Thursday, October 24, 2013

What else should I take besides calcium for my bones (Part V of "Should I take calcium")

Calcium is necessary to build and maintain strong bones, but it is not necessarily sufficient.  To focus in on calcium supplements as a top priority solution to the prevention and treatment of osteoporosis is to lose sight of the complexity of bone-building and maintenance, and to risk the unwanted consequences of too much of a single good thing.

Vitamin K, as mentioned in Part IV of this series, is essential to the modification of proteins integral to blood-clotting and the proper use of calcium.  Vitamin K1, available from plants particularly of the leafy green variety such as kale, is the K form involved with normal blood coagulation.  People are rarely deficient in K1 insofar as clotting is concerned. At times, individuals who have experienced problems such as deep vein thrombosis (clot) in leg veins or pulmonary emboli (blood clots traveling to the lungs) are put on warfarin (aka Coumadin) which partially blocks the function of K1 thus preventing future unwanted clot formation.  Unfortunately, people on long-term warfarin are known to be at greater risk for arterial calcification.

K1 can be converted to K2 by intestinal bacteria.  While there is dispute as to whether or not bacterial K2 is available for absorption into the body through the gut wall, it is known that women with high intake of K1 are less likely to sustain hip fractures, and lettuce intake--a good source of K1--was inversely proportional to future incidence of hip fractures in the Nurses Health Study(1).  Those medical professionals eating lettuce once or more daily had a nearly 50% hip fracture risk reduction compared to those downing one or less salads per week. 

It is difficult to take in enough K1, however, to meet your K2 requirements.  Researchers from The Netherlands compared the efficacy of K1 to K2 in the MK-7 form with respect to the production of proteins essential to proper bone calcification and found the K2 more effective and far more long-acting in its bone-forming functions(2).

Therefore, in order to build strong bones AND keep unwanted calcium out of your blood vessels, daily intake of K2--especially the MK-7 molecule--is absolutely the answer.  Besides the Rotterdam study cited in my previous post, multiple other clinical studies correlate K2 intake with long term vascular health. 

While calcium is good and necessary, vitamin K2 is essential.  Vitamin D, of course, is also crucial as are multiple other micro-nutrients.  In the sixth and final installment of this series, I'll give you my best advice as to "Should you take calcium" and what you should be taking as well for optimal bone and vascular health.
1) Feskanich D et al.  Vitamin K and Hip Fractures in Women, a Prospective Study.  Am J Clin Nutr vol. 69 no. 1 74-79. 
2) Schurgers LJ et al. Vitamin K–Containing Dietary Supplements: Comparison of Synthetic Vitamin K1 and Natto-derived Menaquinone-7. Blood vol. 109 no. 8 3279-3283.                                    

Wednesday, October 09, 2013

The Calcification Paradox (or Part IV of Should I Take Calcium?)

As I mentioned in Part III of this series, there is an inverse association between decreased bone calcification and increased vascular calcification, neither of which is a good thing.  In other words, those who shrink and crumble into the osteopenia/osteoporosis thing are also those most likely to deposit unwanted calcium in their aging blood vessels.  The heart of this supplemental calcium controversy (do I take it or not?) lands squarely here: how does our body calcify that which holds us upright while also preventing calcium build-up where it does not belong? What matters here is not just the necessity of incoming calcium to balance calcium loss but also an ongoing incoming supply of the known co-factors needed for proper calcium use.

Back, once again, to an evolutionary perspective.  In Part II I mentioned our Ice Age ancestors who ate a high-calcium diet of plants and insects and little or no grain--a food source both low in calcium and high in phytates (substances that bind calcium thus preventing effective absorption).  Now let's go back even further to our remote water-based relatives who spent their lives swimming about in calcium-rich seas.  Early evolutionary pressure, therefore, required the development of mechanisms to prevent widespread calcification through their soft, fishy tissues. The ability to survive and thrive depended--still depends!--on the limitation of calcium deposition solely to skeletons be they external shells or, much later, internal bones. Elaborate regulatory mechanisms developed over eons that promote calcium phosphate crystallization in the right place and prevent it elsewhere.

The central actors in strong bone production are cells that package mineral matrix--a mixture of calcium, phosphate, enzymes, and proteins--and then deposit it along collagen fibers also produced by these cells.  This can happen in the right place (in bones that are growing as in children or repairing as in adults) or the wrong place as in aging aortas or arteries.  Cells that can turn into osteoblasts (bonemakers) are not only found within the skeleton but also in the walls of blood vessels.  The most important protein responsible for bone mineralization is osteocalcin which is dependent on vitamin K2 for proper function.  The most important protein responsible for the prevention of mineralization outside of bones is matrix gamma-carboxy glutamic acid which is also dependent on vitamin K2 for proper function.  Do you see where this is going?

I am here to tell you that I had no idea why I've been taking vitamin K2 regularly for the past year except for a vague notion that it was good for bone health.  I'm certain that I learned nothing about this in medical school decades ago when the importance of vitamin K to proper blood clotting was emphasized but no one mentioned its importance to mineralization. For those of you who haven't spent hours studying the literature on vitamin K as I have while writing this series, there are two main forms of K: K1 important to normal blood clotting function, and K2 which is integral to the deposition of calcium in the body.  More on that in Part V.

Recent studies abound on the benefits of K2 with respect to cardiovascular health.  The Rotterdam Study, published in 2004, found that persons with the highest levels of K2 were less than half as likely to die of coronary heart disease or develop severe aortic calcification over a seven year period than those with the lowest levels, and almost 75% less likely to die of anything in that same time period. 

Wow, if you haven't got K2, get some!
1) Geleijnse, J et al.  Dietary Intake of Menaquinone Is Associated with a Reduced Risk of Coronary Heart Disease: The Rotterdam Study. J. Nutr. vol. 134 no. 11 3100-3105.  

Monday, September 16, 2013

Blood Vessel Calcification (or Part III of Should I take calcium?)

Here's the heart of the calcium supplement debate. Does taking extra calcium for prevention and treatment of bone loss associated with aging hasten the calcification of blood vessels, a process which is also associated with aging. That which is normal and healthy for your skeleton, namely the incorporation of calcium crystals into its structure, is neither normal nor healthy within your arteries.  Studies of aging humans and their whole body CT scans suggest that virtually all men and women have some demonstrable vascular calcium by age 70.(1)  Furthermore, the calcification was widespread in 80% of men and 60% of women by that age, and extensive calcification is known to correlate with a high degree of atherosclerosis more commonly known as 'hardening of the arteries'.(2)

This sort of dilemma--a basically good physiological process gone rogue--takes us into a lot of science on calcium, injury, hormones, aging, and inflammation.  The CT scanning study cited above not only confirmed that calcification, and therefore atherosclerosis, is definitely correlated with aging and increases as the years progress, it also, once again, found that menopause with its attendant loss of estrogen is also a time of accelerated progression of vascular disease.  Women under 50 years of age were much less likely than men to have calcium, but the prevalence of calcified vessels greatly increased between 50 and 60, and the gals were as likely as the guys to have calcifications by age 70 (just not as extensive).  Whether or not hormone therapy can slow down this vascular deterioration is another complicated story for another post.

Of note in this discussion, however, is the immune system's response to the presence of calcium crystals in developing atherosclerotic lesions in arteries.  Cells called macrophages which are first responders to bodily harm show up early in the course of blood vessel injury and set immediately to work eating foreign invaders Pac-Man style.  As they gobble up various harmful substances such as oxidized LDL cholesterol or basic calcium phosphate (BCP) crystals, they send out proinflammatory cytokines which are chemical messenger molecules that further activate an immune response.  This is a good thing with regards to incoming foreign bodies such as bacteria or dirt from the sidewalk when you've fallen and scraped your knee, but not so good when it's an ongoing assault from various environmental insults such as LDL-cholesterol, trans-fats, cigarette smoke, or...too much calcium (more on this later).  The inflammation from BCP crystals in activated macrophages "may lead to a positive feed-back loop of calcification and inflammation driving disease progression."(3)  In other words, once blood vessels are disturbed by calcification, the immune response invites the deposition of more calcium.

Here's one more puzzle to set your head reeling (mine is already so why not join me?).  There is a known clinical association between vascular calcification and osteoporosis.  In other words, those of us dealing with loss of bone mineral density are the very people that need to worry most about gaining unwanted vascular mineralization in the form of calcium in our arterial walls.  This suggests a link between bone and vascular metabolism.  Either vascular calcification promotes bone mineral loss, bone loss hastens vascular calcification, or there's a common underlying pathology to both processes.  The latter seems the most likely scenario, and the underlying normal and abnormal physiology of calcification in the body finally leads to some answers about whether or not calcium supplements are a good idea.

More on that in the next post.

1) Matthew A, et al. Patterns and Risk Factors for Systemic Calcified Atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology.                                   
2) Solberg LA, Eggen DA.  Localization and sequence of development of atherosclerotic lesions in the carotid and vertebral arteries. arteries. Circulation; 1971.
3) Nadra, I, et al. Proinflammatory Activation of Macrophages by Basic Calcium Phosphate Crystals via Protein Kinase C and MAP Kinase Pathways. Circulation Research. 96: 1248-1256.

Friday, August 30, 2013

Should I take calcium? Part II

In Part I of this series of posts, I discussed the science behind calcium intake.  In short, what goes out via intestinal loss (at least 150 mg/day or more) and kidney excretion (at least 100 mg/day or more)(1) must be replaced in order to maintain a steady level of calcium in the extracellular fluid (ECF) including blood.  If calcium out is greater than calcium in, the parathyroid glands release a hormone which facilitates breakdown of bone mineral matrix freeing calcium to enter the ECF. Thus, bone-based calcium is not only an integral part of your skeletal strength but also a readily available calcium reserve in case you're running short.

Clinical research scientists who regularly conduct studies on every sort of medical dilemma have compiled an enormous amount of data on the benefits of calcium intake. Starting from an evolutionary perspective--my personal favorite--let's first consider our ancestors from 10,000 years ago when life was quite different but the human genome was not. 

Radiologists and anthropologists from Emory University have determined that our ancestors--both human and primate--ate a lot of high-calcium insects and high-calcium plant food.(2)  These experts estimate that our Stone-Age predecessors took in at least twice as much calcium, mostly from plant based sources, along with more fiber, micronutrients, and protein than we consume with our modern diet. They ate virtually no grains which are not only a poor source of calcium but certain varieties including wheat contain phytates, a compound which binds minerals and decreases their absorption. X-rays of our foreparents' fossilized skeletons confirm that the outer layers of their bones were nearly 20% thicker than ours.  Strong Cro-Magnon structure was the result of a whole lot of outdoor hunting and gathering plus lots of calcium.  The authors of this review conclude that the best-for-modern-bone plan would include a return to the "nutritional pattern for which we have been genetically programmed by evolution."

There is an enormous amount written about the effects of calcium supplementation, with or without vitamin D, in a modern population that avoids the sun and doesn't snack on praying mantises.  The evidence is clear that calcium intake can promote a positive calcium balance--more in than out--which in turn reduces the rate of bone loss and may result in an increase in bone density.  What is not clear is whether or not this has a positive effect on fracture risk. Some experts point out that many of these studies were too short in duration to fully evaluate the long-term benefits of better bone. One study out of France(3) featuring 3,000+ old ladies with added calcium, however, demonstrated decreased fracture risk in just 18 months of follow-up! Half the subjects in this investigation received 1200 mg of calcium plus 800 units of D each day and ended up 43% less likely to have broken their hips by study's end compared with their colleagues who took look-alike placebos.

The US Preventive Services Task Force spent a lot of time reviewing this mountain of medical evidence.  They considered "meta-analyses" that pooled data from multiple studies and concluded that there was not enough evidence to support a recommendation for the use of supplements, and declared that smaller doses (less than 1,000 mg/day calcium and 400 units D) made no dent in fracture risk at all.  Because extra calcium intake can increase the incidence of kidney stones in susceptible persons, the USPSTF graded such dosing as Grade D, i.e. don't do it!, a 'living' on-line textbook for doctors, also considered the data, last updating the section on calcium supplements on August 28, 2013.  The reviewers agreed that the fracture data was variable, but were particularly impressed with the data from the Women's Health Initiative, the same trial that created headline news about negative health outcomes from the long-term use of HRT.  Over 36,000 women were assigned to take 1,000 mg/day of calcium citrate with 400 units of vitamin D or placebo pills.  Those who were most compliant with the regimen, taking at least 80% of the supplements over 7 years of follow-up, had a nearly 30% decreased risk of hip fracture.  Overall, compliant or not, the calcium/D group had a 12% decrease in fractures.

Uptodate's wrapped up their discussion after considering the latest data as of just two days ago by stating "Based upon the meta-analyses discussed above, we recommend 1200 mg of calcium (total of diet and supplement) and 800 int. units of vitamin D daily for most postmenopausal women with osteoporosis."  And, spoiler alert, they took into account the effect of supplemental calcium on the risk of cardiovascular disease.

More on that in Part III.
1) Houillier, P et al.  "What serum calcium can tell us and what it can't".  Nephrol. Dial. Transplant. 21 (1): 29-32.
(2)Eaton, SB and Nelson, DA.  "Calcium in Evolutionary Perspective." Check it out for the calcium content of grasshoppers and moths!
(3)Chapuy, MC et al.  Vitamin D3 and calcium to prevent hip fractures in the elderly women.  N Engl J Med 1992 Dec 3;327(23):1637-42.

Wednesday, August 28, 2013

Should I take calcium? Part I

I have been reading up on that which is good for blood vessels versus that which hastens their demise.  In particular, owning a set of bones increasingly fragile with age, I was curious about the effects of calcium supplementation on vascular health.  Recent headline news from the latest medical research suggests that excess intake of calcium tablets results in deposition of calcium in the walls of arteries--not something you'd wish on your hardworking vessels. I used to recommend adequate calcium intake as  an integral part of the prevention and treatment of age-related bone loss-- 1,000 mg/day total (diet plus  supplements) if on hormone replacement and 1,500 mg/day if not. Now the US Preventive Services Task Force says no. In fact they give a calcium plus D supplementation strategy a "D" grade (which is very strong language for the USPSTF) based on the increased risk of kidney stones but mentioning not at all this vascular business. widely used on-line resource for physicians says yes.
What's an old lady to decide?  Do I recommend extra calcium for myself and for others? 
After two hours of reading, I realized this was a decision so complex that it could not be answered in a single day nor a single post.  I decided to approach the problem according to the 8 components that I believe are the basis for making medical decisions.  In brief,  I think physicians bring three areas of expertise to the process--the science, the evidence from a constantly changing body of medical literature, and their personal practice experience.  Patients (and in this case I'm filling both roles) bring their current situation, their personal medical history, their family history, and their beliefs to the table.  Finally, and unfortunately, the insurance company brings its willingness to pay into the picture.  This is  not important here as calcium and D supplements are not an insurance-covered benefit.

A steady level of circulating calcium in the fluids and blood surrounding our cells is essential to the proper function of multiple organ systems, especially normal nerve conduction.  Too little can cause spasms, seizures, and abnormal heart rhythm; too much leads to confusion, coma, and abnormal heart rhythm.  As a result, a wonderfully orchestrated system controls serum calcium by balancing incoming sources from both intestinal absorption and internal release from bones with outgoing losses through the colon and the kidneys.  If your serum calcium level is normal on your lab panel, you can thank your intestines, kidneys, bones, and parathyroid glands, but you cannot assume that your calcium intake is adequate nor that your bones are holding up okay. 
In order to maintain that crucial balance, calcium in to the extracellular fluid (ECF) must equal calcium out.  Your parathyroid hormone levels rise in response to decreased ECF calcium which quickly leads to release of bone calcium.  In the short term, only superficial bone layers are involved in the release of mineralized calcium from the bone structure, and this loss is easily replenished.  On the other hand, a negative calcium balance over time, amplified perhaps by vitamin D deficiency or an age-related drop in estrogen and testosterone, can lead to a loss of bone density progressing to osteopenia and osteoporosis.  
So calcium balance is critical to bone density along with many other functions.  There are many conditions which can cause abnormal calcium levels, but what we are considering here is the situation of an otherwise healthy aging person trying to maintain bone health through calcium intake without increased risk to the cardiovascular system.  The next post will cover the evidence with regards to calcium intake and bone health.

Sunday, August 25, 2013

Beta-blockers and Cancer

Beta-blockers were first released for clinical use in the 1960s to control angina from coronary artery disease.  They became the go-to drug for hypertension, heart failure, cardiac protection after heart attacks or during surgery, and heart rhythm control.  They work through the blockade of beta-receptors found on many different cell types, preventing cell stimulation through the effects of epinephrine (adrenalin) and norepinephrine on those cell surface sites. These "flight or fight" stress chemicals cause a rise in pulse rate and blood pressure and produce the physical sensations of fear.  As a result, beta-blockade is also useful in controlling anxiety and stage fright.  One of my professors in medical school declared "We should all be on beta-blockers.  After considering the following research, I'm inclined to think he had a good point.

A thick stack of studies supports a mind-body connection in disease. Depression and anxiety have been associated with increased risk of both recurrence and progression of cancer in "the worried not-so-well," a term coined by psychiatrists in Philadelphia. Thanks to Dr. Jacob Schor(1), a Denver naturopath, for putting me on to to a recent article regarding outcomes in women with triple-negative breast cancer(2) (a particularly difficult to treat subset of breast cancer types).

Italian investigators located 800 postmenopausal women diagnosed with TNBC and checked their records to evaluate the effect of beta-blocker usage (prescribed for other conditions) on risk of recurrence and death.  74 of the subjects were on beta-blockers at the time of their diagnosis, and, in the five years that followed, the incidence of recurrence or death in this group was less than half that of those without beta-blockade.  

A number of cancer cell types, including breast and ovarian, are known to have beta-receptors on their cell membranes.  The stress chemicals mentioned above activate a metabolic pathway that promotes unbridled growth of these renegade cells.  Thus, beta-blockers could be down-regulating this process, slowing replication and spread of the tumors.

Beta-blockers are not without side effects--some people feel tired and depressed with regular use.  The pulse slows, and the heart rate response to aerobic exercise is muted.  To further complicate the picture, Boston researchers also published a paper this summer that compared breast cancer deaths over 10 years in nearly 5,000 women diagnosed with Stage I-III tumors as related to use of beta-blockers, ACE inhibitors (another blood pressure drug class) and aspirin(3).  While women on either BP med had reduced rates of death, the most dramatic risk drop occurred in those with regular aspirin use.  As many women on BP meds also take aspirin for cardiac health, the study authors postulate that it may be the aspirin that brings on the benefits.

Should we all be on beta-blockers?  That's still up for debate.
1) Dr. Schor writes an excellent e-mail newsletter.  You can subscribe at

2) Botteri, E, et al. "Therapeutic effect of β-blockers in triple-negative breast cancer postmenopausal women." Breast Cancer Res Treat. 2013 Aug;140(3):567-75. doi: 10.1007/s10549-013-2654-3.

3) Holmes, MD, et al. "Beta blockers and angiotensin-converting enzyme inhibitors' purported benefit on breast cancer survival may be explained by aspirin use." Breast Cancer Res Treat. 2013 Jun;139(2):507-13. doi: 10.1007/s10549-013-2553-7. Epub 2013 May 7.