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 people with a high bone turn-over (for example, athletes). other examples include bone loss during space flight or in people who are bedridden or 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). bilateral oophorectomy (surgical removal of the ovaries) and 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, hyperthyroidism, hypothyroidism, diabetes mellitus type 1 and 2, acromegaly, and adrenal insufficiency. malnutrition, parenteral nutrition and malabsorption can lead to osteoporosis. nutritional and gastrointestinal disorders that can predispose to osteoporosis include undiagnosed and untreated coeliac disease (both symptomatic and asymptomatic people), crohn's disease, ulcerative colitis, cystic fibrosis, surgery (after gastrectomy, intestinal bypass surgery or bowel resection) and severe liver disease (especially primary biliary cirrhosis). people with lactose intolerance or milk allergy may develop osteoporosis due to restrictions of calcium-containing foods. individuals 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 micronutrients such as vitamin k or vitamin b12 deficiency may also contribute. people with rheumatologic disorders such as 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. chronic kidney disease can lead to renal osteodystrophy. hematologic disorders linked to osteoporosis are multiple myeloma and other monoclonal gammopathies, lymphoma, leukemia, mastocytosis, hemophilia, sickle-cell disease and thalassemia. several inherited or genetic disorders have been linked to osteoporosis. these include osteogenesis imperfecta, multicentric carpotarsal osteolysis syndrome, multicentric osteolysis, nodulosis, and arthropathy, marfan syndrome, hemochromatosis, hypophosphatasia (for which it is often misdiagnosed), 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. people with parkinson's disease have a higher risk of broken bones. this is related to poor balance and poor bone density. in parkinson's disease there may be a link between the loss of dopaminergic neurons and altered calcium metabolism (and iron metabolism) causing a stiffening of the skeleton and kyphosis. medication certain medications have been associated with an increase in osteoporosis risk; only glucocorticosteroids 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. it is recommended to use calcium or vitamin d as prevention. 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 antimetabolite 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; this is thought to interfere 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. evolutionary age-related bone loss is common among humans due to exhibiting less dense bones than other primate species. because of the more porous bones of humans, frequency of severe osteoporosis and osteoporosis related fractures is higher. the human vulnerability to osteoporosis is an obvious cost but it can be justified by the advantage of bipedalism inferring that this vulnerability is the byproduct of such. it has been suggested that porous bones help to absorb the increased stress that we have on two surfaces compared to our primate counterparts who have four surfaces to disperse the force. in addition, the porosity allows for more flexibility and a lighter skeleton that is easier to support. one other consideration may be that diets today have much lower amounts of calcium than the diets of other primates or the tetrapedal ancestors to humans which may lead to higher likelihood to show signs of osteoporosis. fracture risk assessment in the absence of risk factors other than sex and age a bmd measurement using dual-energy x-ray absorptiometry (dxa) is recommended for women at age 65. for women with risk factors a clinical frax is advised at age 50. pathogenesis osteoporosis locations the underlying mechanism in all cases of osteoporosis is an imbalance between bone resorption and bone formation. in normal bone, matrix remodeling of bone is constant; 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 & thomas in 1963. osteoclasts are assisted by transcription factor pu.1 to degrade the bone matrix, while osteoblasts rebuild the bone matrix. low bone mass density can then occur when osteoclasts are degrading the bone matrix faster than the osteoblasts are rebuilding the bone. 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, likely due to mesenchymal stem cells biasing away from the osteoblast and toward the marrow adipocyte lineage. 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 of nuclear factor kappa-b ligand) is one of the 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 signaling 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. osteoclast maturation and activity is also regulated by activation of colony stimulating factor 1 receptor (csf1r). menopause-associated increase production of tnf-α stimulates stromal cells to produce colony stimulating factor 1 (csf-1) which activates csf1r and stimulates osteoclasts to reabsorb bone. 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 and is more subject to bone turnover and remodeling. not only is bone density decreased, but the microarchitecture of bone is also 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 the trabecular bone for strength, so 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%. light micrograph of an osteoclast displaying typical distinguishing characteristics: a large cell with multiple nuclei and a "foamy" cytosol. light micrograph of osteoblasts, several displaying a prominent golgi apparatus, actively synthesizing osteoid containing two osteocytes. collapse of vertebra on the right, normal on the left diagnosis multiple osteoporotic wedge fractures demonstrated on a lateral thoraco-lumbar spine x-ray osteoporosis can be diagnosed using conventional radiography and by measuring the bone mineral density (bmd). the most popular method of measuring bmd is dual-energy x-ray absorptiometry. 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, leading to what is known as dowager's hump. dual-energy x-ray dual-energy x-ray absorptiometry (dexa scan) 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 (30–40-year-old:58), healthy adult women reference population. this is translated as a t-score. but because bone density decreases with age, more people become osteoporotic with increasing age.:58 the world health organization has established the following diagnostic guidelines: categoryt-score range % young women normalt-score ≥ −1.085% osteopenia−2.5 < t-score < −1.014% osteoporosist-score ≤ −2.50.6% severe osteoporosist-score ≤ −2.5 with fragility fracture 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, for premenopausal women, z-scores (comparison with age group rather than peak bone mass) rather than t-scores should be used, and the diagnosis of osteoporosis in such women also should not be made on the basis of