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Osteoporosis

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Osteoporosis
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Osteoporosis is a disease of bone in which the bone mineral density (BMD) is reduced, bone microarchitecture is disrupted, and the amount and variety of non-collagenous proteins in bone is altered. Osteoporotic bones are more at risk of fracture. Osteoporosis is defined by the World Health Organization (WHO) in women as a bone mineral density 2.5 standard deviations below peak bone mass (20-year-old sex-matched healthy person average) as measured by DXA; the term "established osteoporosis" includes the presence of a fragility fracture. While treatment modalities are becoming available (such as the bisphosphonates), prevention is still considered the most important way to reduce fracture. Due to its hormonal component, more women, particularly after menopause, suffer from osteoporosis than men. In addition it may be caused by various hormonal conditions, smoking and medications (specifically glucocorticoids) as well as many chronic diseases.

Signs and symptoms

Osteoporosis on its own would not be a significant disease, were it not for the falls which precipitate fractures.

Osteoporotic fractures are those that occur under slight amount of stresses that would not normally lead to fractures in nonosteoporotic people. Typical fragility fractures occur in the vertebral column, hip and wrist. Collapse of a vertebra ("compression fracture") can cause numbness in the right second toe or one or a combination of the following: acute onset of back pain; a hunched forward or bent stature; loss of height; limited mobility and possibly disability. 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.

Pathogenesis

The underlying mechanism in all cases of osteoporosis is an imbalance between bone resorption and bone formation. This is further described by how the pathological condition arises from the normal condition.

Normally

There is always a constant matrix remodeling of bone, where bone formation is performed by the osteoblast cells, whereas bone resorption is accomplished by osteoclast cells.

Bone remodeling is heavily influenced by nutritional and hormonal factors. Calcium and vitamin D are nutrients required for normal bone growth. Parathyroid hormone regulates the mineral composition of bone, with higher levels causing resorption of calcium and bone. Glucocorticoid hormones cause osteoclast activity to increase, causing bone resorption. Calcitonin, estrogen and testosterone increase osteoblast activity, causing bone growth. In addition to estrogen, follicle-stimulating hormone (FSH) affects BMD. In mice, lower levels of FSH mean less resorption by osteoclasts.[1]

Trabecular bone is the sponge-like bone in the center of long bones and vertebrae. Cortical bone is the hard outer shell of bones. Because osteoblasts and osteoclasts inhabit the surface of bones, trabecular bone is more active, more subject to bone turnover, to remodeling.

Pathologically

By various factors, described in detail later in this article, either bone resorption is excessive, and/or bone formation is diminished.

Long before any overt fractures occur, the small spicules of trabecular bone break and are reformed in the process known as remodeling. It is an accumulation of fractures in trabecular bone that are incompletely repaired that leads to the manifestation of osteoporosis. 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 isn't balanced.

Low peak bone mass is important in the development of osteoporosis. Bone mass peaks in both men and women between the ages of 25 and 35, thereafter diminishing.

Risk factors

Risk factors for osteoporotic fracture can be split between modifiable and non-modifiable. However, diseases and disorders have an own section.

The mechanisms influencing the formation of the disease are complex. Most cases do not result from inadequate calcium intake, but include other factors affecting bone matrix formation and reabsorption.

Nonmodifiable

  • history of fracture as an adult
  • Family history of fracture
A Family history of fracture or low bone mass are probably the most important etiological factors of primary osteoporosis. The heritability of the fracture as well as low BMD are relatively high, ranging from 25 to 80 percent.
Estrogen deficiency following menopause is correlated with a rapid reduction in BMD.
  • advanced age
Osteoporosis is overwhelmingly prevalent in postmenopausal women. The loss of estrogen following menopause causes a phase of rapid bone loss. However, it also occurs in men, especially elderly men, where testosterone levels are decreasing.
In addition to hormonal changes, 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 despite adequate correction, dementia, loss of balance and sarcopenia, which is the age-related loss of skeletal muscle.
Osteoporosis can actually be thought of as analogous to sarcopenia. The combination of sarcopenia and osteoporosis results in the significant frailty often seen in the elderly population.

Potentially modifiable

Tobacco smoking inhibits the activity of osteoblasts.

calcium and/or vitamin D deficiency from malnutrition increases the risk of osteoporosis. The problem occasionally arises in calcium deficient adolescents.
  • Insufficient physical activity
Bone performs remodeling in response to physical stress. People who remain physically active throughout life have a lower risk of osteoporosis. The kind of physical activity that have most effects on bone are weight bearing exercises. The bony prominences and attachments in runners are different in shape and size than those in weightlifters. Physical activity has its greatest impact during adolescence, affecting peak bone mass most. In adults, physical activity helps maintain bone mass, and can increase it by 1 or 2%. Physical fitness in later life is associated more with a decreased risk of falling than with an increased bone mineral density.
Conversely, people who are bedridden are at a significantly increased risk.
  • Excess physical activity
Excessive exercise can lead to constant damages to the bones which can cause exhaustion of the structures as described above. There are numerous examples of marathon runners who developed severe osteoporosis later in life.
  • poor health/frailty.
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 elderly and in females. Higher cadmium exposure results in osteomalacia (softening of the bone).[2][3][4]

Medication

For medication potentially causing osteoporosis, the positive effects of them needs to be compared with the degenerative effects on bone.

  • 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.
  • Barbiturates (due to accelerated metabolism of vitamin D) and some other antiepileptics
  • proton pump inhibitors
Proton pump inhibitors inhibits the production of stomach acid: it is thought that reducing the level of stomach acid interferes with calcium absorption.[5]

Debatable

  • Soft drinks
The effects of soft drinks (containing phosphoric acid) on osteoporosis are debatable; soft drinks may merely displace calcium-containing drinks from the diet.

Diseases and disorders

There are many disorders associated with osteoporosis:

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 or a premature ovarian failure cause deficient estrogen production.
In males, on the other hand, testosterone deficiency is the cause.
Glucocorticoid (Cushing's syndrome) or thyroxine (thyrotoxicosis) excess states also lead to osteoporosis.
Those with an otherwise adequate calcium intake can develop osteoporosis due to the inability to absorb calcium. Osteoporotic fracture may indeed be the event that leads to diagnosis that coeliac disease (which affects around one in a hundred people in the West) has affected the patient for many years.
  • Auto-immune and inflammatory

Those who suffer certain auto-immune and inflammatory disorders are prone to have a higher level of cytokines in the body. The overabundance of these proteins increases the body's inflammatory response which may upset the balance of osteoblast and osteoclast activity.

Epidemiology

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, osteoporosis causes a predisposition to more than 250,000 hip fractures yearly. 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 those men and women ages 80 or older.

First vertebral fractures

An estimated 700,000 women have a first vertebral fracture each year. The lifetime risk of a clinically detected symptomatic vertebral fracture is about 15% in a 50-year-old white woman. However, because symptoms are often overlooked or thought to be a normal part of getting older, it is believed that only about one-third of vertebral compression fractures are actually diagnosed.

Distal radius fractures

Distal radius fractures, usually of the Colles type, are the third most common type of osteoporotic fractures. In the United States, the total annual number of Colles' fractures is about 250,000. 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.

Diagnosis

The composition of bones can be investigated by Dual energy X-ray absorptiometry. The rate of bone turnover, on the other hand, can be measured with urine NTx, a byproduct of bone cartilage breakdown. Urine NTx greater than 40 may indicate osteoporosis.

Today, many cases of osteoporosis in developed countries are diagnosed before symptoms develop. This is due to widespread screening for osteoporosis using the DXA scan. With treatment, bone mineral density increases, and fracture risk decreases.

In the absence of treatment, overt osteoporosis is heralded by a fracture. Some fractures, like vertebral compression fractures or sacral insufficiency fractures, may not be apparent at first, appearing to patient and physician as a very bad back ache or completely without symptoms. Hip fractures and wrist fractures are more obvious.

Definition

Dual energy X-ray absorptiometry (DXA, formerly DEXA) is considered the gold standard for diagnosis of osteoporosis. Diagnosis is made 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 diagnostic guidelines as T-score -1.0 or greater is "normal", T-score between -1.0 and -2.5 is "low bone mass" (or "osteopenia") and -2.5 or below as osteoporosis.

When there has also been a low trauma or osteoporotic fracture, defined as one that occurs as a result of a fall from a standing height, the term "severe or established" osteoporosis is used. This is very important, because a person who has already had a fracture is at least 4 times as likely to have another fracture as another person, independent[6] of other health measures.

Osteoporosis can further be separated into primary and secondary osteoporosis. Primary osteoporosis is the form seen in older persons in which bone loss is accelerated over that predicted for age and sex. Secondary osteoporosis, in contrast, results from a variety of identifiable conditions[7].

In order to differentiate between primary and secondary osteoporosis, blood tests and X-rays are usually done to rule out cancer with metastasis to the bone, multiple myeloma, Cushing's disease and other causes mentioned above.

Screening

The U.S. Preventive Services Task Force (USPSTF) recommends that all women 65 years of age or older should be screened with bone densitometry.[8] The Task Force recommends screening women 60 to 64 years of age who are at increased risk. The best risk factor for indicating increased risk is lower body weight (weight < 70 kg).

Clinical prediction rules are available to guide selection of women for screening. The Osteoporosis Risk Assessment Instrument (ORAI) may be the most sensitive strategy[9]

Treatment

There are several alternatives of medication to treat osteoporosis. However, lifestyle changes are also emphasised.

Medication

Bisphosphonate is the main drug for treatment. However, newer drugs are also developed, such as teriparatide and strontium ranelate.

Bisphosphonate

In osteoporosis, bisphosphonate drugs are prescribed. The most often prescribed bisphosphonates are presently sodium alendronate (Fosamax) 10 mg a day or 70 mg once a week, risedronate (Actonel) 5mg a day or 35mg once a week or and ibandronate (Boniva once a month).

Teriparatide

Recently, teriparatide (Forteo, recombinant parathyroid hormone 1-34) has been shown to be effective in osteoporosis. 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. Teriparatide is only licensed for treatment if bisphosphonates have failed or are contraindicated (however, this differs by country and is not required by the FDA in the USA. However, patients with previous radiation therapy, or Paget's disease, or young patients should avoid this medication).

Strontium ranelate

Oral Strontium ranelate (Protelos/Protos/Protaxo/Osseor - Servier) is the first in a new class of drugs called a Dual Action Bone Agents (DABA's). It has proven efficacy in the prevention of both vertebral and non-vertebral fractures (including hip fracture) in patients over the age of 80, who are the most at risk where osteoporosis is concerned. Strontium Ranelate works by stimulating the proliferation of osteoblast (bone building) cells (there is some debate about this), and inhibiting the proliferation of osteoclast (bone absorbing) cells. This means that strontium Ranelate increases BMD by forming new bone, rather than just preserving existing bone. In comparison to bisphosphonates which only act on one aspect of bone remodeling, strontium ranelate also preserves bone turnover, allowing the microarchitecture of the bone to be continuously repaired as it would in healthy bone. Strontium ranelate is taken as a 2g oral suspension daily, and is licenced for the treatment of osteoporosis to prevent vertebral and hip fracture (this may differ by country and is not approved in the USA). 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.

Lifestyle

Changes to lifestyle factors and diet are also recommended, both regarding nutrition and exercise;

Nutrition

Calcium

The patient should include 1200 to 1500mg of calcium daily either via dietary means (for instance, an 8 oz glass of milk contains approximately 300 mg of calcium) or via supplementation. The body absorbs only about 500 mg of calcium at one time and so intake should be spread throughout the day.

However, the benefit of supplementation of calcium alone remains, to a degree, controversial since several nations with high calcium intakes through milk-products (e.g. the USA, Sweden) have some of the highest rates of osteoporosis worldwide, though this may be linked to such countries' excess consumption of protein. A few studies even suggested an adverse effect of calcium excess on bone density and blamed the milk industry for misleading customers. Some nutrionists assert that excess consumption of dairy products causes acidification, which leaches calcium from the system, and argue that vegetables and nuts are a better source of calcium and that in fact milk products should be avoided. This theory has no proof from scientific clinical studies. Similarly, nutritionists believe that excess caffeine consumption can also contribute to leaching calcium from the bones.

In a recent study that examined the relationship between calcium supplementation and clinical fracture risk in an elderly population, there was a significant decrease in fracture risk in patients that received calcium supplements versus those that received placebo. However, this benefit only applied to patients who were compliant with their treatment regimen.[10]

Excess Protein

There are three elements relating to a person's levels of calcium: consumption, absorbtion, and excretion. High protein intake is known to encourage urinary calcium losses and has been shown to increase risk of fracture in research studies. [11][12]. This goes some way to explain why countries with high levels of calcium consumption also have high rates of osteoporosis: despite consuming enough calcium, they are also countries in which people generally consume a lot of meat, therefore protein, thus negating the importance of thier calcium consumption.[13][14][15]

Vitamin D

Increasing vitamin D intake has been shown to reduce fractures up to twenty-five percent in older people, according to recent studies.[16]. The very large Women's Health Initiative study, however, did not find any fracture benefit from calcium and vitamin D supplementation, but these women were already taking (on average) 1200mg/day of calcium (12). Muscle weakness can contribute to falls so it is beneficial for people living with osteoporosis to improve muscle function. Vitamin D deficiency causes muscle weakness.[17]. A meta-analysis of five clinical trials showed 800 IU of vitamin D per day (plus calcium) reduced the risk of falls by 22%.[18]. A different randomized, controlled study showed nursing home residents who took 800 IU of vitamin D per day (plus calcium) having a 72% reduction in the risk of falls.[19]. New NOF vitamin D intake recommendations (July 2007) are adults up to age 50, 400-800 IU daily and those over 50, 800 - 1,000 IU daily.

Others

There is some evidence to suggest bone density benefits from taking the following supplements (in addition to calcium and vitamin D): boron, magnesium, zinc, copper, manganese, silicon, strontium, folic acid, and vitamins B6, C, and K.[20][21] This is weak evidence and quite controversial.

Exercise

Weight-bearing exercise is of great importance for people suffering from the osteoporosis because it helps build bone density and strength.

Thirty minutes of weight-bearing exercise such as walking or jogging, three times a week, has been shown to increase bone mineral density, and reduce the risk of falls by strengthening the major muscle groups in the legs and back.

Prognosis

Patients with osteoporosis who have already had a fracture are at a high risk for additional fractures (the best predictor of fracture is a previous fracture). Treatment for the underlying osteoporosis can reduce the risk of a subsequent fracture considerably.

Hip fractures can lead to decreased mobility and an additional risk of deep venous thrombosis and/or pulmonary embolism. The one year mortality rate following hip fracture is approximately 20%[22].

Vertebral fractures 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.

Although osteoporosis patients have an increased mortality rate due to the complications of fracture, most patients die with the disease rather than of it.

Prevention

Methods to prevent osteoporosis include changes of lifestyle. However, there are medications that can be used for prevention as well.

Lifestyle

Lifestyle prevention of osteoporosis is in many aspects inversions from potentially modifiable risk factors.

  • Exercise
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.
  • Nutrition
A proper nutrition is a diet sufficient in calcium and vitamin D. Patients at risk for osteoporosis (e.g. steroid use) are generally treated with vitamin D and calcium supplements. In renal disease, more active forms of Vitamin D such as paracalcitol 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.
  • Quiting tobacco smoking
Tobacco smoking inhibits the activity of osteoblasts.
  • Drinking moderately of alcohol
  • Avoiding heavy metals

Medication

Just as for treatment, bisphosphonate can be used in cases of very high risk.

Other medicines prescribed for prevention of osteoporosis include raloxifene (Evista), a selective estrogen receptor modulator (SERM).

Estrogen replacement 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; hopefully new research will provide guidance. In men, testosterone replacement therapy is also an effective treatment.

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 Lobstein.[23] The American endocrinolgist Fuller Albright linked osteoporosis with the postmenopausal state.[24]

See also

References

  1. ^ Cell 125, 247 (2006)
  2. ^ 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". Lancet. 353 (9159): 1140–4. PMID 10209978. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ Zhu G, Wang H, Shi Y, Weng S, Jin T, Kong Q, Nordberg G (2004). "Environmental cadmium exposure and forearm bone density". Biometals. 17 (5): 499–503. PMID 15688853. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ Kazantzis G (2004). "Cadmium, osteoporosis and calcium metabolism". Biometals. 17 (5): 493–8. PMID 15688852. {{cite journal}}: Unknown parameter |month= ignored (help)
  5. ^ Yang YX, Lewis JD, Epstein S, Metz DC (2006). "Long-term proton pump inhibitor therapy and risk of hip fracture". JAMA. 296: 2947–53. PMID 17190895.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ 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 Association. 99 (4): 412–8. PMID 17444431.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ [1] health-cares.net
  8. ^ "Screening for osteoporosis in postmenopausal women: recommendations and rationale". Ann. Intern. Med. 137 (6): 526–8. 2002. PMID 12230355.
  9. ^ Martínez-Aguilà D, Gómez-Vaquero C, Rozadilla A, Romera M, Narváez J, Nolla JM (2007). "Decision rules for selecting women for bone mineral density testing: application in postmenopausal women referred to a bone densitometry unit". J. Rheumatol. 34 (6): 1307–12. PMID 17552058.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ Prince, RL (2006). "Effects of Calcium Supplementation on Clinical Fractures and Bone Structure: Results of a 5-Year, Double-Blind, Placebo-Controlled Trial in Elderly Women". Archives of Internal Medicine. 166: 869–875. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  11. ^ Feskanich, D (1996). "Protein consumption and bone fractures in women". American Journal of Epidemiol. 143: 472–9. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  12. ^ Abelow, BJ (1992). "Cross-cultural association between dietary animal protein and hip fracture: a hypothesis". Calcified Tissue International. 50: 14-18. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  13. ^ [2]Harvard University Health Servies: Calcium
  14. ^ The Doctor Will See You Now: Nutrition
  15. ^ [3]Diet Prevents Osteoporosis, Joseph Keon
  16. ^ Bischoff-Ferrari, HA (2005). "Fracture Prevention With Vitamin D Supplementation: A Meta-analysis of Randomized Controlled Trials". The Journal of the American Medical Association. 293: 2257–2264. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  17. ^ Holick, MF (2006). "Resurrection of vitamin D deficiency and rickets". The Journal of Clinical Investigators. 116: 2062–72.
  18. ^ Bischoff-Ferrari, HA (2006). "Estimation of Optimal Serum Concentrations of 25-hydroxyvitamin D for Multiple Health Outcomes". American Journal of Clinical Nutrition. 84: 18–28. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  19. ^ Broe, KE (2007). "A Higher Dose of Vitamin D Reduces the Risk of Falls in Nursing Home Residents: A Randomized, Multiple-Dose Study". The Journal of the American Geriatrics Society. 55: 234–9. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  20. ^ Gaby, Alan R., Preventing and Reversing Osteoporosis, 1994. ISBN 0-7615-0022-7
  21. ^ Kessler, George J., The Bone Density Diet, 2000. ISBN 0-345-43284-3
  22. ^ Medical Physiology, Boron & Boulpaep, ISBN 1-4160-2328-3, Elsevier Saunders 2005. Updated edition. 1300 pages.
  23. ^ Lobstein JGCFM. Lehrbuch der pathologischen Anatomie. Stuttgart: Bd II, 1835.
  24. ^ Raisz L (2005). "Pathogenesis of osteoporosis: concepts, conflicts, and prospects". J Clin Invest. 115 (12): 3318–25. PMID 16322775.

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