Osteoporosis Drug Stops Growth of Breast Cancer Cells, Even in Resistant Tumors, Study Suggests

June 15, 2013 — A drug approved in Europe to treat osteoporosis has now been shown to stop the growth of breast cancer cells, even in cancers that have become resistant to current targeted therapies, according to a Duke Cancer Institute study.

The findings, presented June 15, 2013, at the annual Endocrine Society meeting in San Francisco, indicate that the drug bazedoxifene packs a powerful one-two punch that not only prevents estrogen from fueling breast cancer cell growth, but also flags the estrogen receptor for destruction.

"We found bazedoxifene binds to the estrogen receptor and interferes with its activity, but the surprising thing we then found was that it also degrades the receptor; it gets rid of it,” said senior author Donald McDonnell, PhD, chair of Duke’s Department of Pharmacology and Cancer Biology.

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Image: Osteoporosis in vertebra showing 3 microfractures
Dr. Michael Klein University of Alabama, AL
Polarized light, 15x Objective

There’s a common misconception we need to eat dairy products to maintain healthy calcium levels, despite osteoporosis being less prevalent in countries with limited dairy and meat consumption. Humans can’t subsist on a Rhinoceros’ diet of grasses, but we can easily get enough calcium from plant based sources.

Proteins causing daytime sleepiness tied to bone formation, providing target for osteoporosis

Orexin proteins, which are blamed for spontaneous daytime sleepiness, also play a crucial role in bone formation, according to findings by UT Southwestern Medical Center researchers. The findings could potentially give rise to new treatments for osteoporosis, the researchers say.

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Orexins are a type of protein used by nerve cells to communicate with each other. Since their discovery at UT Southwestern more than 15 years ago, they have been found to regulate a number of behaviors, including arousal, appetite, reward, energy expenditure, and wakefulness. Orexin deficiency, for example, causes narcolepsy – spontaneous daytime sleepiness. Thus, orexin antagonists are promising treatments for insomnia, some of which have been tested in Phase III clinical trials.

UT Southwestern researchers, working with colleagues in Japan, now have found that mice lacking orexins also have very thin and fragile bones that break easily because they have fewer cells called osteoblasts, which are responsible for building bones.

“Osteoporosis is highly prevalent, especially among post-menopausal women. We are hoping that we might be able to take advantage of the already available orexin-targeting small molecules to potentially treat osteoporosis,” said Dr. Yihong Wan, Assistant Professor of Pharmacology, the Virginia Murchison Linthicum Scholar in Medical Research, and senior author for the study, published in the journal Cell Metabolism.

Osteoporosis, the most common type of bone disease in which bones become fragile and susceptible to fracture, affects more than 10 million Americans. The disease, which disproportionately affects seniors and women, leads to more than 1.5 million fractures and some 40,000 deaths annually. In addition, the negative effects impact productivity, mental health, and quality of life. One in five people with hip fractures, for example, end up in nursing homes.

Orexins seem to play a dual role in the process: they both promote and block bone formation. On the bones themselves, orexins interact with another protein, orexin receptor 1 (OX1R), which decreases the levels of the hunger hormone ghrelin. This slows down the production of new osteoblasts and, therefore, blocks bone formation locally. At the same time, orexins interact with orexin receptor 2 (OX2R) in the brain. In this case, the interaction reduces the circulating levels of leptin, a hormone known to decrease bone mass, and thereby promotes bone formation. Therefore, osteoporosis prevention and treatment may be achieved by either inhibiting OX1R or activating OX2R.

“We were very intrigued by this yin-yang-style dual regulation,” said Dr. Wan, a member of the Cecil H. and Ida Green Center for Reproductive Biology Sciences and UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center. “It is remarkable that orexins manage to regulate bone formation by using two different receptors located in two different tissues.”

The central nervous system regulation through OX2R, and therefore promotion of bone formation, was actually dominant over regulation through OX1R. So when the group examined mice lacking both OX1R and OX2R, they had very fragile bones with decreased bone formation. Similarly, when they assessed mice that expressed high levels of orexins, those mice had increased numbers of osteoblasts and enhanced bone formation.

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"The bones in our bodies are alive, growing and changing all the time. The constant process of bones growing and changing is known as bone remodeling. While in microgravity, astronauts experience an increased rate of bone loss. This loss is similar to osteoporosis. Understanding bone loss associated with microgravity can help researchers understand the mechanisms of bone loss in a wide range of disorders" [x]

Thin, fragile struts of bone, called trabeculae, are characteristic of severe osteoporosis. Image courtesy of David Gregory and Debbie Marshall, Wellcome Images.

Boning Up on Osteoporosis

Our bones are living tissues in a constant state of healthy repair and renewal. When that doesn’t happen or doesn’t happen enough, bones can become more hollow and vulnerable to sudden fractures and breaks, which can lead to even more serious health complications.

The condition is called osteoporosis, and it’s a national affliction: More than 44 million Americans currently suffer from low bone density (LDB) or osteoporosis. As our population ages, that number will likely grow. The National Osteoporosis Foundation estimates half of all Americans over the age of 50 will suffer from (LBD) or the disease itself by 2020.

Many things cause or contribute to osteoporosis. The biggest factors are age and gender. The majority of people with osteoporosis are older and female. It’s estimated that one in two women and one in four men over the age of 50 will break a bone due to osteoporosis.

A lot is known about osteoporosis, but the disease can still be pretty confusing. For example, the Institute of Medicine (IOM), which advises the federal government on health issues, has recommended that women older than 50 supplement their diets with calcium and vitamin D, but the U.S. Preventive Services Task Force (USPSTF), another health advisory group, recently said there’s no evidence that supplementation makes a measurable difference.

For some answers, we turned to Deborah Kado, MD, and Heather Hofflich, DO. Both are specialists in treating osteoporosis in the UC San Diego Health System.

Q: Where do you stand on the issue of vitamin D and calcium supplements? The IOM says women older than 50 should consume 1,200 milligrams of calcium daily to promote bone health, but the USPSTF has said low supplemental doses of calcium or vitamin D are ineffective in helping prevent fractures and the evidence for higher doses is unclear.

Kado: The USPSTF is correct in concluding that the available evidence does not support calcium or vitamin D supplementation as effective for preventing fractures. But it is clear that having adequate calcium in the diet and sufficient vitamin D are important in maintaining bone health. My recommendation (in line with current FDA regulations) is that older women and men should take about 1,200 mg of calcium daily. The average American consumes about 500 to -600 mg, so I usually advise that additional calcium supplementation of about 600mg is ideal.

With regard to vitamin D, having sufficient levels is important for optimizing the amount of calcium in the bone. This vitamin helps ensure adequate calcium absorption from the gut and also favors keeping a good balance of calcium in the bone. I generally recommend 800 to 1,000 IU daily of vitamin D3.

Q: What about findings that suggest high calcium intake may increase the risk of heart disease in women?

Kado: Even prior to recent publications suggesting that women who take calcium supplementation greater than 800 mg daily are at increased risk of heart attacks and mortality, there were some physicians who voiced belief that taking calcium could lead to calcium build-up in the arteries. However, this assumption is simply an hypothesis with no sound evidence to support it. My personal view is that patients should be aware of their daily calcium intake, try to achieve at least 600 mg and generally not take more than 800 mg daily in supplements.

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13 October 2013

Sniffing Out Glue

Our bodies are held together by a sort of molecular glue called collagen. It’s the most common protein in the body, and forms tough fibres that hold our innards in place and help everything from organ growth to cell movement. But how this ever-abundant protein is replenished presents something of a gap in our knowledge. Scientists took advantage of recent advances in microscope technology to take a new look at the problem, watching what happens when collagen (white strands pictured) is introduced to skin. They could see how different parts of cells (labeled in red, blue and green) dealt with the influx, and identified the ways they break it down. This is an important revelation as too much collagen can lead to fibrosis, too little can cause osteoporosis and osteoarthritis, and collagen control is central to the strategy cancer cells employ to spread around the body.

Written by Anthony Lewis

Thomas H. Bugge
National Institutes of Health, Bethesda,
Originally published under a Creative Commons Attribution license
Published in J. Cell Biol.

Regarding US government recommendations that tend to encourage dairy consumption in the name of preventing osteoporosis, Nestle notes that in parts of the world were milk is not a staple of the diet, people often have less osteoporosis and fewer bone fractures than Americans do. The highest rates of osteoporosis are seen in countries where people inside the most dairy foods.
—  Eating Animals, Jonathan Safran Foer

Boning up on calcium

Calcium is the fifth most abundant element (by mass) on Earth and the fifth-most abundant dissolved ion in seawater, following sodium, chloride, magnesium and sulfate.

The human body, on the other hand, is an entirely different matter.

To hear some nutritionists and supplement companies tell it, people aren’t getting enough calcium in their diet, especially women. The federal government recommends women and men younger than 50 consume 1,000 milligrams of calcium per day. The recommendation increases after that, rising to 1,200 milligrams for post-menopausal women and men after age 70.

Calcium, of course, is a key component in building strong, dense bones in childhood and maintaining them throughout life. Roughly 99 percent of the body’s calcium supply is stored in bones and teeth, with the remainder used for functions like neurotransmitter release and muscle contractions.

The mineral is particularly vital to women after menopause when the drop in estrogen precipitates bone loss and the possibility of osteoporosis—a thinning and loss of bone tissue over time, which makes bones more vulnerable to fractures and breaks. Researchers estimate that about one in five American women over the age of 50 has osteoporosis; about half of all women over the age of 50 will have a fracture of the hip, wrist or vertebra due to osteoporosis. (The scanning electron micrograph above, courtesy of Alan Boyd, University College London, depicts a severely hollowed out, osteoporotic bone.)

There are, however, health concerns associated with getting too much calcium.

First, the extra calcium can build up in the bloodstream and cause painful stones when excreted through the kidneys in urine.

More recently, some studies have suggested that excess calcium causes coronary arteries to harden in susceptible individuals, and may precipitate heart attacks.

So perhaps think twice about taking a calcium supplement, especially if you already enjoy a calcium-rich diet. Dairy products are the best source, of course: A single glass of milk has 300milligrams of calcium, a couple ounces of cheese has 200 to 300 mg. That’s roughly half of the daily recommendation for most people right there. Non-dairy sources of calcium include broccoli, oranges, salmon and fortified cereals, which also contain added vitamin D, which is needed to help the body absorb calcium.

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