The terror of osteoporosis has by now, been embedded in our female (and male) psyche. Hip fractures can lead to death and/or permanent disability. Spinal fractures lead to severe pain and loss of physical stature which has helped lead to that demeaning portrayal of aging women as “little old ladies”. There are a plethora of ads that make us want to do something. So I thought I would try to do my part by writing this 101 on bone loss. Don’t forget osteoporosis is a life altering disease with huge financial burdens. There are foundations and institutes that solely deal with this disease. For more information you can go to http://www.nof.org

Our bones comprise a living tissue that is always under flux. Their form and composition is determined by cells that lay down new bone (osteoblasts) and cells that act as “pac-men” and chop away causing bone resorption (osteoclasts). Put simply there is on-going filling and drilling. If all is well in our bones’ environment (normal menstrual cycles and estrogen production, adequate nutrition, no underlying disease and no adverse medications) the filling usually outpaces the drilling, at least until we reach the age of 30. This is our age of best bone mass. But when the drilling overcomes the filling, our bone mass diminishes and our bones become weakened (osteopenia), eventually porous (osteoporosis) and may finally may break.

The process of drilling and bone loss is somewhat complicated. Forgive me if I use some technical terms here. There are pro-resorptive hormones that act via their receptors on the bone building cells to induce something called RANKL. When there is enough “free” RANKL, it is able to activate RANK on precursors of the bone eating cells (remember they are called osteoclasts). RANK then stimulates these pre-osteoclasts to fuse together and differentiate into mature osteoclasts. Free RANKL also activates these mature osteoclasts “telling” them to resorb bone. To make matters worse free RANKL then protects these bone gobbling cells from dying! They can keep going on and on…like that energizer bunny.

We seem to have a bad guy in this bone story…it’s excessive free RANKL which gives the go ahead for bone eating cells to develop, multiply and resorb bone. It can get nasty. Although destruction of bone may be necessary for formation of new bone, its unopposed course has been countered.  RANKL can be rendered inactive if it is bound up. (Think Samson with his hair shorn.) The substance that does the binding and deactivation of RANKL is called OPG (I know this gets too full of initials, but it’s easier to use than the full word… osteoprotgerin).

Estrogen reduces RANKL production and increases the synthesis of OPG (at this point I have to say OMG). The estrogens we produce during our reproductive lives have helped prevent free RANKL from encouraging osteoclasts to eat away at bone. Indeed when we lose our estrogen production at menopause, free RANKL is released and during the first 5 to 6 years of menopause, most women lose 2 to 3% of their bone mass each year.

The most commonly used medications for osteoporosis, the bisphosphonates (Fosomax, Actinel, Boniva and Reclast to name a few) reduce the function but not the number of activated osteoclasts. The FDA is currently considering a medication that actually targets the RANKL pathway and stops osteoclast development. More on this (and comparisons of therapeutic medications) in future newsletters….

Several months ago I wrote a newsletter on the current recommendations for osteoporosis therapy based on the World Health Organization (WHO) Fracture Risk Algorithm, (FRAX). We no longer use a bone density test as the sole indicator of fracture risk. (See the article titled “Assessing Our Bone Strength” in the newsletter archives).

Now where does calcium and Vitamin D come into our bone health picture? Deficiencies of either will prevent bone formation by the osteoblasts. Both calcium and Vitamin D are necessary for the complex pathway that leads to bone “creation” and maintenance.

Let’s start with Vitamin D… It is produced in our skin as a result of UV radiation from sun rays. The darker our skin, the less the UV rays get absorbed. Those of us, who are dark skinned, are not sun exposed (think winter on the East Coast) or who effectively block the sun with clothing or sun block will get less than the recommended Vitamin D. Vitamin D is added to milk products, calcium supplements and multivitamins but the amount is often not enough. More than half of healthy adults have blood Vitamin D levels that are lower than that which is recommended for fracture risk reduction (30ng/mL of 25 OH Vitamin D). Many bone experts now recommend that we take at least 1,000 IU of D3 (which is over the counter type of Vitamin D) and if older than 65, to take 2,000 IU a day.

Because of the high prevalence of Vit D deficiency, I check 25OH Vitamin D levels on many of my patients, especially those who are found to have low bone densities. If a deficiency is found I prescribe 50,000 IU of D2 weekly for 2 to 3 months, then recheck the blood; if the level has risen sufficiently I tell my patient to resume standard dosing. If, however she has had a fractured hip, I increase Vitamin D until her blood level is 40 to 60 ng/ml.

Now what about calcium? Some of the newer studies seem to show no benefit of calcium intake greater than 800mg per day in women who are NOT vitamin D deficient. But when we talk about essential intake of calcium we have to consider its absorption and bioavailability. Many medications interfere with calcium absorption. These include (especially when taken at the same time as a calcium supplement) fiber, H2 blockers and protein-pump inhibitors (that treat acid reflux), corticosteroids and anticonvulsants. Moreover, there can be adverse interactions between calcium supplements and several medications if they are taken together: Calcium may cause a decreased absorption of iron, zinc and magnesium. Calcium also reduces thyroid, tetracycline and quinine antibiotic absorption.  And it turns out that caffeine increases urinary calcium excretion.

The amount of calcium we absorb in supplements also depends on the type of calcium we take. The most common, calcium carbonate, requires stomach acid for absorption. (Hence the manufacturers recommend taking it with food). But as we get older we naturally produce less stomach acid. And to add insult to getting an older and crankier GI system, gastric acid is reduced by all those medications we take to treat our acid reflux. So I recommend that my older patients and those who take acid reflux meds supplement their calcium intake with calcium citrate for better bioavailability.

Yes this is complicated…But now that you understand a bit more about what your bones go through to carry you though your life, I hope you will treat them with respect and provide them with their essentials. If you are at risk for bone loss and fracture make sure you discuss tests and therapies with your physician (and if you are my patient, with me). It’s never too late to support your support.

I normally use my web site to update my patients and readers about recently published studies and/or health recommendations. Several weeks ago I wrote about the need to get the seasonal flu vaccine, and indeed my nurse gave it to many of you (and me). I also promised to let you know when the H1N1 vaccine is available in our office.  As I write this, we have not received our order. I will keep you posted.

Departing from my usual weekly missive, I thought I would share a personal viral story. I flew to London with my husband two weeks ago (he had meetings there and hey, why not go with him?) I didn’t feel well before we left, but the airline (it was British Air) wanted a huge sum to change the ticket. So I boarded and slept the entire journey hoping that I once I arrived I would feel better. I was worse. Aside from an elevated temperature, I had all the symptoms of the flu. So I followed the advice that I have given those of you at high risk (although I don’t really fall into the CDC high risk category….I am neither a young child, adolescent, nor pregnant and have no chronic lung or immune issues….but I am a health care provider), and I started tamiflu. Four days later despite bed rest and the medication, I was still sick. To make matters worse, there was no chicken soup to be had from room service. Before continuing our trip, I thought I had better make sure I did not have pneumonia. My husband had a friend who gave him the name of a private consultant in London. After dropping his name (that of the friend), I got an appointment at the end of the day. The office was a short taxi ride from the hotel. I actually “dressed up” for the visit, after all I didn’t want a doctor in London to think that an American physician walked around in jeans. We were ushered into the most beautiful waiting room I had ever seen. It had high ceilings with ornate molding above, original art on the walls and simple but exquisite couches below. The mahogany tables were covered by art books, and a tactful display of travel and fashion magazines. I was asked to fill out an information sheet that requested my name, address and phone numbers. On that same sheet was a note that stated that American Express was not accepted, but that cash, check or other credit cards would be….moreover the bill would not be forwarded to national health. The charge for a consultation only versus a consultation with exam was also posted. There were no HIPPA forms

Despite feeling truly lousy I was awed by my surroundings. And when the doctor himself came out to the waiting room to usher us into his consulting room, I felt I must be special; until I noticed that he didn’t have a nurse. Doctor XXX was an elegant, handsome man in his 50’s with an impeccable English accent. I liked him instantly. He took a very comprehensive history and I strove to give answers in our universal medical lingo. After all I didn’t want to be considered as “just” a sick patient. But and as we spoke and I listened to my answers I realized that had I (in my white coat habitat) asked the same questions I would indeed have come up with the diagnosis of “typical flu”, or for billing code purposes, upper respiratory virus. When he heard I had self medicated with tamiflu, he smiled deprecatingly. “I had H1N1, it was just a mild flu and I was better in 3 days.” He went on to tell me that many of his patients have had it and although tamiflu was available in Great Britain, it was not as frequently prescribed as in the USA.  That’s when I noticed that his cough, although in a lower octave, was worse than mine! I was not about to argue….he had the stethoscope. So I meekly asked him to check my lungs. We went into his exam room and I duly inhaled and exhaled. “I hear no rales or ronchi” (the sounds that indicate partial obstruction to the bronchi) he pronounced. “I suppose you would like me to check your blood for infection?”  And then without washing his hands or putting on gloves he expertly drew blood from my cubital vein and applied a band aid. “The results will be ready tomorrow. If you want an x-ray I can send you to hospital this evening”. It turns out that there was no x-ray machine in the office. Although I was assured that the hospital was only a ten minute taxi ride away, I felt too ill to attempt the journey and the possible wait. So we paid the bill (it was discounted, I assume for professional status) and went back to the hotel. The next day he called and told me that my blood count was “stupendously normal”….and asked if I still wanted the x-ray. I didn’t….the chance of my having pneumonia with a stupendous blood test was slim, and in truth I was feeling better.

I am not telling this story to disparage the doctor, but to point out the difference in medical practice between the USA and Great Britain, even with private care. In many ways he was right. I did not need an x-ray and if I had waited, my flu would have probably run its course without medication. Our expectation for instant diagnosis and subsequent immediate cure makes us the patients, demand a lot of probably unnecessary tests and yes, as the physicians, over prescribe. Did I have H1N1? I’ll never know….once the symptoms have passed. Will I get the H1N1 vaccine once it’s available?….Yes.

I’m home now and feel better. Don’t worry, by now I am not infectious!

Do Fertility Drugs Increase the Risk for Ovarian Cancer?

When couples are desirous of a pregnancy and just can’t seem to conceive on their own they are willing to try everything. I know… I ran a fertility clinic in Tel Aviv decades ago. At that time, we offered therapies for women who had ovulatory problems, blocked tubes, and men with low sperm counts. When we found no obvious problem with either the woman or the man and they could not conceive after trying for a year, we would arbitrarily use fertility therapies and combine them with insemination. Clomiphene was the first drug of choice. This anti-estrogen pill is prescribed in the beginning of the cycle (usually the 5th day after the period starts). It “fools” the pituitary gland into “thinking” that there is no estrogen on board. So the pituitary works harder and spurts out the hormone FSH (follicle stimulating hormone) which then induces the follicles in the ovary to develop and eventually (after the medication is stopped) produce an egg which can undergo fertilization. This medication is still used as first line therapy in many infertile or non-ovulating women.

If the clomiphene didn’t work, we would start  injections of hormones that “replaced” or caused the secretion of FSH and LH (luteinizing hormone) The latter, given in the form of HCG (sorry about all these initials, the latter stands for human chorionic gonadotropin) signals the follicle, and orders it to release the egg. With current IVF (I’m not sure you need this, but it stands for in vitro fertilization) therapies, we use many of these same medications.

Obviously there have been concerns about use of these therapies. The most immediate: failure to achieve pregnancy, multiple pregnancies and resultant early pregnancy loss, prematurity and pregnancy complications. Reproductive experts have (and should) inform prospective patients about all of these risks. But what about risks that could affect a woman’s health or her longevity?

Incessant ovulation increases the risk of ovarian cancer…Perhaps it’s the constant “bruising” of the ovaries’ surface as the follicle bursts and the egg is extruded. Perhaps the ongoing hormonal changes and/or induction of those changes by FSH and LH cause cellular mutations that can result in cancer. We do know that full term pregnancies and use of birth control pills (both of which stop ovulation for 9 months or years) are protective and decrease ovarian cancer risk. We also have statistics that show that women who were never pregnant are at a higher risk for this malignancy.

But what about the risk to women who take ovulatory stimulating medications in order to conceive…will the drugs put them at risk for ovarian cancer? A recent and very large study of treated women with follow-up for 35 years found that there was “no convincing association between use of fertility drugs and risk of ovarian cancer”. The study was carried out in Denmark where patient records on treatment and disease are stellar. Data from over 54,000 women with infertility who were referred to all the Danish clinics for 35 years between 1963 and 1998 was assessed. They reported that the risk for ovarian cancer was not significantly affected by use of clomiphen, human chorionic gonadotropins ( HCG), gonadotropins (LH and FSH) and gonadotropin releasing hormone. Nor did this change when they calculated the number of cycles, duration of drug use or the pregnancies of the women in the study!

So can we rest on our fertility drug laurels? Almost…when the authors looked at a very particular subtype of ovarian cancer called serous ovarian cancer they found that clomiphene users did have a 67% increase of this type of cancer when compared to women who had not taken this drug, especially after 15 or more years. The actual number of these cases found was small and hence even if the stat 67% sounds ominous, it’s an increase of a very, very slight incidence and remains rare. It may even be an artifact.

Remaining infertile is in itself a risk for ovarian cancer. The use of fertility medication and the advances in reproductive assisted technologies have reversed a condition that can cause unremitting anguish and health-compromising depression for hundreds of thousands of couples.

I consider this published report to be one that allows me to reassure my patients that ovarian cancer risk is miniscule or non existent….for those who have used fertility medications in the past and women who will now begin a quest to overcome their infertility.

I’ve been inundated with phone calls and questions about articles that have appeared in the media which have suggested that there is a link between hormone use and lung cancer. Lung cancer is the second most common cancer in women (first is breast cancer) and is the leading cause of cancer deaths. We all know that tobacco smoking is the major risk for this dreaded disease and indeed 84% of male lung caner cases can be attributed to smoking. However, only 46% of cases in women seem to result from cigarettes. Researchers have been searching for other causes including supplemental hormones. Approximately 24% of women older than 40 years are currently using hormones in the United States. So if there is an association it could be huge!

Multiple studies have looked at a possible link between hormone use and lung cancer. The results are fairly inconsistent. Here are a few:

  • A study of 23,244 Swedish women with 6.4 years of follow up, found a slight increase risk in lung cancer. This was calculated as an odds ratio of 1.3 (women who did not smoke were 1.0) so this means there was possible 30% increase in risk above that of non smokers.
  • The Women’s Health Initiative that included 16, 000 women on Prempro found no association between post menopausal hormone therapy and lung cancer, with follow up of 5.2 years.
  • The Cancer Prevention Study II Nutrition Cohort which consisted of 72,772 women found a decrease lung cancer risk associated with hormone therapy for post menopausal women. This study had 12 years of follow up.
  • A case control study in the United States with 499 lung cancer cases and 519 control (that means the number of women with lung cancer were compared to those who did not have cancer) as well as a German study with 811 lung cancer cases and 912 controls found either no significant association or protection against lung cancer for “ever use” of female hormones.
  • A recent study published in Menopause: The Journal of the North American Menopause Society included 2,861 women who were aged 31 to 79 years at enrollment and were followed for a 31 year period of time. They were interviewed every 4 years and asked whether they smoked, how much, if they had quit, for how long and if they were taking oral contraceptives, estrogen, or pills for hot flashes, or to regulate periods. The findings showed that 35.8% were using hormones at time of enrollment. The hormone users were also more likely to be current or former smokers than those who were not taking hormones. Eighty seven women developed lung cancer. There was no association between hormone use and lung cancer in general. But (and there I always a “but” in medical studies), a separate calculation for the women who were 55 years and older, found that lung cancer risk was increased with an odds ratio of 1.58, whereas in women younger than 55 years, lung cancer risk was reduced with an odds ratio of 0.44.

The statisticians feel that overall this is a null finding….in other words not significant for or against the effect of hormones on lung cancer. The conflicting results in all these studies certainly leave pause for concern and need for future large and long term research.

It is estimated that it takes 18 to 30 years from time of smoke exposure to lung cancer development. In the Ranch Bernado study hormone users were slightly heavier smokers and had longer duration of smoking, which may have caused that slight increase in lung cancer in the older women who used hormones. At this point my advice is not to smoke and quit if you do; but if you don’t you probably should abstain from hormone use

So there I was giving a lecture “somewhere” other than California. The organizers took me to dinner in a “fancy” French restaurant. The private dining room was booked for a wedding reception and as the bride arrived with her attendants I could not help but notice two young women who were visibly pregnant… and smoking. To make matters worse one held a nearly empty bottle of beer. I so wanted to go up to these women and suggest that they were increasing their risk of preterm labor, diminishing their progeny’s physical and mental growth and ultimately risking fetal and/or neonatal death, but of course, did not.

I strongly advise women to quit cigarette smoking before they conceive (or before they start to smoke, whichever comes first) for their own health. But if it’s too late, I should have a method to offer them on how to quit while they are pregnant. Although I have never been a smoker, I understand from many friends and family how difficult it can be. “Cold Turkey” describes my lack of cooking skills at Thanksgiving and is also the preferable way to quit while pregnant, but may just be too difficult.

Thank goodness, the data from a study of 100,000 pregnant women in Denmark and their offspring has shown a reasonable substitute, nicotine replacement therapy (NRT). Despite the fact that women who used nicotine replacement therapy were more likely to be over the age of 35 and drink two or more alcoholic drinks per week during pregnancy, they were NOT at increased risk of stillbirth compared to women that neither smoked nor used NRT. The women who continued to smoke throughout their pregnancy had a significantly increased rate of stillbirth as well as the risk of having a child with oral cleft, malformations of the circulatory system and/or digestive system. Those who stopped but used NRT were at reduced risk.

The important fact is that although NRT does contain nicotine, it doesn’t have the other 2999 chemicals that are present in cigarette smoke (yuck!). The American College of Obstetrics and Gynecology has stated in an official opinion that although, quitting cold turkey is best, women who cannot quit smoking without assistance may use NRT during pregnancy. They recommend that NRT products that provide intermittent nicotine — such as gum or lozenges– be tried before resorting to products that provide a constant dose (the nicotine patch)

Perhaps I should have offered one of these products to those pregnant and smoking women that were in the restaurant.

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