Osteoporosis: A Disease of Grave Concern

The disease which makes the bone more prone to fractures is known as osteoporosis and the name indicates porous bones. The bone mineral density (BMD) reduces followed by deterioration of micro-architecture of bone and alteration of bone proteins. World Health Organization (WHO) defines that the bone mineral density in osteoporosis is less than 2.5 as measured by DXA. The disease may be classified as primary type 1, primary type 2 or secondary. Primary 1 or postmenopausal osteoporosis is very frequently noticed in women after the menopause. Primary 2 or senile osteoporosis is common after the age of 75 and is observed in both males and females in the ration of 2:1. Secondary osteoporosis can affect both men and women at any age in equal proportion. This disease crops up due to prolonged use of glucocorticoids so also known as glucocoticoid-induced osteoporosis. Lifestyle changes and sometimes medications can reduce the risk of this disease. Lifestyle changes comprise diet, exercise and fall-prevention. Fall-prevention includes exercise to tone deambulatory muscles, proprioception-improvement excercises and equilibrium therapies. Exercise and its anabolic effect can reduce the risk as well as cure this disease. Medication involves calcium, vitamin D, bisphosphonates and others. This disease is actually a component of frailty syndrome.

Osteoporosis results in declination of strength of bones that makes them fragile. The bones become abnormally porous similar to the sponge. The skeleton weakens and is more prone to fractures. Osteopenia is a condition where the bones are slightly less dense than the normal bone but this dense feature is not comparable to that found in osteoporosis. Protein, calcium and collagen are the chief constituents that are responsible for the strength of the bone. Bones that are affected by osteoporosis may break very easily after a very minor injury that in general cannot cause harm to the normal bone. This break or fracture of the bone may be in the form of cracking or collapsing. Spine, hips, ribs and wrists are the major portions of body that are frequently affected by this disease and can be fractured by a minor dent. The disease cannot be characterized by specific symptoms but the major noticeable sign is increased risk of fractures. Individuals suffering from this disorder generally encounter with fractures after a very minute injury which normal individuals generally do not face. These fractures are known as fragility fractures.

Fractures form the well identified symptom of osteoporosis. In older individuals these fractures result in devastating acute and chronic pain that results in further disability and even early mortality. The fractures may be asymptomatic and the symptoms of vertebral collapse are sudden back pain, radiculopathic pain and spinal cord compression. Multiple vertebral fractures result in stooped posture, loss of height, chronic pain and reduced mobility. Fractures of the long bones often require surgery. Hip fracture requires prompt surgery and many serious risks are also associated with it particularly deep vein thrombosis, pulmonary embolism and increased mortality. Fracture Risk Calculators consider a number of factors that are responsible for fractures and they are bone mineral density (BMD), age, smoking, alcohol usage, weight and gender. FRAX and Dubbo are the well known fracture risk calculators known in the present era.

Osteoporosis is also associated with the increased risk of falling and it causes fractures of hip, wrist and spine. The risk of falling is increased by impaired eyesight which may be due to glaucoma and macular degeneration. Balance disorder, movement disorders, dementia and sarcopenia are other factors that also increase the risk of falling. Collapse may result due to cardiac arrhythmias, vasovagal syncope, orthostatic hypotension and seizures. Removal of hurdles from the environment can reduce the risk of falls. The risk factors for osteoporotic fractures can be placed under the category of modifiable and non-modifiable ones. Apart from these factors some diseases are also known that also result in this disorder and in some cases medication also increases the risk of osteoporosis. Caffeine is not a risk factor for this disease. The most important risk factors for this disorder are increased age, female gender, and estrogen deficiency after menopause or oophorectomy that causes rapid declination of bone mineral density while in males reduction in testosterone levels can result in osteoporosis. The individuals with family history of this disorder are at increased risk and the incidence is 25-80%. About 30 genes can be considered responsible for this disease and small stature can be responsible for osteoporosis.

A number of potentially modifiable factors can be considered responsible for osteoporosis for example excess usage of alcohol although lower doses of alcohol have a beneficial effect on human body. Bone density starts increasing as the alcohol intake is increased. Chronic heavy drinking also causes increased risk of fractures. Vitamin D deficiency among old individuals is very common and this mild insufficiency of vitamin D is due to increased production of the parathyroid hormone (PTH). Increased secretion of this hormone causes bone resorption that result in bone loss. Positive association has been noticed between serum 1, 25-dihydroxycholecalciferol levels and bone mineral density while PTH is negatively associated with bone mineral density. Tobacco smoking is an independent factor for osteoporosis as it inhibits the activity of osteoblasts. Smoking also results in increased breakdown of exogenous estrogen, earlier menopause, lower body weight and all these factors result in lower bone density. Research has shown that consumption of high protein diet also increases loss of calcium from the bones in the urine.

Nutrition plays an important role in maintenance of strong bones. Lower dietary calcium, phosphorus, zinc, magnesium, iron, fluoride, boron, copper, and vitamins A, E, K and C also cause lower bone density. Excess of sodium and high blood acidity have a negative effect on bones. Lower intake of proteins by older individuals also increases the risk of lower bone density. Imbalance of omega 6 to omega 3 polyunsaturated fats is other risk factors. Underweight is another factor that causes this disease. Excessive exercise also has a negative effect over bones as noticed in marathon runners later in their lives. In women heavy exercise results in decreases estrogen levels that increases the risk of osteoporosis. Heavy metals also play a very important part in occurrence of this disease. A strong association has been found between cadmium, lead and bone disease. Low level exposure of cadmium results in increased loss of bone mineral density in both males and females causing increased risk of fractures which is more common in females. Higher cadmium exposure causes osteomalacia. Some studies have indicated that excessive consumption of the soft drinks also increase the risk of osteoporosis.

Osteoporotic bone fractures cause considerable pain, reduced quality of life, lost workdays and disability. About 30% of the individuals that suffer from the hip fracture require long-term nursing care. Older individuals develop pneumonia followed by blood clots in the leg veins. These blood clots may later invade the lungs due to prolonged bed rest after the hip fracture. The risk of death of the patient also increases due to this disease. About 20% of the women suffering from hip fracture die very early. A person suffering from spine fracture due to osteoporosis is at increased risk of experiencing another fracture in the near future. About 20% of the postmenopausal women who suffer from the vertebral fracture are also at the risk of suffering from another vertebral fracture in the following years.

Osteoporosis is an important health issue. In the United States about 44 million individuals suffer from low bone density out of which the 55% of the individuals belong to the age of 50 or more. Lots of dollars are spent for the treatment of such individuals. One in two Caucasian women will suffer from fracture due to this disease in her lifetime. About 20% of the individuals suffering from the hip fracture will die in the following year. About one-third of the individuals experiencing hip fracture are transferred to the nursing homes for long-term care. With increasing age the chances of this disease and the cases of fractures increase exponentially.

Bone density can be calculated by the total amount of bone present in the skeletal structure. Higher the bone density stronger is the bone. It is greatly influenced by the genetic factors which in turn are also affected by the environmental factors and medications. Men have higher bone density as compared to the women and similarly African Americans have higher bone density than the Caucasian Americans. The bone density starts accumulating during the childhood and reaches its peak at the age of 25 and can be maintained for about 10 years. Bone density starts depleting with the rate of 0.3-0.5% every year as a result of aging in both men and women after the age of 35. Bone density is also maintained by the levels of estrogen in women. Bone density reduces after menopause as the estrogen levels start declining. During the first 5-10 years after menopause women experience reduction of bone density with the rate of 2-4%. So about 20-30% of bone strength is lost during this period. The increased rate of loss of bone density in women after menopause is the major cause of osteoporosis in them and is also known as postmenopausal osteoporosis.

The National Osteoporosis Foundation has suggested that the individuals belonging to some specific groups must undergo dual energy X-ray absorptiometry (DEXA or DXA) and these include all postmenopausal women who are below 65 years of age and are at the risk of getting affected with osteoporosis. All the women who are above 65 years of age and postmenopausal women with fractures must undergo this therapy. Women who are about to start the treatment for osteoporosis and those who have 50 medical conditions associated with osteoporosis must undergo dual energy X-ray absorptiometry. A number of diseases and disorders have been found to be coupled with osteoporosis. For some of these diseases the mechanism that affects the bone metabolism is known while for others the mechanism is somewhat complex and not clearly understood. In common terms immobilization results in bone loss for example, localized osteoporosis can occur after prolonged immobilization of a fractured limb. This condition has been frequently observed in the athletes.

Other examples of bone loss are space flight or people using wheel chairs due to some reasons. Hypogonadal states cause secondary osteoporosis and include Turner syndrome, Klinefelter syndrome, Kallman syndrome and anorexia nervosa. In females hypogonadism crops up due to estrogen deficiency. It can appear as early menopause or from prolonged premenopausal amenorrhea. A bilateral oophorectomy or premature ovarian failure also causes declination of the estrogen levels. In males the deficiency of testosterone is responsible for secondary osteoporosis.

Endocrine disorders namely Cushing's syndrome, hyperparathyroidism, thyrotoxicosis, hypothyroidsm, diabetes mellitus type 1 and 2, acromegaly and adrenal insufficiency also cause osteoporosis. Reversible bone loss has been noticed in pregnancy and lactation. Malnutrition, malabsorption and parenteral nutrition also cause this disease. Coeliac disease, Crohn's disease, lactose intolerance, surgery and severe liver disease and some other gastrointestinal disease can also be the root cause of osteoporosis. Inadequate uptake of calcium, vitamin D, vitamin K and vitamin B12 can also cause bone loss. Patients suffering from rheumatoid arthritis, ankylosing spondylitis and systemic lupus erythematosus combined with some systemic disorders like amyloidosis and sarcoidosis also result in osteoporosis. Renal insufficiency can cause osteodystrophy. Hematologic disorders like multiple myeloma, monoclonal gammopathies, lymphoma, leukemia, sickle cell anemia and thalassemia can also cause osteoporosis. Several inherited disorders like Marfan syndrome, osteogenesis imperfect, hemochromatosis, hypophosphatasia, glycogen storage diseases, Ehlers-Danlos syndrome and Gaucher's disease also result in bone loss. Parkinson's disease and chronic obstructive pulmonary disease also result in osteoporosis.

Certain medications are also found to be associated with the increased risk of osteoporosis and only steroids and anticonvulsants play a major role in this category. Steroid induced osteoporosis (SIOP) which generally arises due to usage of glucocorticoids. Barbiturates, phenytoin and antiepileptic drugs also increase the metabolism of vitamin D resulting in bone loss. L-thyroxine taken for the cure of thyrotoxicosis also increases the risk of bone loss. Several drugs like aromatse inhibitors, methotrexate, certain anti-metabolite drugs and gonadotropin-releasing hormone agonists also cause bone loss. Anticoagulants like heparin and warfarin also increase the risk of osteoporosis. Proton pump inhibitors interfere with the calcium absorption resulting in chronic phosphate binding that increases the risk of osteoporosis.

Chronic lithium therapy also causes osteoporosis. Imbalance between bone resorption and bone formation is the major mechanism underlying this disease. There is continuous remodeling of the bone matrix and 10% of the bone mass may undergo remodeling at any time. This process of remodeling occurs in the bone multicellular units (BMU) that were first discovered by Frost in 1963. Bone is resorbed by the osteoclast cells that are derived from the bone marrow and after that new bone is deposited by the osteoblasts.

There are three major mechanisms which contribute in the development of osteoporosis. These include inadequate peak bone mass in which the skeleton develops insufficient mass and strength during growth, excessive bone resorption and inadequate formation of new bone during remodeling. All these mechanisms together contribute in the development of fragile bone tissue. Hormonal factors strongly participate in bone resorption for example, estrogen deficiency increases bone resorption as well as decreases deposition of new bone which is a normal process in the weight-bearing bones. The amount of estrogen required to suppress this process is generally lower than that needed for the stimulation of uterus and breast. The α-form of estrogen receptor seems to play an important role in bone turnover and calcium metabolism also plays an important role in this process. Deficiency of calcium and vitamin D result in impaired bone formation and even the parathyroid glands react actively when the calcium level is low and secrete the parathyroid hormone that increases bone resorption. Calcitonin secreted by the thyroid glands also participates in bone resorption but the role is not very clear.

Osteoclasts are activated by a number of molecular signals of which the best studied is RANKL. This molecule is produced by the osteoblasts and other cells namely the lymphocytes that together activate the RANK molecule. Osteoprotegerin (OPG) binds strongly to RANKL and results in increased bone resorption. RANKL, RANK and OPG are closely related to the tumor necrosis factor and its receptors. Local production of eicosanoids and interleukin also play significant role in bone turnover and their excess or reduced production may play a positive role in development of osteoporosis. Trabecular bone is the sponge-like bone that is present at the terminal portion of the long bones and the vertebrae. Cortical bone is the hard outer shell of bones and middle of the long bones. As the osteoblasts and osteoclasts mark the surface of the bones the trabecular bone is subjected to turnover and remodeling and so the bone density decreases and the microarchitecture of bone also gets distorted. The weaker spicules of the trabecular bone are replaced by weak bones. Hip, wrist and spine are at the higher risk of being fractures so they have higher trabecular to cortical bone ratio. These areas of body rely on trabecular bone for strength and any imbalance in remodeling may result in degeneration of these areas. Loss of trabecular bone begins at the age of 35 and the process if 50% frequent in females and 30% in males.

Osteoporosis can be diagnosed by radiotherapy and by measuring the bone mineral density (BMD) and the most popular method for this is the dual energy X-ray abosorptiometry (DEXA). Certain blood tests and even investigations associated with bone cancer can be performed. Conventional radiotherapy alone or in combination with MRI and CT scan is very effective for the diagnosis of osteopenia. A number of clinical decision rules have been made to predict the risk of fractures which are liable to occur in this disease. The QFracture score was developed in 2009 which is based on age, BMI, smoking status, alcohol usage, rheumatoid arthritis, diabetes type 2, cardiovascular disease, corticosteroids, liver disease and history of falls in men. In females, hormone replacement therapy, history of osteoporosis, menopausal symptoms and gastrointestinal malabsorption are taken into account. The Dual energy X-ray absorptiometry is now-a-days considered as the most powerful tool for the diagnosis of this disease. Osteoporosis is generally diagnosed when the bone mineral density (BMD) is less than or equal to 2.5 and the values are generally indicated by using a T-score. World Health Organization (WHO) has set certain standards for the disease identification like if T-score is greater than 1.0 then the individual is normal, if it is between 1.0-2.5 then the person may have osteopenia and if it is less than 2.5 then the condition is identified as osteoporosis. Chemical biomarkers are the perfect tools for identifying bone degradation. The enzyme cathepsin K carries out the breakdown of type 1 collagen protein and so is an important constituent in bones. Increased urinary excretion of C-telopeptides also serves as a biomarker for this disease.

Quantitative computer tomography gives a separate estimate of bone mineral density (BMD) for trabecular and cortical bones in mg/cm3. This technique can be performed at both axial and peripheral sites, is sensitive to time, can analyze a region of any shape and size and excludes irrelevant tissues like fat and muscles but it also suffers from some drawbacks like it requires a high radiation dose, CT scanners are large and expensive and results are more dependent on the operator. Quantitative ultrasound can be performed for disease diagnosis as it has many advantages like modality is small, no ionizing radiation is required, results can be achieved very quickly with greater accuracy and the cost of the device is also very low. Calcaneus is the most preferred skeletal site used while using this device. The US Preventive Services Task Force (USPSTF) in 2011 recommended that all the women who are of 65 years or more must be screened with bone densitometry as they are at increased risk of getting affected with osteoporosis.

Changes in the lifestyle can help to prevent the risks associated with osteoporosis. Tobacco smoking and inadequate alcohol intake are in general linked with this disease and if they are stopped then the risk may be minimized. Balanced nutrition and proper exercise also delay bone degradation. Proper diet includes efficient intake of calcium and vitamin D.

People suffering from this disease are generally given Vitamin D tablets and calcium supplements especially biophosphonates. Vitamin D supplements are alone not enough to prevent the risk of fractures so they are coupled with calcium supplement to minimize the risk. Calcium supplements are generally available in two forms namely calcium carbonate and calcium citrate. Calcium carbonate is generally very cheap so selected my majority of individuals and is generally taken along with food while calcium citrate is expensive, more effective and can be taken without food. Patients taking H2 blockers or proton pump inhibitors are suggested to take calcium citrate as they are not able to absorb calcium carbonate. In patients with renal disease, more active forms of vitamin D like cholecalciferol are recommended as kidney is unable to generate calcitriol from calcidiol which is the storage form of vitamin D. Vitamin D3 supplements are generally recommended by the doctors.

Intake of high dietary proteins is associated with increased excretion of calcium in urine so the risk of fractures is increased. Studies indicate that protein is essential for calcium absorption but excessive protein inhibits this process.

Estrogen Hormone therapy after the menopause has shown positive results in preventing bone loss, increase bone loss and risk of fractures. It is helpful in preventing fractures in postmenopausal women. Estrogen can be taken orally or as a skin patch. It is also available in combination with progesterone and can be taken orally of as skin patch. Progesterone along with estrogen reduces the risk of uterine cancer. Women who had undergone hyeterectomy can also take estrogen as they don't have the risk of uterine cancer. FDA has recommended the antiresorptive drugs to be the most effective agents against osteoporosis as they decrease the level of calcium loss from the bones. Biophosphonates are most effective antiresorptive agents as they reduce the risk of fractures especially those associated with hip, wrist and spine.

Fosamax, Actonel, Boniva and Reclast are the most popularly available biophosphonates. To reduce side effects all biophosphonates are taken orally generally 30 minutes before breakfast. Food, calcium supplements, iron tablets, vitamins, antacids reduce the absorption of oral biophosphonates and thereby reducing their effectiveness. Therefore, they must be taken orally in the morning only.

Calcitonin is a hormone that is approved by FDA to be used against osteoporosis. Calcitonins can be derived from a number of animal species but those obtained from salmon are most effect in preventing bone loss. Calcitonin injection can be given intravenously, subcutaneously or intransally. Intranasal administration is the most effective method. This hormone is very effective in preventing bone loss in the postmenopausal women and also increases bone density along with strengthening of spine. It is a weaker antiresorptive agent than biophosphonates. It is not as effective as estrogen in increasing bone density and bone strengthening. It is also not very effective in preventing spine and hip fractures. For these drawbacks it is not the first choice of treatment for the women suffering from osteoporosis. The common side effects that are generally observed after taking the dose of calcitonin are nausea and flushing. Patients using Miacalcin Nasal Spray may suffer from running nose or nose bleeds, skin rash and fushing may also develop when injected subcutaneously.

Vitamin K also plays an important role in stimulating collagen production, promoting bone health and reducing the risk of fracture. Vitamin K is of two types particularly vitamin K1 and K2. K1 is found in the green leafy vegetables and K2 is found in various forms especially menaquinone-4 (MK4) and menaquinone-7(MK7). MK4 is most intensely researched by the researchers and is found to be effective in reducing the risks associated with fractures in osteoporosis. MK4 is produced in testes, pancreas and arterial walls by the conversion of K1 in body. MK7 is not produced in human body but is converted in the intestine by the action of bacteria on K1. MK4 and MK7 both are found in the dietary supplements given in United States for bone health. The US FDA has not approved any form of vitamin K for treatment of this disease. MK7 has not shown any effectiveness for reducing the risk of fractures. In clinical trials MK4 has shown positive results in reducing the risks associated with fractures and are used for treating the patients of this disease as it is approved by the Ministry of Health in Japan since 1995. In Japan, the patients are given daily doses of MK4 with the quantity reaching up to 45 mg. About 87% reduction in risks associated with fractures have been noticed. MK4 has also reduced the risk of fractures caused by corticosteroids, anorexia nervosa, cirrhosis of liver, postmenopausal osteoporosis, Alzheimer's disease and Parkinson's disease in the clinical trials.

A number of studies have shown that aerobics, weigh bearing and resistance exercises can increase the bone mineral density in the postmenopausal women. The Bone-Estrogen-Strength-Training (BEST) Project at the University of Arizona has identified six different weight bearing exercises that are helpful in maintaining the bone mineral density among the patients of osteoporosis. One year of regular jumping has helped in increasing the bone mineral density as well as moment of inertia of the proximal tibia in the normal postmenopausal women. Exercise combined with hormone replacement therapy has also shown positive results. In choosing the appropriate medication for a patient suffering from osteoporosis the physician checks all the aspects that are associated with the family background as well as the severity of disease. If a postmenopausal woman suffers from hot flashes and vaginal dryness then hormone replacement therapy is the best option as it can prevent osteoporosis. If prevention and treatment is the only option left in osteoporosis then doses of biophosphonates are given. Biophosphonates are best for treating postmenopausal women with this disease.

Calcitonin is a weaker antiresorptive agent than biophosphonates and is prescribed for the individuals who do not react to other medications.

Patients with moderate to severe osteoporosis effective biophosphonates are recommended. The long-term usage of corticosteroids can increase the risk of osteoporosis. These substances decrease calcium absorption from the intestine, increase loss of calcium in urine from the kidneys, increase loss of calcium from bones. To reduce these risks patients are advised to have adequate intake of calcium and vitamin D. additional doses of other medicines along with calcium and vitamin D are also prescribed by the physicians. The American Medical Association (AMA) and other reputable medical associations recommend that repeat bone density testing should not be performed while monitoring osteoporosis treatment. Patients with osteoporosis have high rate of mortality due to fractures which may be lethal. Hip fractures decrease mobility and increase the risk of additional complications like deep venous thrombosis and pneumonia. The chances of hip fractures increase by 13.5% in patients with osteoporosis.Vertebral fractures however reduce the chances of death but increase other risks like chronic pain of neurogenic origin, multiple fractures can cause kyphosis associated with breathing impairment. Quality of life also gets reduced.

The relationship between age and reduction in bone mineral density and increased risk of fracture was first given by Astley Cooper and pathological appearance of osteoporosis was given by a French pathologist, Jean Lobstein. American endocrinologist Fuller Albright first studied the relation between osteoporosis and menopause. Discovery of biophosphonates for the treatment of osteoporosis brought a revolution in medical science in 1960s. A number of organizations in the present scenario are working in raising awareness about this disease. The National Osteoporosis Society was set up in 1986in the United Kingdom for creating awareness about diagnosis, prevention and treatment of this disease. The National Osteoporosis Foundation works for prevention of osteoporosis and risk of fractures, promoting good bone health and general awareness among people against this disease by use of medical professional as well as education. The International Osteoporosis Foundation (IOF) also works for the programs associated with good bone health. The Orthopedic Research Society also works in this area.

Navodita Maurice

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