Winter Miscellany – December 2020

Alzheimer's, Dengue, Vegan Diets and Osteoporosis... and, yes, a little COVID-19, too.

By Michael Jorrin, "Doc Gumshoe", December 22, 2020

That title is just to remind you that there’s a whole lot more going on in the health/medical area than COVID-19.   But the pandemic has a very large untidy footprint which is making a mark on a great many aspects of health-care in general.

One recent example which could not possibly have escaped my attention, since it was front and center on the front page of the NY Times, is that a great many hospitals throughout the US are stretched to the utmost, and in many cases, stretched well beyond the utmost.   A map showed where the intensive care units were filled to capacity and even beyond.   In twenty such locations, more than 100% of the ICU beds were occupied.   A lot of these were in Florida and Alabama, but some were in other parts of the country.   For example, in Albuquerque, New Mexico (where I used to live), the figure the Times gave for ICU occupancy was 116%.

It’s hard to figure exactly what that means.   I’m guessing that hospitals grab beds from other non-intensive care units and jam them somehow into the ICU.   But obviously there’s a limit to that.   I’m also guessing that some patients who under normal circumstances might have been admitted to the ICU are either admitted to other parts of the hospital or deemed not so seriously ill or injured and sent home.

In any case, it’s a high-stress situation for the hospital staff and for the patient as well.   The hospital is not going to put a patient with COVID-19 in the maternity ward or in the space where patients are recovering from surgery.   It’s a dilemma, and the well-being and health of patients and hospital workers is certain to be affected.

Another way that the pandemic is adversely affecting other health-care areas is that many non-COVID-19 patients are omitting normal care of their health conditions such as diabetes, various cardiac conditions, rheumatoid arthritis and other diseases that need regular attention.   And patients are not keeping up with health maintenance practices such as annual physicals.

One way that COVID-19 has had a major effect beyond those of the infection itself is that the pandemic has led to a large increase in the number of deaths attributed to causes other than COVID-19.   The Centers for Disease Control has released overall mortality figures, and during the eight-month period from March 15 to November 14, the numbers of deaths from several conditions was well above the expected number.   Here are some figures:

Cause Deaths Above 

Normal                                                           

Percent Above

Normal

Diabetes 8,500 15%
Alzheimer’s

Disease

Dementia

21,300 12%
High Blood Pressure   7,600 11%
Pneumonia & Flu   3,000 11%

Other diseases and conditions also saw significant increases in mortality, including coronary heart disease, stroke, and sepsis.   And the increases in mortality in some specific areas soared way above the national average increases as shown above.   For example, New Jersey residents experienced a 37% increase in the numbers of deaths from diabetes; New Mexico saw a 29% increase in the numbers of deaths from Alzheimer’s disease and dementia; and New York City had an increase of 39% in deaths from high blood pressure and a 50% increase of deaths from pneumonia and flu.

It is notoriously difficult to designate a specific cause of death.   It is certainly possible that some of the approximately 40,000 excess deaths attributed to the four conditions named in the chart above were actually COVID-19 deaths.   And, it is certainly also possible that some of the ~ 300,000 deaths currently attributed to COVID-19 were the result of other diseases or conditions.

The argument that at least some of those excess deaths may in reality be due to COVID-19 is supported by the evidence that COVID-19 has a great many comorbidities.   A study in more than 70,000 patients diagnosed with COVID-19 in the early days of the pandemic found that 69 of 1,724 diagnosis codes were strongly associated with COVID-19.   That included 27.6% of patients diagnosed with viral pneumonia, 22.6% of those diagnosed with respiratory failure, 11.8% of those diagnosed with acute kidney failure, and 10.4% of those diagnosed with sepsis.

That does not mean that those patients definitely had COVID-19, but that there is a strong probability that they had that disease.   However, my guess is that many or most of those deaths assigned to diabetes as the cause were related to patients failures to maintain contact with their health-care provider and thus with failure to keep on top of their symptoms and what they had to do in order to manage their disease.   That would also, in all probability, be the case with patients diagnosed with viral pneumonia and respiratory or kidney failure.  Whether or not those excess deaths were specifically due to COVID-19, in my view, most of them were related to the pandemic is some way.   Patients skipped their follow-up visits or chose not to go to the hospital emergency department because they thought that they would probably be exposed to the coronavirus, which was more dangerous than the chronic condition they were accustomed to living with.

As we see, COVID-19 has had a major effect on morbidity and mortality from non-COVID-19 conditions.   Therefore, with a decline in COVID-19 mortality (as vaccines and herd immunity take effect), we can expect a concurrent decline in the excess mortality from these other causes.

So, let’s take a look at a few other health-related news items that have come our way.   The first of these was no surprise to skeptics like Doc Gumshoe.

A vegan diet is strongly linked to a higher risk of bone fracture

This finding was the result of a very large cohort study in the UK, in which 55,000 subjects were followed for 20 years on average.   The data was self-reported, both as to diet and to incidents of bone fracture.

The overall conclusion, surprising to some, was that vegans had a 43% higher risk of bone fractures than meat-eaters.   Vegans, as I’m sure you know, scrupulously abstain not only from meat, but also from fish, and from foodstuffs derived from any animal, such as eggs and dairy products.   This makes it difficult for vegans to consume sufficient calcium to maintain bone health.

Hip fracture risk was 2.3 times higher in vegans than in people who consumed meat, which is equivalent to 15 more cases per 1,000 people over a 10-year span.   Vegans also had higher risks of bone fractures elsewhere in the body, including legs and vertebrae.

Of that initial pool of 55,000 people, over 29,000 were meat-eaters, 8,000 were fish-eaters, 15,500 were vegetarians, and nearly 2,000 were vegans.

During the approximately 20-year time of the study, over 3,900 fractures occurred: 566 broken arms, 889 broken wrists, 945 broken hips, 366 broken legs, 520 broken ankles and 467 fractures of other bones, including the ribs, spine, or collar-bone.   The study, called the Epic-Oxford Study, was published in November.   (Tong T. BMC Medicine 2020;18:353-)

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It should be noted that this study was purely observational.   The study subjects were not instructed regarding their diets.   They reported in general terms whether they were vegans, vegetarians, fish eaters, or meat eaters, and also reported on their histories.   There are no data on whether calcium supplements were used by study subjects.

Earlier studies have found that vegans and vegetarians have lower bone mineral density than persons who eat meat, and also lower intakes of dietary protein.   These characteristic make the link between vegan diets and bone fractures intuitively likely.

That does not mean that the vegan diet provides no benefits.   To the contrary:

A low-fat vegan diet has positive effects on body weight, insulin sensitivity,  metabolism and lipid levels

This was reported on November 30th in JAMA Network Open.   (Kahleova H. JAMA Netw Open 2020;3(11):e2025454. doi:10.1001)  A study in 224 overweight or obese adults (BMI between 28 and 40) assigned half the subjects to the low-fat vegan diet.   Since no meals were provided, the half of participants who were randomized to the low-fat vegan diet were instructed to follow a diet of about 75% carbohydrates, 15% protein, and 10% fat from vegetables, grains, legumes, and fruits, without animal products or added fats. These individuals also took 500 μg/d of vitamin B12.

Over the 16-week trial period, the overweight/obese adults on the vegan diet lost, on average, 13 pounds, while the subjects in the control group, which had made no changes in their diet, maintained their weight throughout the duration of the trial.

There were other benefits as well.   The subjects on the low-fat vegan diet also experienced a significant (P < 0.001) increase in the insulin sensitivity index.   They also saw a 14% increase in energy expenditure over the course of three hours following a breakfast of 720 calories.   This was also evaluated as highly significant (P < 0.001).   The low-fat vegan diet also led to significant decreases in lipid levels, including a 34.4% decrease in lipids in liver cells.

In comparison with the study that found that adherence to the vegan diet led to an increased risk of bone fractures, this study was well-controlled.   The study participants on the low-fat vegan diet were carefully instructed as to what to include and what to exclude from their diets.   It is intuitively likely that a low-fat diet would lead to weight loss and to a decrease in lipid levels.

Would it be possible to come up with a dietary plan that delivers some of the benefits of the vegan diet without exposing the followers of that plan to the increased risk of bone fractures?   My guess is that something like the Mediterranean diet would just about fill the bill.   Not to define it too strictly, the Mediterranean diet means less meat, more fish, plenty of vegetables, fruits and nuts, olive oil rather than butter or lard, and a glass of wine or so.

Next, a recent development that will probably not have any consequences for members of the Gumshoe tribe but could lead to major benefits to millions of people around the world.

Modified mosquitoes greatly reduce Dengue virus infections 

This finding was the result of a trial in the Yogyakarta, a city of 400,000 in the island of Java in Indonesia.   The city was divided into 24 zones, and these 24 zones were randomly divided one to one to receive modified mosquitoes or not.   The modified mosquitoes were infected with Wolbachia, a parasitic organism that naturally infects more than half of all insect species, but not Aedes aegypti, which is the mosquito that transmits the Dengue virus.   Wolbachia has a number of effects on the hosts it infects, one of which is preventing transmission of the Dengue virus.   Mosquitoes infected with Wolbachia transmit the infection to their offspring, so that the population of mosquitoes modified in that way will grow and spread.

Three years after the cluster-randomized trial began in Yogyakarta, rates of Dengue cases were 2.3% in the zones where the modified A. aegypti mosquitoes had been released, versus 9.4% in the other “untreated” zones.   This represented a reduction of 77.1% in virologically confirmed Dengue cases, which was the study’s primary end point.   A key secondary end point was Dengue cases requiring hospitalization, which was 86.2% lower in the “treated” zones.

The study’s findings were reported by Katherine Anders, MSc, PhD, of Monash University in Clayton, Australia, in a presentation of the American Society of Tropical Medicine and Hygiene’s annual meeting.

Efforts to control and limit the spread of other mosquito-borne diseases by modifying mosquitoes have been attempted elsewhere with varying degrees of success.   The benefit of addressing these diseases by altering the disease-carrying capacities of the mosquito vectors is large, not only in terms of absolute effectiveness, but in terms of economy.   Specifically with regard to the Dengue virus in that particular Indonesian region, it is far less expensive to tinker with a mosquito population, which will multiply on its own, than it would be to treat or vaccinate every human inhabitant of the region.

Now let’s take a look at a couple of busts.

Omega 3 fatty acid supplements no better than placebo in reducing cardiovascular events

The rationale for omega 3 supplements is that fish, such as salmon, that are rich in omega 3 fatty acids, are widely regarded as “heart healthy.”   So, what is it in the fish that makes them so heart healthy?   Must be those omega 3s.

Epanova is a mix of eicosapentaenoic acid (EPA) and docosaexaenoic acid (DHA).   In the STRENGTH clinical trial, Epanova didn’t lower cardiovascular events any more than a corn oil placebo in subjects at elevated cardiovascular risk due to elevated triglyceride levels.   However, subjects treated with Epanova had greater incidence of new onset atrial fibrillation.   The STRENGTH trial was stopped early because the omega 3 treatment was delivering zero benefit to patients at relatively high risk.   (Nicholls SJ JAMA. 2020;324(22):2268-2280)   The trial authors included a roster of the most respected cardiovascular specialists, including Dariush Mozaffarian, Paul Ridker, and Steven Nissen.

In another trial, OMEMI, conducted in elderly heart attack survivors in Norway, another supplement containing both EPA and DHA also failed to deliver any benefit in terms of reduced cardiovascular event rates compared with a corn oil placebo.   Again, subjects receiving the omega 3 experienced more new-onset atrial fib than did the placebo group.  The two groups also had the same 5.5% incidence of all-cause mortality.   (Kalstad AA. CirculationNAHA.120.052209. Pub 15/11/20)

These trials revived questions about a previous omega 3 trial, REDUCE-IT, which used only pure EPA with no added DHA, and did report benefits from the omega 3 supplement.   It has been suggested that adding DHA to the supplement is detrimental to the benefits of pure EPA.   On the other hand, it has also been suggested that in REDUCE-IT there may have been a harmful interaction between the statins that the patients were taking and the mineral oil (not corn oil) placebo that was used in the control group, thus giving the treatment arm an unfair advantage in clinical outcomes.   Commenting on the REDUCE-IT trial, Steven Nissen said that it should be done over from scratch.

Whether these two trials will have any effect on the sale of omega 3 supplements is anyone’s guess.   My guess is that they will not have much effect.   People may prefer buying a bottle of pills over the counter to seeking out the fish department in the supermarket and shelling out for a salmon.   Speaking for myself only, I greatly prefer the salmon, which is delicious with dill mayonnaise or potlatch.

The next item is not exactly a bust, but might be a disappointment to some women.

Continuing oral bisphosphonates for more than 5 years is of questionable benefit.

This topic requires a bit of review.   Oral bisphosphonates came into being with the introduction of the drug Fosamax (alendronate) which was approved by the FDA in 1995, and quickly came into wide use, along with the kindred drugs Actonel (risedronate), Reclast (zoledronate), and Boniva (ibandronate).   These drugs were almost certainly responsible for the steady decline in the number of hip fractures sustained by women on Medicare over the age of 65, from 931 per 100,000 in 2002 to 730 per 100,000 in 2015.   But this decline came to a screeching halt after 2015.   If the reduction in the number of these events had continued to the present, it is estimated that about 11,500 fewer women would have broken their hips.

However, about ten years after the introduction of Fosamax and other bisphosphonates, the news of genuinely scary side effects began to trickle out.   One of those effects was osteonecrosis of the jawbone, leading to fractures.   The other was a fracture of the femur – the long bone of the upper leg – called atypical femoral fracture.   Although these adverse events were relatively rare, as the news of these events spread, the use of bisphosphonates plummeted, falling by about 50% between 2008 and 2012.   This reduction in the use of bisphosphonates likely accounted for the end of the decline in hip fractures.

While in persons with osteoporosis bisphosphonates reduce the risk of fracture by as much as 50%, they are not recommended for persons whose degree of bone loss has not progressed to osteoporosis.   In the great majority of cases, hip fractures occur in persons with osteoporosis.   Scrupulous health professionals shrink from calling osteoporosis the “cause” of hip fractures, or of vertebral fractures, which are also very much associated with osteoporosis.   Usually, the immediate cause is a fall, but in a person whose bones had not become porous, such falls do not necessarily result in a fracture.   The fall is the precipitating event, but the underlying cause is the fragility of the bones.

The question remains: how long should women with osteoporosis continue taking oral bisphosphonates?   A recent retrospective cohort study of nearly 30,000 women who completed five years of oral bisphosphonate treatment reported that those women who continued therapy for an additional five years didn’t see a significant difference in cumulative incidence of hip fracture compared with women who only stayed on therapy for two additional years.   The study was published in JAMA Network Open on December 7.   (Izano MA. JAMA Netw Open. 2020;3(12):e2025190. doi:10.1001)

Women who remained on therapy for only two additional years actually saw a small decrease in the incidence of hip fractures – 2.2 fewer per 1,000 individuals.   But those women who continued taking on a bisphosphonate for five more years experienced an increase in hip fracture incidence – 3.8 per 1,000 individuals.

Overall, the 5-year cumulative hip fracture incidences were as follows:

  • Those women who discontinued bisphosphonate therapy after the initial five years experienced 23.0 hip fractures per 1,000 individuals./li>
  • Those who took a six-month holiday from bisphosphonate therapy and then resumed therapy for two additional years: 20.8 per 1,000 individuals.
  • Those who continued bisphosphonates for five additional years: 26.8 per 1,000 individuals.

The investigators pointed out that a Task Force of the American Society for Bone and Mineral Research recommended in 2015 that low-risk patients should consider a bisphosphonate “drug holiday” after five continual years of treatment. But on the other hand, women at high risk for fracture should continue with ongoing treatment.   Benefits beyond five years are not clear.

In an effort to add more clarity to the essential question – should women who have been on a bisphosphonate for five years continue treatment, and if so, for how long? – the investigators looked at data from 29,685 women ages 45 to 80 from Kaiser Permanente Northern and Southern California.   All women had initiated oral bisphosphonate therapy with a  bisphosphonate and completed the initial five years of treatment from 2002 to 2014.   After the initial five years of treatment, about 37% of women were identified as having osteoporosis. During the five years of follow-up after the completion of the initial five years of therapy, 507 incident hip fractures occurred.

The researchers noted that the rates of incident hip fracture were similar whether or not the women took a six-month “grace period” of discontinuation in between their initial five years of therapy and continuation of therapy.

If anything is clear, it’s clear that very little clarity has been added to the essential question of how long bisphosphonate treatment should be continued.   I recall that when bisphosphonates first came into use, they were hailed as the solution to the long-recognized problem that women commonly experienced after menopause, that is, a reduction in bone mineral density, resulting in some cases in osteoporosis and a risk of fractures that in many cases were life-shortening.   The picture has turned out to be not quite so rosy.   As we see, bisphosphonates do reduce the incidence of fractures, but they are not the single perfect solution.

Doc Gumshoe does not have an easy answer to the question of how to stave off osteoporosis and its accompanying risks.   However, I will put it on my agenda to devote a future piece to bone health and how best to maintain it.

Now, here’s a promising bit of news relating to Alzheimer’s disease.

A blood test for Alzheimer’s disease is as accurate as other, more expensive and invasive tests

What that means is that it will facilitate research into Alzheimer’s that could very likely lead to effective treatment options.

The specific biomarker that the blood test detects is tau protein phosphorylated at threonine 217.    Threonine is one of the essential amino acids.   Tau protein occurs particularly in neurons, and tangles of tau proteins, sometimes called neurofibrillary tangles, are characteristically found in the brains of Alzheimer’s patients.

In a study involving three selected cohorts, that biomarker, labeled p-tau217 discriminated Alzheimer’s from other neurodegenerative diseases with significantly higher accuracy than established plasma and MRI biomarkers, successfully distinguishing persons with AD from healthy controls.   The study was published in Alzheimer’s & Dementia on December 7, 2020.   (Kvartsberg H. https://doi.org/ 10.1002/alz.043467)

The study determined that p-tau217 levels increased over time in the brains of individuals with AD, but not in the brains of persons with other forms of dementia.   A particularly telling finding was that in one of the three groups evaluated in the study, a cohort of Colombians who are genetically disposed to develop AD at a fairly early age, the biomarker was found as long as 20 years before the estimated onset of mild cognitive impairment.   In the Colombian cohort, identified in the Colombian autosomal-dominant Alzheimer’s registry, significant differences were seen in p-tau217 levels between mutation carriers and non-carriers as early as age 25.

Perhaps the most important benefit of this test is that it will greatly facilitate investigation of treatment options for AD.   The type of treatment for AD that would truly make a major difference is one that could be instituted well in advance of the actual symptoms of AD and would prevent those symptoms from manifesting and progressing to severe dementia.   As we saw, the biomarker was detected as much as 20 years before the estimated onset of the earliest AD symptoms.   That’s when preventive treatment options would ideally be initiated.

Commenting on the study, Howard Fillit, MD, of the Alzheimer’s Drug Discovery Foundation in New York City, said “I really think this is going to be a huge advance in Alzheimer’s disease. It’s almost like the first steps that blood tests for cholesterol in heart disease took back in the 1950s and ’60s.   This might be the first of many blood tests for tau that may come out, but this one is good enough.”

* * * * * * *

In the comments on the previous Doc Gumshoe piece about COVID-19, quite a number were questions about new developments in the pharma world – drugs, vaccines and the like.   I looked briefly at some of these, and I mean briefly. In general, I don’t venture an opinion about these developments when they’re still in relatively early stages.   I know that many Gumshoe denizens are perhaps more keenly interested in the prospect of the pharma outfit’s stock than in the merit of their product.   I have zero expertise in those matters, and I’m also exceedingly loath to venture an opinion on the products when they’re in the early stages.   But some of the individual subjects are interesting, and I will look into them in a sequel to this installment.   In the meantime, I wish everyone an excellent holiday, and I look forward to hearing from you.   Thanks and best, Michael Jorrin (aka Doc Gumshoe)

 

[ed. note: Michael Jorrin is a longtime medical writer (not a doctor), who I dubbed “Doc Gumshoe” many years ago — he writes health and medicine-focused columns for our readers a couple times a month, and though he does not generally cover investment ideas he has agreed to our trading restrictions. You can find his past columns here.]


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fred88
Irregular
fred88
December 22, 2020 10:21 am

Thanks for this Michael. Actually, it would be very good if the test for detecting AD actually works as well as you described, truly game changing.

As a mater of fact, speaking of the Tau protein, there is actually a medication that seems to be working. It apparently stops the progress of the disease (even restores the cognitive functions in some early stage patients and so early detection would be crucial), although it does not cure the disease. Contrary to most R&D done by the big pharmas on AD in trying to control or eliminate the amyloid plaque, the company that has developed the medication has actually targeted the tau protein tangles by stopping the tangling and by untangling existing ones in early stage cases. The company is called TauRx (www.taurx.com) and its medication is called LMTX. TauRx has been established some 18 years ago, is headquartered in Singapore (for fundraising and ta