Osteoporosis ("porous bones", from Greek: οστούν/ostoun meaning "bone" and πόρος/poros meaning "pore") is a progressive bonedisease that is characterized by a decrease in bone mass and density which can lead to an increased risk of fracture. In osteoporosis, the bone mineral density (BMD) is reduced, bone microarchitecture deteriorates, and the amount and variety of proteins in bone are altered. Osteoporosis is defined by the World Health Organization (WHO) as a bone mineral density of 2.5 standard deviations or more below the mean peak bone mass (average of young, healthy adults) as measured by dual-energy X-ray absorptiometry; 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. Secondary osteoporosis may arise at any age and affect men and women equally. This form 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.
The risk of osteoporosis fractures can be reduced with lifestyle changes and in those with previous osteoporosis related fractures medications. Lifestyle change includes diet, exercise, and preventing falls. The utility of calcium and vitamin D is questionable in most. Bisphosphonates are useful in those with previous fractures from osteoporosis but are of minimal benefit in those who have osteoporosis but no previous fractures. Osteoporosis is a component of the frailty syndrome.
Illustration depicting normal standing posture and osteoporosis
Osteoporosis itself has no symptoms; its main consequence is the increased risk of bone fractures. Osteoporotic fractures 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 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. These fractures may also be asymptomatic. The most common osteoporotic fractures are of the wrist, spine, shoulder and hip. The symptoms of a vertebral collapse ("compression fracture") are sudden back pain, often with radicular 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.
Risk factors for osteoporotic fracture can be split between nonmodifiable and (potentially) modifiable. In addition, osteoporosis is a recognized complication in specific diseases and disorders. 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.
The most important risk factors for osteoporosis are advanced age (in both men and women) and female sex; 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.
Heredity: 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%. At least 30 genes are 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. Early menopause/hysterectomy is another predisposing factor.
Build: A small stature is also a nonmodifiable risk factor associated with the development of osteoporosis.
Excess alcohol: Although small amounts of alcohol are probably beneficial (bone density increases with increasing alcohol intake), chronic heavy drinking (alcohol intake greater than three 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. Tobacco smoking has been proposed to inhibit 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 dietary protein: Research has found an association between diets high in animal protein and increased urinary calcium, and have been linked to an increase in fractures. 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. No interventional trials have been performed on dietary protein in the prevention and treatment of osteoporosis.
Underweight/inactive: Bone remodeling occurs in response to physical stress, so physical inactivity can lead to significant bone loss.Weight bearing exercise can increase peak bone mass achieved in adolescence, and a highly significant correlation between bone strength and muscle strength has been determined. The 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 low bone density in elite male endurance athletes, others have instead seen increased leg bone density.
Heavy metals: A strong association between cadmium and lead with 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 soft drinks (many of which contain phosphoric acid) may increase risk of osteoporosis, at least in women. Others suggest soft drinks may displace calcium-containing drinks from the diet rather than directly causing osteoporosis.
Many diseases and disorders have been associated with osteoporosis. For some, the underlying mechanism influencing the bone metabolism is straightforward, 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 use wheelchairs for various reasons.
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.
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.
Chronic lithium therapy has been associated with osteoporosis.
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 disperses 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.
Osteoclast, with bone below it, showing typical distinguishing characteristics: a large cell with multiple nuclei and a "foamy" cytosol.
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 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.
Osteoblasts, several displaying a prominent Golgi apparatus, actively synthesizing osteoid containing two osteocytes.
The activation of osteoclasts is regulated by various molecular signals, of which the receptor activator for nuclear factor κB ligand (RANKL) 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 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.
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 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%.
Multiple osteoporotic wedge fractures demonstrated on a lateral thoraco-lumbar spine X-ray
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. 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 is useful, both by itself and in conjunction with CT or MRI, for detecting complications of osteopenia (reduced bone mass; preosteoporosis), 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 absorptiometry (DXA) 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:
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 densitometric criteria alone.
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.
Quantitative computed 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.
The U.S. Preventive Services Task Force (USPSTF) recommend that all women 65 years of age or older be screened by bone densitometry. Additionally they recommend screening women with increased risk factors that puts them at risk equivalent to a 65 year old. There is insufficient evidence to make recommendations about the intervals for repeated screening and the appropriate age to stop screening. In men the harm versus benefit of screening for osteoporosis is unknown. A number of tool exist to help determine who is reasonable to test.
Lifestyle prevention of osteoporosis is in many aspects the inverse of the potentially modifiable risk factors. As tobacco smoking and high alcohol intake have been linked with osteoporosis, smoking cessation and moderation of alcohol intake are commonly recommended as ways to help prevent it.
Weight-bearing endurance exercise and/or exercises to strengthen muscles improve bone strength in those with osteoporosis. Aerobics, weight bearing, and resistance exercises all maintain or increase BMD in postmenopausal women. Fall prevention can help prevent osteoporosis complications. There is some evidence for hip protectors specifically among those who are in care homes.
As of 2013 there is insufficient evidence to determine if supplementation with calcium and vitamin D results in greater harm or benefit in men and premenopausal women. Low dose supplementation (less than 1 gm of calcium and 400 IU of vitamin D) is not recommended in postmenopausal women as there does not appear to be a difference in fracture risk. It is unknown what effect higher doses have. There however may be some benefit for the frail elderly living in care homes.
While vitamin D supplementation alone does not prevent fractures, combined with calcium it might. There however is an increased risk of myocardial infarctions and kidney stones. Vitamin K supplementation may reduce the risk of fractures in post menopausal women; however there is no evidence for men.
Bisphosphonates are useful in decreasing the risk of future fractures in those who have already sustained a fracture due to osteoporosis. This benefit is present when taken for three to four years. They have not been compared directly to each other, though, so it is not known if one is better. Fracture risk reduction is between 25 and 70% depending on the bone involved. There are concerns of atypical femoral fractures and osteonecrosis of the jaw with long term use, but these risk are low. With evidence of little benefit when used for more than three to five years and in light of the potential adverse events, it may be appropriate to stop treatment after this time in some.
Teriparatide ( a recombinant parathyroid hormone ) has been shown to be effective in treatment of women with postmenopausal osteoporosis. Some evidence also indicates strontium ranelate is effective in decreasing the risk of vertebral and nonvertebral fractures in postmenopausal women with osteoporosis. Hormone replacement therapy, while effective for osteoporosis, is only recommended in women who also have menopausal symptoms.Raloxifene, while effective in decreasing vertebral fractures, does not affect the risk of nonvertebral fracture. And while it reduces the risk of breast cancer, it increases the risk of blood clots and strokes.Denosumab is also effective for preventing osteoporotic fractures. In hypogonadal men, testosterone has been shown to improve bone quantity and quality, but, as of 2008, no studies evaluated its effect on fracture risk or in men with a normal testosterone levels.Calcitonin while once recommended is no longer due to the associated risk of cancer with its use and questionable effect on fracture risk.
Certain drugs like alendronate, etidronate, risedronate, raloxifene and strontium ranelate can be helpful for the primary prevention of osteoporotic fragility fractures in postmenopausal women.
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 additional risks of numerous complications (such as deep venous thrombosis and/or pulmonary embolism, and pneumonia). The six-month mortality rate following hip fracture is around 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), 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.
Osteoporosis affects 55% of Americans aged 50 and above. Of these, approximately 80% are women. One in three women and one in 12 men over the age of 50 worldwide are estimated to 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 are responsible for the most serious consequences of osteoporosis. In the United States, more than 250,000 hip fractures annually are attributable to osteoporosis. A 50-year-old white woman is estimated to have 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.
Between 35 and 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 women aged 68.8 on average studied for 15 years, 324 had already suffered a vertebral fracture at entry into the study and 18.2% developed a vertebral fracture, but that risk rose to 41.4% in women who had a previous vertebral fracture.
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.
Fragility fractures of the ribs are common in men as young as age 35. 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.
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.
^ abcBrian K Alldredge; Koda-Kimble, Mary Anne; Young, Lloyd Y.; Wayne A Kradjan; B. Joseph Guglielmo (2009). Applied therapeutics: the clinical use of drugs. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. 101–3. ISBN0-7817-6555-2.
^ abcWHO (1994). "Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group". World Health Organization technical report series843: 1–129. PMID7941614.
^Kim DH, Vaccaro AR (2006). "Osteoporotic compression fractures of the spine; current options and considerations for treatment". The spine journal : official journal of the North American Spine Society6 (5): 479–87. doi:10.1016/j.spinee.2006.04.013. PMID16934715.
^Waugh, EJ; Lam, MA, Hawker, GA, McGowan, J, Papaioannou, A, Cheung, AM, Hodsman, AB, Leslie, WD, Siminoski, K, Jamal, SA, Perimenopause BMD Guidelines Subcommittee of Osteoporosis, Canada (2009 Jan). "Risk factors for low bone mass in healthy 40–60 year old women: a systematic review of the literature". Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA20 (1): 1–21. doi:10.1007/s00198-008-0643-x. PMID18523710.Check date values in: |date= (help)
^Ojo F, Al Snih S, Ray LA, Raji MA, Markides KS (2007). "History of fractures as predictor of subsequent hip and nonhip fractures among older Mexican Americans". Journal of the National Medical Association99 (4): 412–8. PMC2569658. PMID17444431.
^Abelow BJ, Holford TL and Insogna KL (1992). "Cross-cultural association between dietary animal protein and hip fracture: a hypothesis". Calcified tissue international50 (1): 14–18. doi:10.1007/BF00297291. PMID1739864.
^Hegsted M, Schuette SA, Zemel MB and Linkswiler HM (1981). "Urinary calcium and calcium balance in young men as affected by level of protein and phosphorus intake". The Journal of nutrition111 (3): 553–562. PMID7205408.
^Kerstetter, J. E.; Kenny, A. M.; Insogna, K. L. (2011). "Dietary protein and skeletal health: A review of recent human research". Current Opinion in Lipidology22 (1): 16–20. doi:10.1097/MOL.0b013e3283419441. PMID21102327. edit
^Bonjour, J. P. (2005). "Dietary protein: An essential nutrient for bone health". Journal of the American College of Nutrition24 (6 Suppl): 526S–536S. PMID16373952. edit
^Kerstetter JE, O'Brien KO, Insogna KL (2003). "Dietary protein, calcium metabolism, and skeletal homeostasis revisited". Am. J. Clin. Nutr.78 (3 Suppl): 584S–592S. PMID12936953.
^Schoenau E, Werhahn E, Schiedermaier U, Mokow E, Schiessl H, Scheidhauer K, Michalk D (1996). "Influence of muscle strength on bone strength during childhood and adolescence". Hormone Research45 (Suppl. 1): 63–66. doi:10.1159/000184834. PMID8805035.
^Pollock, N.; Grogan, C.; Perry, M.; Pedlar, C.; Cooke, K.; Morrissey, D.; Dimitriou, L. (2010). "Bone-mineral density and other features of the female athlete triad in elite endurance runners: A longitudinal and cross-sectional observational study". International journal of sport nutrition and exercise metabolism20 (5): 418–426. PMID20975110. edit
^Gibson, J.; Mitchell, A.; Harries, M.; Reeve, J. (2004). "Nutritional and exercise-related determinants of bone density in elite female runners". Osteoporosis International15 (8): 611–618. doi:10.1007/s00198-004-1589-2. PMID15048548. edit
^Hetland, M. L.; Haarbo, J.; Christiansen, C. (1993). "Low bone mass and high bone turnover in male long distance runners". The Journal of Clinical Endocrinology and Metabolism77 (3): 770–775. PMID8370698. edit
^Brahm, H.; Ström, H.; Piehl-Aulin, K.; Mallmin, H.; Ljunghall, S. (1997). "Bone metabolism in endurance trained athletes: A comparison to population-based controls based on DXA, SXA, quantitative ultrasound, and biochemical markers". Calcified tissue international61 (6): 448–454. doi:10.1007/s002239900366. PMID9383270. edit
^MacKelvie, K. J.; Taunton, J. E.; McKay, H. A.; Khan, K. M. (2000). "Bone mineral density and serum testosterone in chronically trained, high mileage 40–55 year old male runners". British journal of sports medicine34 (4): 273–278. PMC1724199. PMID10953900. edit
^Staessen J, Roels H, Emelianov D, Kuznetsova T, Thijs L, Vangronsveld J, Fagard R (1999). "Environmental exposure to cadmium, forearm bone density, and risk of fractures: prospective population study. Public Health and Environmental Exposure to Cadmium (PheeCad) Study Group". Lancet353 (9159): 1140–4. doi:10.1016/S0140-6736(98)09356-8. PMID10209978.
^Tucker KL, Morita K, Qiao N, Hannan MT, Cupples LA, Kiel DP (2006). "Colas, but not other carbonated beverages, are associated with low bone mineral density in older women: The Framingham Osteoporosis Study". Am. J. Clin. Nutr.84 (4): 936–42. PMID17023723.
^Gourlay M, Franceschini N, Sheyn Y (2007). "Prevention and treatment strategies for glucocorticoid-induced osteoporotic fractures". Clin Rheumatol26 (2): 144–53. doi:10.1007/s10067-006-0315-1. PMID16670825.
^Yasuda, Y; Kaleta K, Brömme D (2005). "The role of cathepsins in osteoporosis and arthritis: Rationale for the design of new therapeutics". Advanced Drug Delivery Reviews57 (7): 973–993. doi:10.1016/j.addr.2004.12.013. PMID15876399.
^Meunier, Pierre (1998). Osteoporosis: Diagnosis and Management. London: Taylor and Francis. ISBN1-85317-412-2.
^Rud, B; Hilden, J; Hyldstrup, L; Hróbjartsson, A (2009 Apr). "The Osteoporosis Self-Assessment Tool versus alternative tests for selecting postmenopausal women for bone mineral density assessment: a comparative systematic review of accuracy". Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA20 (4): 599–607. doi:10.1007/s00198-008-0713-0. PMID18716823.Check date values in: |date= (help)
^Body, JJ; Bergmann, P; Boonen, S; Boutsen, Y; Bruyere, O; Devogelaer, JP; Goemaere, S; Hollevoet, N; Kaufman, JM; Milisen, K; Rozenberg, S; Reginster, JY (2011 Nov). "Non-pharmacological management of osteoporosis: a consensus of the Belgian Bone Club". Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA22 (11): 2769–88. doi:10.1007/s00198-011-1545-x. PMC3186889. PMID21360219.Check date values in: |date= (help)
^Bonaiuti D, Shea B, Iovine R,et al. (2002). "Exercise for preventing and treating osteoporosis in postmenopausal women". Cochrane Database of Systematic Reviews (3): CD000333. doi:10.1002/14651858.CD000333. PMID12137611.
^Kasturi, GC; Adler, RA (2011 Jun). "Osteoporosis: nonpharmacologic management". PM & R : the journal of injury, function, and rehabilitation3 (6): 562–72. doi:10.1016/j.pmrj.2010.12.014. PMID21478069.Check date values in: |date= (help)
^ abcdMoyer, VA; on behalf of the U.S. Preventive Services Task, Force* (2013 Feb 26). "Vitamin D and Calcium Supplementation to Prevent Fractures in Adults: U.S. Preventive Services Task Force Recommendation Statement". Annals of Internal Medicine. doi:10.7326/0003-4819-158-9-201305070-00603. PMID23440163.Check date values in: |date= (help)
^Avenell, A; Gillespie, WJ; Gillespie, LD; O'Connell, D (2009 Apr 15). "Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis". Cochrane Database of Systematic Reviews (2): CD000227. doi:10.1002/14651858.CD000227.pub3. PMID19370554.Check date values in: |date= (help)
^DIPART (vitamin D Individual Patient Analysis of Randomized Trials) (2010). "Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe". BMJ340: b5463. doi:10.1136/bmj.b5463. PMC2806633. PMID20068257.
^Bolland, MJ; Avenell, A; Baron, JA; Grey, A; MacLennan, GS; Gamble, GD; Reid, IR (2010 Jul 29). "Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis". BMJ (Clinical research ed.)341: c3691. doi:10.1136/bmj.c3691. PMC2912459. PMID20671013.Check date values in: |date= (help)
^Bolland, MJ; Grey, A; Avenell, A; Gamble, GD; Reid, IR (2011 Apr 19). "Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access dataset and meta-analysis". BMJ (Clinical research ed.)342: d2040. doi:10.1136/bmj.d2040. PMC3079822. PMID21505219.Check date values in: |date= (help)
^Cockayne, S; Adamson J, Lanham-New S, Shearer MJ, Gilbody S, Torgerson DJ (2006). "Vitamin K and the Prevention of Fractures: Systematic Review and Meta-analysis of Randomized Controlled Trials". Archives of Internal Medicine166 (12): 1256–61. doi:10.1001/archinte.166.12.1256. PMID16801507.
^ abWells, GA; Cranney, A; Peterson, J; Boucher, M; Shea, B; Robinson, V; Coyle, D; Tugwell, P (2008 Jan 23). "Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women". Cochrane Database of Systematic Reviews (1): CD001155. doi:10.1002/14651858.CD001155.pub2. PMID18253985.Check date values in: |date= (help)
^ abWells, G; Cranney, A; Peterson, J; Boucher, M; Shea, B; Robinson, V; Coyle, D; Tugwell, P (2008 Jan 23). "Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women". Cochrane Database of Systematic Reviews (1): CD004523. doi:10.1002/14651858.CD004523.pub3. PMID18254053.Check date values in: |date= (help)
^ abWhitaker, Marcea; Guo, Jia, Kehoe, Theresa, Benson, George (9 May 2012). "Bisphosphonates for Osteoporosis — Where Do We Go from Here?". New England Journal of Medicine366 (22): 120509140014000. doi:10.1056/NEJMp1202619.
^Wells, GA; Cranney, A; Peterson, J; Boucher, M; Shea, B; Robinson, V; Coyle, D; Tugwell, P (2008 Jan 23). "Etidronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women". Cochrane Database of Systematic Reviews (1): CD003376. doi:10.1002/14651858.CD003376.pub3. PMID18254018.Check date values in: |date= (help)
^Han, SL; Wan, SL (February 2012). "Effect of teriparatide on bone mineral density and fracture in postmenopausal osteoporosis: meta-analysis of randomised controlled trials". International journal of clinical practice66 (2): 199–209. doi:10.1111/j.1742-1241.2011.02837.x. PMID22257045.
^O'Donnell, S; Cranney, A, Wells, GA, Adachi, JD, Reginster, JY (2006-07-19). "Strontium ranelate for preventing and treating postmenopausal osteoporosis". Cochrane Database of Systematic Reviews (3): CD005326. doi:10.1002/14651858.CD005326.pub2. PMID16856092.
^Hannan EL, Magaziner J, Wang JJ, et al. (2001). "Mortality and locomotion 6 months after hospitalization for hip fracture: risk factors and risk-adjusted hospital outcomes". JAMA285 (21): 2736–42. doi:10.1001/jama.285.21.2736. PMID11386929.
^Brenneman SK, Barrett-Connor E, Sajjan S, Markson LE, Siris ES (2006). "Impact of recent fracture on health-related quality of life in postmenopausal women". J. Bone Miner. Res.21 (6): 809–16. doi:10.1359/jbmr.060301. PMID16753011.