Showing posts with label Osteoporosis. Show all posts
Showing posts with label Osteoporosis. Show all posts

Monday, October 21, 2013

Researchers discover link between NOX4 enzyme and osteoporosis

Genkyotex, the leading developer of NOX enzyme inhibitors, announced today that a group of collaborators have discovered a link between the enzyme NOX4 and development of osteoporosis. These results, published online in the Journal of Clinical Investigation doi:10.1172/JCI67603), indicate that inhibitors of NOX4, such as GKT137831 developed by Genkyotex could lead to a novel way of treating patients with osteoporosis. GKT137831, the first in class NOX1 and 4 inhibitor, has shown favorable safety and pharmacokinetic profiles in Phase I studies, and following a recently FDA approved IND will enter a Phase II trial in patients with diabetic nephropathy.
"Osteoporosis is a common disease of bone that causes fractures and pain in almost one in three women," said Prof. Katrin Schröder, Institute of Cardiovascular Physiology, Faculty of Medicine at the Goethe University, Frankfurt. "Data from our studies clearly indicate that NOX4 plays a role in osteoclast generation, which triggers bone resorption and loss. In our studies we found that NOX4 was induced in human osteoporosis, and inhibiting NOX4 could reduce bone loss in mice."
Dr. Ursula Ney, CEO of Genkyotex commented: "The data from these studies provide compelling evidence for a role of NOX4 in the development of osteoporosis and builds on the growing evidence of the NOX enzymatic pathway in a number of common and often difficult to treat diseases, as well as confirming the therapeutic potential for our small molecule NOX inhibitors. Genkyotex will continue to assess the therapeutic potential of NOX4 inhibition in bone loss, including in patients with chronic kidney disease."
Details of the Studies
Initially, researchers conducted a series of studies using mice lacking NOX4 (knock-out) and found that bone of NOX4 knock-out mice had wider, thicker trabeculae that had also 30% greater density compared to wild type mice. Importantly, this effect was specific for NOX4, as genetic deletion of NOX2 or NOX1 had no effect.

Osteoporosis Causes

Osteoporosis is less common in men than in women because men have larger skeletons, their bone loss starts later and progresses more slowly, and they have no period of rapid hormonal change and bone loss.
As with other tissues in the body, bone tissue is alive and constantly changing, remodelling and rebuilding, and bone mass and strength can be affected by factors such as geneticshormones, physical exercise and diet (especially intake of calcium, phosphate, vitamin D, and other nutrients).
Problems with any of these factors can result in more bone loss than bone rebuilding thereby causing osteoporosis which can occur at any age - broken wrists, hips and spinal bones are the most common fractures and while it is more widespread in older age, younger people can sometimes be affected.
Osteoporosis occurs when the struts which make up the mesh-like structure within bones become thin, causing bones to become fragile and break easily following a minor bump or fall and though fractures can occur in different parts of the body, the wrists, hips and spine are most commonly affected.
Bones contain collagen (protein), calcium salts and other minerals and each bone is made up of a thick outer shell known as cortical bone and a strong inner mesh of trabecular bone which looks like a honeycomb, old and worn out bone is broken down by cells called osteoclasts and replaced by bone building cells called osteoblasts.
This process of renewal is called bone turnover and in childhood, osteoblasts work faster, enabling the skeleton to increase in size, density and strength and during this period of rapid bone growth, it takes the skeleton just two years to completely renew itself whereas in adults this process takes seven to ten years.
Somewhere between the ages of 16 and 18, bones stop growing in length but bone density continues to increase slowly until a person reaches their late 20s, when the balance between bone demolition and bone construction becomes stable.
Around 35, bone loss increases very gradually as part of the natural ageing process and this can lead to osteoporosis and an increased risk of broken bones, especially in later life - women are particularly susceptible because bone loss becomes more rapid for several years following the menopause.
Osteoporosis is only painful if fractures occur and having thin, fragile bones in themselves are not painful but osteoporosis means it is more likely that you have a 'greater risk of fracture' which can result in pain and other problems.
Osteoporosis does not generally slow or stop the healing process and bones that break because of osteoporosis will still heal in the same way as they do in people who do not have osteoporosis, usually over a six to eight week period.
Broken wrists can be the first indication of osteoporosis and often occur in middle aged women who have put out their arm to break a fall - healthy bones should be able to withstand a fall from standing height.
Hips broken as a result of osteoporosis occur most commonly in the late 70s or 80s usually as a result of a fall and can affect all aspects of life.
While full recovery is always possible it will often depend on how well someone is before the broken hip occurs and often regaining fully mobility and independence can be difficult requiring the support of physiotherapists and social care services.
Falling is common in later life because of poor balance and co-ordination, leading to a higher risk of breaking a hip, something which could have a significant impact on quality of life.
Reducing risks of falling may be a way of reducing risks of fracture as breaking a hip when older can have a major impact on a person's independence and can create a fear of falling which makes older people nervous to engage in everyday activities.
Fractures due to osteoporosis of the bones in the spine (vertebrae) usually occur in the lumbar (lower) or thoracic (middle) area of the spine and while they do not interfere with the spinal cord or result in paralysis or loss of sensation except in very unusual cases they can cause height loss or spinal curvature.
A fracture of one or more of the vertebrae can occur as the result of an awkward movement, like reaching up to get something from a kitchen cupboard or lifting heavy shopping bags. Sometimes, they may occur spontaneously, with very little cause, such as following an episode of coughing or sneezing.
If fractures are numerous and severe they can lead to significant height loss and curvature causing shortness of breath, protruding stomach, indigestion problems and stress incontinence.
Other bones such as the humerus (upper arm), ribs or the pelvis may also break if they are fragile.
Less common types of osteoporosis such as idiopathic juvenile osteoporosis is an unusual condition in young people where broken bones occur spontaneously without an apparent underlying problem, sometimes due to other factors such as corticosteroid use, brittle bone disease (osteogenesis imperfecta) or because a child is immobile.
Osteoporosis associated with pregnancy is also a rare condition when bones, usually in the spine or hip, break easily during or after pregnancy.
Osteoarthritis differs from osteoporosis and is a disease that affects the joints in the body causing them to become damaged - hips, knees and knuckles can be affected and so can joints in the spine and both osteoarthritis and osteoporosis occurs more commonly as people age.
Another rare condition is transient migratory osteoporosis which can cause chronic pain and is also associated with sudden loss of bone density, usually in a hip and is unlike 'ordinary' osteoporosis which is only painful when broken bones have occurred.
The pain eventually dissipates but sometimes recurs in another part of the body and referral to a pain clinic may be necessary to help deal with the pain problems associated with this condition.
Complex regional pain syndrome CRPS affects a hand, foot, wrist, ankle or knee but can spread up a whole limb; although often triggered by a minor injury or previous broken bone, the reason for continuous pain is poorly understood - sometimes the pain is traced to a specific nerve injury but sometimes not and there is often a loss of bone density in the affected area. This is a localised problem and does not result in general osteoporosis.
Osteoporosis and fragility fractures can be prevented by maximising bone strength during childhood, adolescence and early adulthood, when the skeleton is growing.
By 'banking' plenty of bone in these years, the skeleton is in a better position to withstand the bone loss that occurs with advancing age and this can be achieved by undertaking plenty of weight bearing exercise and eating a well balanced, calcium-rich diet.
Whatever age or sex, a healthy diet is vitally important to ensure strong bones and a diet which includes a wide variety of foods from the four main groups - fruit and vegetables, carbohydrates such as bread, potatoes, pasta and cereals, milk and dairy products and proteins such as meat, fish, eggs, pulses, nuts and seeds, will all help provide all the vitamins, minerals and energy needed to reduce the risk of chronic diseases such as osteoporosis.
Experts also recommend people cut down on saturated fats, sugar and salt and they say exercise is very important for everyone at all stages of their lives, but is especially important for people with osteoporosis who are at risk of fracture.
Things that can increase your chances of developing osteoporosis include:
  • being female
  • small, thin body (under 127 pounds)
  • family history of osteoporosis
  • being postmenopausal or of an advanced age
  • Caucasian or Asian race, but African American and Hispanic women are also at significant risk for developing the disease
  • abnormal absence of menstrual periods or having an eating disorder, such as anorexia nervosa or bulimia that can cause menstrual periods to stop before menopause, and loss of bone tissue from too much exercise
  • low testosterone levels in men
  • a diet low in dairy products or other sources of calcium and vitamin D
  • inactive lifestyle
  • long-term use of glucocorticoids (medicines prescribed for many diseases, includingarthritisasthma, and lupus) anti-seizure medications; gonadotropin releasinghormone for treatment of endometriosis; aluminum-containing antacids; certaincancer treatments; and excessive thyroid hormone
  • cigarette smoking and drinking too much alcohol

Further Reading

Osteoporosis Symptoms

Osteoporosis is often called a silent disease because bone loss occurs without symptoms. People may not know that they have osteoporosis until their bones become so weak that a sudden strain, bump, or fall causes a hip to fracture or a vertebra to collapse.
Collapsed vertebrae may initially be felt or seen in the form of severe back pain, loss of height, or spinal deformities such as kyphosis (severely stooped posture).Osteoporosis is often called a silent disease because bone loss occurs without symptoms. People may not know that they have osteoporosis until their bones become so weak that a sudden strain, bump, or fall causes a hip to fracture or a vertebra to collapse. Collapsed vertebrae may initially be felt or seen in the form of severe back pain, loss of height, or spinal deformities such as kyphosis (severely stooped posture).
Osteoporosis in the vertebraeOsteoporosis in the vertebrae can cause serious problems for women. A fracture in this area occurs from day-to-day activities like climbing stairs, lifting objects, or bending forward
  • Sloping shoulders
  • Curve in the back
  • Height loss
  • Back pain
  • Hunched posture
  • Protruding abdomen
Osteoporosis can happen to any of your bones, but is most common in the hip, wrist, and in your spine, also called your vertebrae. Vertebrae are important because these bones support your body to stand and sit upright. See the picture to the left.

Further Reading

What is Osteoporosis?

Osteoporosis is a condition that means your bones are weak, and you're more likely to break a bone. Since there are no symptoms, you might not know your bones are getting weaker until you break a bone! You can't "catch" osteoporosis or give it to someone else. 'Osteoporosis' literally means 'porous bones' and is often referred to as the 'fragilebone disease' in an increased risk of fractures of the hip, spine, and wrist. Osteoporosis is often called a "silent" disease because it has no discernable symptoms until there is a bone fracture.
A broken bone can really affect a woman's life. It can cause disability, pain, or loss of independence. It can make it harder to do daily activities without help, such as walking. This can make it hard to participate in social activities. It can also cause severe back pain and deformity.Osteoporosis
Often people are unaware that they have such fragile bones until their first fracture and while osteoporosis affects both men and women, women, particularly those over 50, are more susceptible - experts suggest that one out of every two women and one in five men over 50 will have an osteoporosis-related fracture in their lifetime.
To gauge the scale of the problem it is worth noting that 10 million Americans have already been diagnosed with osteoporosis and 34 million more have low bone mass, placing them at increased risk for this disease and experts say unless dietand lifestyle changes take place by 2020 half of all Americans over 50 will have weak bones.
Approximately three million people in the UK have osteoporosis, and there are over 230,000 fractures every year as a result, in Australia 1.3 million or 6.7% of the population have already been diagnosed with osteoporosis - and almost 75% of those are over age 55.
Arthritis and osteoporosis are among the world's leading causes of pain and disability, and impose a substantial burden on health systems and as many countries have increasing aging populations, diseases which affect older citizens present significant challenges to governments juggling health budgets.
For older people, weak bones can be a deadly affair - in the elderly, a broken hip increases the risk of death over a three month period by as much as four times and surviving the injury often results in a downward health spiral with one in five people with a hip fracture ending up in a nursing home within a year.
Many others become isolated, depressed, or frightened to leave home because they fear they will fall.
Those most at risk of developing osteoporosis are people over the age of 50, women in particular, those with a low body weight, smokers, excessive alcohol drinkers,those with a history of fractures, and some medical conditions including rheumatoid arthritis, hyperthyroidism and parathyroid disease.
Other conditions may also be associated with osteoporosis such as diabetes and HIV (AIDS) and organ transplant recipients and people with some respiratory diseases may also be at more risk - some medicines such as corticosteroid tablets, anti-epileptic drugs and breast and prostate cancer drugs, also increase the risk
As a rule doctors will recommend treatments depending on an individual's situation - treatments for osteoporosis are taken to reduce the risk of broken bones and are being increasingly prescribed for people with a high risk of fracture.
Unfortunately, most of the drugs used to reduce the risk of broken bones in people with osteoporosis can cause side effects in some people, though these will depend on a lot of different factors.
Some of the bisphosphonate tablets can cause inflammation to the food pipe (oesophagus), sore throat and swallowing difficulties, musculoskeletal pain and chest pain.
Injectable bisphosphonates sometimes cause flu-like symptoms for a few days and raloxofine (Evista) and strontium ranelate (Protelos) slightly increase the risk of blood clots.
In order to reduce the risk of side effects there are strict instructions regarding how the bisphoshonate tablets are taken - for example, alendronic acid must be taken first thing in the morning, on an empty stomach, before the first food of the day. 
The good news is that new treatments are continually being developed for osteoporosis and many are currently undergoing testing - these include anti-RANK ligand antibodiessuch as denosumab which have an effect on bone breakdown by inhibiting a localhormone called RANK ligand which affects the control of bone turnover.
Other research is examining growth hormones and the role played by genes and existing drugs are also being updated and improved. Ibandronate (Bonviva), for example, is available as an intravenous injection as well as a tablet.