The last time osteoporosis came up in the gospel according to Doc Gumshoe it was in the context of “not good news.” Starting in the year 2002, there had been a 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.
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.
Almost certainly, the decline in hip fractures was due to the introduction of the drug Fosamax (alendronate), which was approved by the FDA in 1995 and fairly quickly came into wide use. Admittedly, this drug was initially overprescribed, not only to patients (mostly women) with frank osteoporosis, but to many, many women in the early stages of bone loss, termed osteopenia. Fosamax and other kindred drugs including Actonel (risedronate), Reclast (zoledronate) are in the bisphosphonate class, and while in persons with osteoporosis they 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.
About ten years after the introduction of Fosamax and other bisphosphonates, the news of genuinely scary side effects began to trickle out. One 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. As the news of these adverse 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.
It didn’t seem to make much difference when the health-care authorities tried to assure potential candidates for this therapy that the incidence of these side effects was extremely rare – somewhere between one case in 10,000 patients to one case in 100,000 patients. The reaction in many people seems to have been that they preferred to accept the risks associated with osteoporosis than the risk of these truly terrifying incidents.
… but what are the risks associated with osteoporosis?
The quick answer is, a good deal more substantial than most people think. Osteoporosis is thought by many, especially women, to be an almost inevitable consequence of aging. If asked what they fear more, osteoporosis or breast cancer, most women would surely respond that breast cancer is much more scary than osteoporosis. And yet, if we consider the statistics, it’s by no means so open and shut. For one thing, the incidence of osteoporosis is higher than that of breast cancer – about 15.4% across all age brackets for osteoporosis in women, versus 12.4% for breast cancer. And breast cancer mortality has declined since 1990, by 39% through 2015. That decline has resulted in 322,000 deaths averted. Currently, the 5-year mortality rate for women diagnosed with breast cancer is about 10%.
In contrast, about half of women with osteoporosis will experience some kind of fracture, and these fractures can have dire consequences. Studies of mortality in women following hip fractures report significantly higher mortality rates than in women with breast cancer. A study in elderly patients with hip fractures reported a one-year mortality rate of 21.2%, which is, as you will note, almost double the five-year mortality with breast cancer. Another study found a five-year mortality of 32.3% in individuals following hip fracture.
About a third of all patients who experience hip fractures are discharged to a nursing home, and most of these do not recover the level of activity they enjoyed before their fracture. Moreover, individuals who have osteoporotic fractures, whether of the hip or the vertebrae, are at three times the risk of another fracture due to the frailty of their bones.
All in all, it would not be an exaggeration to say that osteoporotic fractures present far more of a risk to life and to quality of life than breast cancer.
What happens in osteoporosis?
One might think of osteoporosis as a natural process gone off the tracks. Contrary to what most people might assume, even fully mature bones are in a constant state of change, called “remodeling,” in which older bone tissue is being replaced with new, stronger bone tissue. Our bones consist mostly (about 70%) of crystalline calcium salts deposited in a framework which is 90% to 95% collagen fibers. Collagen is a protein consisting of amino acids twisted together to form long, strong fibers. It is these fibers that provide tensile strength to our muscles, tendons, ligaments, and skin. Collagen also provides tensile strength and a degree of elasticity to our bones.
Bone remodeling is a continuation of the process through which our bones grew in the first place, from the tiny bones of an infant to the much larger, heavier bones of a mature adult. Bone growth is also responsive to the stress placed on the bones. A weight lifter will develop much thicker and heavier bones than a sedentary person.
The agents that do the bone remodeling are osteoclasts and osteoblasts. The osteoclasts are fairly large cells of the phagocyte type, meaning that they devour all manner of substances, including foreign particles, bacteria, dead cells, and waste. Osteoclasts are able to absorb both the solid part of the bone – the crystalline calcium part – and the collagen. They usually eat away at the bone for a few weeks, making tunnels up to one millimeter in diameter. Then, their job done, they retreat, and the osteoblasts move in. These are much smaller cells, and they keep at their job of depositing new bone tissue for up to several months. First, the organic tissue is deposited, including collagen. This is followed by deposition of the crystalline calcium. Typically, the new bone tissue is stronger and more resilient than the bone that has been removed by osteoclasts. Bone remodeling has several functions in addition to replacing old, brittle bone with stronger bone. The process can modify both the shape and the thickness of the bone to adapt to external stresses. And the bone acts as a reservoir of calcium as well as other minerals for other physiologic needs, as we’ll see.
Osteoporosis is the result of an imbalance between the activity of the osteoclasts and the osteoblasts. Bone absorption takes place more quickly than bone deposition. To some degree, this is a normal result of ageing – as activity decreases, there is less need for new, strong bone growth. But it is also a result of hormonal changes, particularly in post-menopausal women. Estrogen stimulates bone formation, and inhibits the osteoclasts that remove bone tissue. The decline in estrogen secretion that takes place in menopause has the reverse effect – the osteoclasts gain the upper hand, the osteoblasts are inhibited, and the bone gradually becomes more porous, spongy, and fragile. Whether this process results in frank osteoporosis depends on a number of factors, which we’ll discuss. As noted earlier, about 15% of women develop osteoporosis, which means that 85% of women are spared.
Osteoporosis is defined as bone density lower than 2.5 standard deviations (SDs) below the mean bone density in healthy adults. Individuals whose bone density falls between 1.0 and 2.5 SDs below the mean are classified as having low bone mass, which used to be called “osteopenia.” The term “osteopenia” has fallen out of favor, not because it is inaccurate, but because being labeled as having osteopenia made many persons (and many of their physicians) think that they had a disease that required treatment, leading to overprescribing of bisphosphonates.
The role of calcium in our bones and elsewhere in our bodies
As we would correctly assume, most of the calcium in our bodies is in our bones. But calcium has several important physiological roles other than solidifying our skeletons and our teeth. About 1% of the calcium in our bodies is in our cells, and 0.1% is in the extracellular fluid, including the bloodstream and lymphatic fluid, also termed “plasma.” Calcium is vital in blood clotting and the transmission of nerve impulses, and calcium ions are what trigger our muscles to contract. The entry of calcium ions into cardiac muscle cells and the muscle cells in our arterial system, signaling contraction, are an intrinsic part of the cardiac cycle. In fact, drugs that reduce the entry of calcium ions into these muscle cells, called “calcium-channel blockers,” are standard treatments for hypertension.
The amount of calcium in the plasma fluid remains remarkably constant. If the calcium concentration rises above the normal level of 9.4 milligrams per deciliter, the excess calcium above that level is very quickly conveyed to the bones, where it is stored. And if it falls below that level, calcium from the bones is quickly recruited to return the level to normal. About 1% of the calcium in our bones is in the form of soluble calcium phosphate.
What factors contribute to the development of osteoporosis?
Simply being a member of the female gender increases the chances of developing osteoporosis by a factor of about 3.5. The overall prevalence of osteoporosis in men is about 4.3%, compared with the15.4% prevalence in women, as stated earlier. The prevalence in each gender increases with age, reaching 34.9% in women over the age of 80 and 10.9% in men in the same age range.
But gender is only one of many factors. Here’s a list of just some of those factors:
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- Cigarette smoking significantly increases the risk of osteoporosis
- Lack of exercise – weight-bearing exercise adds mass to the bones
- Any condition that prevents or hinders normal walking
- General nutritional deficiencies, especially a lack of sufficient calcium in the diet
- Vitamin D deficiency either because it is lacking in the diet or insufficient exposure to sunlight
- Being underweight and with small body frame
- Excessive alcohol consumption
- Having sustained fractures as an adult
- Family history of osteoporosis
- Caucasian race – white people have about double the rate of osteoporosis as people of African descent.
- Chronic inflammation, such as in inflammatory bowel disease, rheumatoid arthritis, some diseases of the liver
- Conditions resulting in malabsorption of nutrients, such as celiac disease
- In women, chronically low estrogen levels, which may occur in menopause, but also with early removal of both ovaries, or with some forms of chemotherapy that can have toxic effects on the ovaries
- In women, interruption of menstrual cycle, which may be due to excessive exercise training or diets leading to very low body fat, as in anorexia
- In men, low testosterone levels (hypogonadism)
- Thyroid and parathyroid malfunctions
- Long-term use of some common medications can contribute to osteoporosis.
These include heparin (an anti-clotting agent), Dilantin (prescribed to some persons with epilepsy or seizure disorders), Phenobarbital (a barbiturate, mostly used as a sedative), and some steroids such as prednisone.
Some of those factors we can attempt to modify or control; some, obviously, we cannot. A petite white woman, well past menopause, whose mother, also a petite white woman, had osteoporosis, fell and broke her hip, and died in a nursing home a year later, is evidently at a higher risk of osteoporosis than many of her fellow human beings.
That doesn’t mean that she’s destined to the same fate. But what can she do?
What can we do to prevent osteoporosis?
If we look at that unsettling list of factors contributing to osteoporosis, there are some that are clearly modifiable. Our petite white woman can, for one thing, quit smoking. She can keep moving – go for walks, ride her bike, dig weeds out of her garden, take out the garbage while her lazy bum of a husband watches TV…. She can stop being super-careful about eating cheese and butter and all those calcium-rich dairy products that might make her gain weight and loose her sylph-like silhouette. Some things are more important than having a figure like Twiggy.
Supposing a person is not getting enough calcium in his/her diet, the first and easiest answer most people think of is calcium supplementation. To this, Doc Gumshoe says, “not so fast.” The need for supplements obviously varies with the amount of calcium in a person’s diet. Individuals who stay away from dairy products will find it difficult to get anywhere near the amount of calcium they need without supplements, but moderate amounts of milk, cheese, yoghurt and the like can push to calcium total to the desirable range. Here are the daily requirements for calcium for individuals at various ages and under various circumstances (the total numbers can include dietary calcium and calcium derived from supplements):
- 800 mg/day for children 1 to 10 years old
- 1,000 mg/day for men, premenopausal women, and postmenopausal women also taking estrogen
- 1,200 mg/day for teenagers and young adults 11-24 years of age
- 1,500 mg/day for postmenopausal women not taking estrogen
- 1,200 mg-1,500 mg/day for pregnant and nursing mothers
But the total intake of calcium should not generally exceed 2,000 mg per day. The concentration of calcium in the plasma is closely monitored and adjusted rapidly, mostly through the action of the parathyroid hormone (PTH). When calcium levels fall below the normal range, PTH secretion increases, triggering more removal of calcium from the reservoir in our bones to balance the levels in the plasma. Chronic calcium deficiencies in the plasma can sometimes be normalized through this action for as long as a year, but this cannot continue indefinitely without significantly depleting the calcium content of the bones, resulting in reduced bone mass and osteoporosis. Conversely, when calcium levels go above the normal range, PTH secretion decreases, and the excess calcium is returned to the bones.
It would be a mistake, however, to assume that there’s no such thing as too much calcium in our daily intake. While most of the calcium in our diet is excreted in the feces, if we take in more than can be kept in the normal range through the action of PTH, there is a chance that some of the calcium can wind up in the wrong places – those being the walls of our arteries. This particular threat is not likely to affect our petite white woman, even if she greatly increases her input of triple-crème Brie. It mostly affects persons who have elevated cholesterol levels and who may already have coronary artery disease, diabetes, or advanced kidney disease.
Calcification of the arteries has been known for a long time. Early students of anatomy were surprised to find that when they exhumed cadavers for study, the blood vessels in some of these cadavers were stiff and brittle, while in most cadavers, blood vessels had completely shrunk to no more than thin threads. What was holding these stiff and brittle blood vessels together was the crystallization of calcium salts within the cholesterol in the arterial wall. They had become more like rigid tubes.
The possibility of coronary artery calcification should be taken as no more than a note of caution that indiscriminate calcium supplementation – “the more the better” – is invariably a good thing.
Another note of caution concerns the relationship between calcium supplementation and colon health. For several years, it had been thought that calcium supplementation was a positive factor in colon health. Now, we can’t be quite so sure. In fairly large study – 2000 subjects for ten years – patients who had a history of polyps in the colon were assigned to take either daily calcium supplements, daily vitamin D supplements, both, or neither, for a period of five years. Those who took calcium alone or a combination of calcium and vitamin D were more likely to have polyps 6 to 10 years after the start of the study. Vitamin D alone did not increase the risk for polyps. And calcium absorbed from the diet did not increase the risk of polyps.
So, with regard to calcium, it’s fine if it comes from food, but consult with your physician before you start taking the supplements. And, by the way, it may be best to shun the supplements that claim to be “completely natural,” e.g., ground-up oyster shells or bone meal. These may contain lead, not a good thing.
Vitamin D supplementation?
That’s a different question altogether. The need for vitamin D supplementation has been around for a long time, since well before anyone knew anything about vitamin D, which wasn’t identified until the 1920s. Cod liver oil, rich in vitamin D, began to be used in the early 19th century because it was effective in warding off rickets, which has turned out to be a result of vitamin D deficiency. It was not easy to get enough vitamin D from a normal diet unless the diet consisted mostly of fatty fish and seafood. Today, many items on the supermarket shelves are reinforced with vitamin D, including milk and orange juice, so perhaps it’s a bit easier than when I was a kid and my mother gave me a spoonful of cod liver oil every day.
My mother was zealously guarding against rickets, which was a common disease in children. Children with rickets suffer from defective bone growth – their bones are soft and become malformed. They frequently become severely bow-legged. And the simple reason is a vitamin D deficiency, which results in a diminished ability to absorb calcium and phosphorus from their food. Since calcium and phosphorus are what bones are made of, the consequences are weak and soft bones.
Why do we humans need more vitamin D than we can normally obtain from our daily diets? Is this not evidence of a serious error in the way we’re adapted to life on planet Earth? Well, no. We have the ability to synthesize enough vitamin D for our needs, but in order to accomplish this, we have to have adequate sun exposure. Perhaps before we became so darn civilized, our species spent many more hours per day in the sunlight and thereby made enough vitamin D to grow healthy bones. But no more. And we don’t need to issue yet another warning that we need to be careful about the amount of ultraviolet light that we expose ourselves to.
So it certainly appears that at this stage in the evolution of mankind from outdoor to indoor creatures, vitamin D supplementation is the answer. The question is, how much supplementation do we need? Let’s start from the premise that most of what we eat and drink has very small amounts of vitamin D. Yes, cod liver oil is an excellent source – a tablespoonful of CLO contains about 1400 international units (IUs) of vitamin D. But how many of us regularly consume CLO these days? In contrast, a 3 ounce serving of cooked salmon (not much, according to my standards!) contains 450 IUs, and the same amount of canned tuna contains about 150 IUs. Most of the food items that we consume are in the low double digits. And when we get to something like Swiss cheese, that’s 6 IUs per ounce. The fortified products – milk, orange juice, yoghurt, etc, do a little better, but nowhere near enough to meet the requirements as proposed by the Food and Nutrition Board of the Institute of Medicine of the National Academy of Health, which I append here:
|Table 2: Recommended Dietary Allowances (RDAs) for Vitamin D |
|0–12 months*||400 IU
|1–13 years||600 IU
|14–18 years||600 IU
|19–50 years||600 IU
|51–70 years||600 IU
|>70 years||800 IU
Those amounts of vitamin D are probably enough to maintain calcium and phosphorus absorption at levels sufficient to support adequate bone health, and – again probably! – stave off osteoporosis. Those numbers would be the sum of dietary vitamin D and vitamin D supplementation, but since on most days most people don’t take in even 100 IUs of vitamin D through their diets, it would be probably okay to take those numbers as the amount of supplementation that is necessary.
However, there’s a major twist in the story. The evidence has been mounting in recent years that vitamin D has important pleiotropic effects, which is to say that it brings us benefits totally apart from its role in calcium and phosphorus absorption. For example:
- In a trial at Boston University, a cohort of people with hypertension had their vitamin D levels doubled through exposure to ultraviolet light. After three months, their blood pressure returned to normal, and after nine months it continued to be normal. One theory is that vitamin D reduces blood pressure by decreasing renin output; renin is thought to play a role in hypertension.
- In a study in JAMA in more than 3,000 veterans, those who consumed more than 645 IU of vitamin D a day along with more than 4 grams per day of cereal fiber had a 40% reduction in their risk of developing colon polyps, which are frequently precursors of colon cancer.
- A study in Neurology indicated that women who get at least 400 IUs of vitamin D are 40% less likely to develop multiple sclerosis compared with those not taking vitamin D supplements.
These findings should be taken as pointers to areas where further research is needed. But in the meantime, a number of scientists who have studied vitamin D’s effects have stated that the recommended levels of vitamin D supplementation are far too low. Supplementation ranging between 1000 and 2000 IUs, and in some cases up to 3000 IUs, is commonly recommended. Again, the amount of supplementation depends on a number of factors, and should be decided in consultation with a physician.
What if, despite all preventive measures, osteoporosis still occurs?
As we said earlier, osteoporosis is defined as bone mineral density at least 2.5 standard deviations lower than the average peak bone density in young adults. This is usually referred to as the “T-score.” The test to determine bone mineral density (BMD) is a dual-energy X-ray absorptiometry scan (DXA), which measures BMD in the hip, spine, and forearm. It takes perhaps 15 minutes to perform and exposes patients to much lower levels of radiation than do standard chest X-rays. The DXA scan is much more accurate than standard X-rays, which only reveal osteoporosis when it has progressed to potentially dangerous levels.
BMD values between 1.0 and 2.5 standard deviations below the mean indicate a state of low BMD called osteopenia that has not progressed to osteoporosis. In general, drug treatment for osteopenia is not recommended; however, in some cases, as in a person with a long history of heavy smoking, some physicians might suggest initiating treatment even before the 2.5 T-score has been reached. Other factors pointing to earlier intervention include a history of steroid use, rheumatoid arthritis, or family history of osteoporosis.
The bisphosphonates were the first class of drugs with a demonstrated capacity to slow the progression of osteoporosis. Bisphosphonates were known and tinkered with in the 19th century, and some agents in this category were studied in relation to bone metabolism as early as the 1960s, but it was not until 1999 that the first drug in this class, Fosamax (alendronate) got its FDA approval.
Fosamax and its successor drugs have a similar mechanism of action. They have a very high affinity for a bone mineral (hydroxyapatite) and are preferentially incorporated into the specific sites where active bone remodeling is taking place. Any bisphosphonate that is not retained in the skeletal structures is rapidly eliminated in the urine. The binding of bisphosphonates to hydroxyapatite inhibits the breakdown of this bone mineral, suppressing bone resorption by this means. In addition, bisphosphonates induce programmed cell death in osteoclasts, which as we discussed earlier, are the agents of bone resorption. Thus, bisphosphonates slow down the process through which calcium is removed from the bone. However, the bisphosphonates have no effect on osteoblasts, so they neither accelerate nor delay bone growth.
Following the launch of Fosamax, several other bisphosphonates were introduced. These drugs all have the same mechanism of action, but they differ in other respects, including dosing schedules and side effects. For example, while Fosamax can cause irritation of the esophagus, the next bisphosphonate to come along, risedronate (Actonel), is significantly less likely to cause that particular side effect. Ibandronate (Boniva) differs in that it is available in an intravenous formulation that may be taken every three months. For comparison, Fosamax is taken by mouth once a week. Reclast (zoledronate) differs from all other bisphosphonates in that it is given by means of an intravenous infusion once a year.
Data purporting to show differences in the efficacy of these drugs in preventing bone fractures are open to interpretation. They all appear to be effective, based on the data showing the large decline in the number of fractures after the introduction of this class of drugs, and the leveling off of this decline following the bad news about the side effects, which we discussed earlier. However, there is little basis for choosing one of these agents over the others on the basis of efficacy.
Options other than bisphosphonates
While the bisphosphonates deal with osteoporosis by reducing the removal of calcium from bones, there are some agents that actually promote the growth of new bone. One of these is Forteo (teriparatide; Eli Lilly) is a synthetic version of the human parathyroid hormone, which helps to regulate calcium metabolism. Forteo is administered as a once-daily subcutaneous injection. Long-term safety data on Forteo are not yet available, so the FDA has approved this drug only for 24 months, after which patients switch to a bisphosphonate to preserve the bones from loss.
Another drug in this category is Tymlos (abaloparatide; Radius Health), a parathyroid-related protein analog, which was granted FDA approval in April of 2017. Similar to Forteo, Tymlos stimulates bone growth through its action on osteoblasts. It too is given by once-daily subcutaneous injections. The bone-building effects of Tymlos do not continue indefinitely – after two years they tend to peter out, so FDA approval of this drug is for 24 months only, similar to Forteo. After that period, patients would most likely be advised to continue their treatment with a bisphosphonate. Tymlos is at present approved only for use in patients with severe osteoporosis, which is defined as a history of osteoporotic fracture or multiple risk factors for fracture, and also for use in patients who have exhausted all other available osteoporosis treatment options.
Neither Prolia nor Tymlos are inexpensive drugs, particularly when compared with bisphosphonates. The price tag for Tymlos is about $19,500 per year, and Forteo may be even more costly, particularly in view of Eli Lilly’s practice of upping their prices by anywhere from 9% to 15% twice a year. This is apt to make health insurers reluctant to approve those agents, regardless of their effectiveness in promoting new bone growth, even if for only a limited span of time.
The most recent addition to the roster of agents that combat osteoporosis is Prolia (denosumab), from Amgen. Prolia received FDA approval on May 21, 2018. This drug is a monoclonal antibody that binds to RANKL, a chemical messenger that activates RANK, which is on the surface of osteoclasts, thus preventing the RANKL-RANK interaction. That interaction, prevented by Prolia, is what sets the osteoclasts to work on absorbing and carrying off bone tissue. The mechanism of action is thus different from that of the bisphosphonates, but the ultimate effect is similar. Prolia is given by injection twice yearly. An alternative formulation of denosumab, Xgeva, is used to prevent the spread of cancer from solid tumors to the bone, and is given to men with advanced prostate cancers that have penetrated beyond the prostate capsule.
Where do we come out?
If you’ve read this far, you probably noticed that Doc Gumshoe devoted way more space to preventing osteoporosis than to treating it. That’s because, as you have seen, treatment for osteoporosis at its best in no way comes close to being a cure. The most effective treatment modalities slow down the removal of bone tissue and, for a time, aid in its replacement with new bone tissue. The effects of this treatment might be described as exchanging the bone remodeling characteristics of an 80-year old with those of a much younger person – for a period of time, at least.
A better strategy would be not to let those remodeling characteristics become those of an 80-year old by avoiding the habits that adversely affect that pattern in the first place. At the risk of being tedious, I’ll pound the table with just a few – don’t smoke, do exercise, and do consult with a health-care provider regarding calcium and vitamin D supplements.
Osteoporosis has been known for a long time. It was named in the first part of the 19th century, but the fragility of the bones of old folks has long been taken for granted. The assumption was that osteoporosis was a natural and inevitable result of aging, which struck some people more severely than others. The big change is that this is no longer so. Osteoporosis can be prevented, perhaps not with absolute certainty, but if we adopt those relatively painless lifestyle habits, the odds are strongly in our favor. And if osteoporosis nevertheless strikes us, we do have some treatment options that work quite well. Osteoporosis is not fate. It’s just one more disagreeable trial that we need to avoid if we can.
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Many thanks to the Gumshoe congregation for all the comments, which certainly come from all points of the compass. While working on this particular epistle, I’ve been trying to keep track of a number of interesting and promising developments in various corners of the health-care arena, and I’ll be reporting on some of those soon. Best to all, Michael Jorrin (aka Doc Gumshoe)
[ed. note: Michael Jorrin, who I call Doc Gumshoe, is a longtime medical writer (not a doctor) who writes for us about medicine and health a couple times a month. He has agreed to our trading and disclosure restrictions, but does not generally write directly about investments. His ideas, thoughts and words are his own, and you can see all his past pieces here.]