IOF) (headquartered in Nyon, Switzerland) functions as a global alliance of patient, medical and research societies, scientists, health care professionals, and international companies concerned about bone health.

The Orthopaedic Research Society (headquartered in Rosemont, IL, US) is a research and professional development society that has emphasized osteoporosis research, treatment and prevention for many years.