Part One of this opus ended with a few paragraphs that approached the question of what we can do to prevent osteoporosis. Prevention is more important in the management of osteoporosis than in most medical conditions. Yes, preventing a disease is always preferable to treating it once the disease takes hold. There are cures, of course, for many, many diseases – including for many forms of cancer – but osteoporosis is not one of them. As we’ve said, osteoporosis is essentially a manifestation of aging, and until some form of “curing” aging is discovered, the process of bone loss will affect all of us.

The question is, can we effectively slow it down enough to evade its most serious consequences? And the answer to that question is an emphatic “yes, we can!” But in order to do that, we need to take several specific steps.

As I observed in the first part, the great majority – about 90% – of people who sustain osteoporotic fractures are entirely unaware that they have become osteoporotic. So the first step is to keep track of the condition of one’s bones. This can be done fairly simply, by having a bone scan, described in detail in Part One. If the bone scan indicates that bone loss is approaching, trending in a dangerous direction, it’s probably time to take up preventive measures.

Those measures, also described in detail in Part One, mostly have to do with exercise and diet, and they can be effective up to a point. However, if bone loss has passed a certain point, there are now medications available that can significantly reduce the chances of sustaining an osteoporotic fracture. That’s what will be discussed in this installment.

But first, is there anything that we can do to boost the nutrients that we need to maintain bone health? Let’s look first at supplements.

Calcium supplementation?

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 the 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 a 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 might appear 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 minimum requirements.

The Institute of Medicine puts the recommended dietary allowance, or RDA, for vitamin D at 600 international units (IU) per day for young adults and 800 IU per day for adults older than 70. Other experts suggest that adults’ vitamin D needs are much higher. For example, the Endocrine Society recommends up to 1,500 to 2,000 IU of vitamin D daily for adults.

However, a recent study published in the New England Journal of Medicine appears to contradict the premise that vitamin D supplementation is the easy answer to countering the effects of osteoporotic fractures. In this large study, with 25,871 participants followed for a median of 5.3 years, supplemental vitamin D3, as compared with placebo, did not have a significant effect on total fractures, which occurred in 769 of 12,927 participants in the vitamin D group and in 782 of 12,944 participants in the placebo group.

Vitamin D supplementation does have a clear benefit in terms of countering inflammation – the higher the levels of vitamin D, the lower the levels of CRP (C-reactive protein, an inflammation marker). Another likely benefit was just noted in a paper in the Annals of Internal Medicine, published just a few days ago. Vitamin D supplements were shown to reduce the likelihood that a person at risk for diabetes would progress to clinical diabetes. The authors estimated that vitamin D supplements could prevent several million persons with prediabetes from becoming diabetic.

So, while we can question whether vitamin D pills are the answer to prevent osteoporotic fractures, we certainly don’t favor tossing them in the trash. By and large, they are valuable, and more evidence regarding their effect on fractures may yet emerge.

Vitamin K

We don’t hear much about vitamin K, perhaps because it’s abundantly available in leafy green vegetables, so the supplement boosters can’t point to widespread vitamin K deficiencies as something that can only be corrected through their patented supplement.

Vitamin K helps the body produce osteocalcin, which is a protein essential in bone formation. And it blocks substances that contribute to bone decay. People with vitamin K deficiencies have less bone strength and are more likely to experience fractures.

There is abundant research to back up the claim that vitamin K is highly important in bone health. In a review of 13 studies published in Annals of Internal Medicine, most of the studies showed that taking vitamin K increased bone density. In the famous Nurses’ Health Study, women who got at least 100 mcg of vitamin K were 30% less likely to experience hip fractures than women who got less, and similar results were found in the Framingham Heart Study.

Vegetables that supply enough vitamin K in a single serving to satisfy the daily requirement include spinach, Brussels sprouts, broccoli, collard greens, scallions, asparagus, and cabbage.

What about medications?

Up to this point we’ve been discussing the nutritional components that support bone health and help stave off osteoporosis. But when a disease or medical condition is mentioned, the automatic quick response is, “What medications are available for treatment?”

Bisphosphonates

The first choice for treating a patient with osteoporosis is likely to be in the bisphosphonate class. Bisphosphonates have been known since the 1800s, but a member of that class specifically targeting osteoporosis was not FDA approved until 1994. That drug was Fosamax (alendronate). When Fosamax arrived, a common reaction in the healthcare field was that the severe consequences of osteoporosis could henceforth be avoided.

What Fosamax and the other drugs in the bisphosphonate class do is inhibit the bone-reducing activity of the osteoclasts and, to a certain degree, boost the bone-building activity of the osteoblasts. Here are the current members of the bisphosphonate class:

• Alendronate (Fosamax, from Merck). Fosamax is approved to prevent and treat osteoporosis in postmenopausal women and also in men. In a large trial with more than 12,000 women, Fosamax reduced the risk of fractures of the vertebrae by 45% and of hip fractures by 40%. We need to note that the women in this study had already experienced fractures, and were probably already at higher risk. The drug increases bone mass in the hip and spine as effectively as hormone therapy. The benefits of Fosamax persist for as long as five years after the drug is discontinued. It is available in tablet form taken daily, also a weekly tablet and a weekly liquid. Fosamax can be difficult to digest, and may cause nausea, heartburn, or irritation of the esophagus.
• Ibranonate (Boniva, from Roche). Boniva was FDA approved in 2006. The bone-strengthening effects of Boniva are limited to the spine, and it has not been shown to decrease hip fractures. It is available as a monthly tablet or a quarterly intravenous injection. Boniva can be difficult to digest and may cause nausea, heartburn, or irritation of the esophagus. The intravenous injection may cause fever or flu-like symptoms.
• Risedronate (Actonel, from Procter & Gamble) was FDA approved in 1998. In a clinical trial comparing Fosamax and Actonel, both drugs reduced fracture risk by the same percentage, although Fosamax raised bone density more than Actonel. It is available as a daily, weekly, or monthly tablet. Actonel can be difficult to digest and may cause nausea, heartburn, or irritation of the esophagus. It is generally well-tolerated.
• Zoledronic acid (Reclast, from Novartis) was FDA approved in 2007. A three-year study comparing Reclast with placebo demonstrated that treatment with Reclast reduced the risk of vertebral fracture by 70% and of hip fractures by 41%. It is given by annual 15-minute intravenous infusions, or bi-annual infusions for prevention. Reclast may cause fever, flu-like symptoms, or muscle and joint aches for several days after infusion. Kidney function may be temporarily affected.

Starting a few years after the introduction of the first bisphosphonate, there was 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.

That’s almost certainly because 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 after 2015.

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.

In 2016, a task force of the American Society for Bone and Mineral Research advocated a “drug holiday” after 5 years of continuous bisphosphonate therapy. More than 80% of US physicians consider a drug holiday after long-term bisphosphonate treatment. A systematic review showed that a drug holiday of 12 months in patients with 2 years or more of previous bisphosphonate exposure might be safely executed without a subsequent increase in fractures. In contrast, bisphosphonate discontinuation of more than 3 years has been associated with an increased rate of hip fractures.

As Doc Gumshoe looks at these data points, it looks like the right schedule might be two years on bisphosphonates followed by one year off.

Selective estrogen receptor modulators (SERMs)

Another class of drugs used to treat osteoporosis are the selective estrogen receptor modulators (SERMs). Many women use estrogen to ease some of the symptoms that occur during and after menopause, when estrogen production diminishes. Up to 2002, women also used estrogen to counter bone loss and stave off osteoporosis, but the use of estrogen products for this purpose diminished greatly after a study (the Women’s Health Initiative) was published which found that women taking estrogen supplements were at higher risk of breast cancer, heart disease, stroke, and blood clots in the circulatory system. The Women’s Health Initiative has been severely criticized, mostly on procedural grounds, but by and large women have not continued to use estrogen products to prevent bone loss.

SERMs mimic some of estrogen’s benefits without leading to its negative consequences. They attach to cellular receptors in a way that fosters bone growth.

• Raloxifene (Evista, from Eli Lilly) was the first SERM approved for the prevention of osteoporosis. It got the FDA nod in 1997 for the prevention of osteoporosis in postmenopausal women, and then in 1999 for the treatment of osteoporosis in postmenopausal women. Then in 2007, the FDA approved Evista to reduce the risk of breast cancer in postmenopausal women with osteoporosis.
• Bazedoxifene is available in US as (Duavee, from Wyeth/Pfizer) in combination with estrogen. It gained FDA approval in 2013 to reduce the symptoms of menopause and to prevent, but not treat, osteoporosis in women who have not had surgery to remove the uterus. Duavee has not been demonstrated to reduce the incidence of bone fractures.

Monoclonal antibodies

There are monoclonal antibodies targeting a number of different diseases. The ones which have most recently made big news take aim (with varying results) at Alzheimer’s – remember aducanumab and lecanemab? You can spot them by their names, which end in mab, for monoclonal antibody. They are copies of human antibodies, made with genetically engineered cells. Two monoclonal antibodies have been approved for the treatment of osteoporosis.

• Denosumab (Prolia, from Amgen) got FDA approval in 2010 for treating osteoporosis in postmenopausal women at high risk of fractures. It was later approved for treating osteoporosis in men and also for treating glucocorticoid-induced osteoporosis. And it has received approvals for increasing bone mass in women who are getting certain treatments for breast cancers, and for men who are receiving androgen deprivation therapy for nonmetastatic prostate cancer. (Androgen, the male sex hormone, tends to support bone growth, but also favors the growth of prostate cancer.) Prolia is not approved for prevention of osteoporosis. Its mechanism of action is to reduce the formation and action of osteoclasts, which are the agents that remove bone material. Prolia is given by subcutaneous injections every six months.
• Romosozumab (Evenity, also from Amgen) is the most recent drug in this arena. It received FDA approval in 2019 for the treatment of osteoporosis in women who are at high risk of fracture or who cannot take any of the other approved drugs for this purpose. What it does is interrupt the messages that tell the osteoblasts (the bone builders) to stop working, so new bone growth can continue without interruption. It essentially tricks the body into building new bone. It is given once a month by subcutaneous injection.

Hormones

Using hormones for treatment of osteoporosis is controversial. One would think that, since the slowing of bone growth and the increase in bone loss are linked with the decline in hormone production that comes with menopause, hormone supplementation would be axiomatic. However, most doctors are currently reluctant to prescribe hormone treatment to combat postmenopausal symptoms including bone loss, especially since there are other drugs that achieve the same objectives without the risks that may come with hormone treatment.

• Teriparatide (Forteo, from Eli Lilly) is a synthetic version of parathyroid hormone, for the treatment – but not prevention – of osteoporosis. Forteo was FDA-approved in 2002. It is available as a once-a-day injection. It fosters the generation of new bone, but has no effect on bone loss. The Endocrine Society recommends switching from Forteo to a drug of the bisphosphonate class after two years of use. There is evidence that Forteo reduces vertebral fractures by about two thirds and other fractures by about a half.
• Abaloparatide (Tymlos, from Radius Health) works very much like Forteo, fostering the generation of new bone growth. It received FDA approval in 2017 for the treatment of osteoporosis in women at high risk for fracture, and in 2022 for the treatment of osteoporosis in men at high risk for fracture. The package insert recommends that Tymlos be used for not more than two years. It should be followed by a drug that prevents bone resorption, such as a bisphosphonate.
• Calcitonin (Fortical, from Upsher Smith Laboratories; and Miacalcin, from Novartis) inhibits bone resorption by osteoclasts. The principal source of calcitonin in medications is salmon. In 2012 the European Medicines Agency recommended that calcitonin not be used to treat osteoporosis because of increases in cancer risks, and Canada’s health agency took the calcitonin nasal spray off the market because of the overall increase in risks. In the US, the FDA’s recommendation is that calcitonin should be used only in cases where patients cannot tolerate any other osteoporosis drugs. Sales of both drugs have largely been discontinued.

What can we conclude?

In the past 30 years or so, we have gone from a condition in which osteoporosis was an inevitable part of aging, to a significant modification of that situation. Yes, osteoporosis is part of the natural aging process, but we have multiple ways of countering its harmful effects. We have a much better understanding of the factors that contribute to bone health, and we have a number of drugs that can affect the underlying and ongoing processes that determine bone health. Bone health can be boosted considerably by paying attention to what we eat every day, and a diet that contributes to bone health is not hard to follow, with an emphasis on calcium (dairy products, salmon, sardines, and many green vegetables) and vitamin D (salmon and sardines again, fortified vitamin D, and fortified milk). And let’s not forget exercise! Also, there are medications, some of which prevent bone loss – i.e., slow down the osteoclasts that are nibbling on our bones – and some of which boost bone growth – i.e., encourage the osteoblasts in building new bone.

All in all, we’re in a far better place than we were a generation ago! We can’t prevent aging, but we now can do much to modify many of the consequences of aging. There’s a great deal of research going on in this area, and I’m confident that better options are coming.

* * * * * * *

Doc Gumshoe has been silent on the subject of COVID-19 for the past little while, and, like all of us, I look forward to a time, in the not-too-distant future (I hope!) when COVID becomes just an item in medical history. But it’s still around, and there continue to be bits of news that we need to keep on top of. So, look for that in the next installment. In the meantime, many thanks for your comments (and keep’em coming!) Best to all, Michael Jorrin (aka Doc Gumshoe)

[ed note: Michael Jorrin, who I dubbed “Doc Gumshoe” many years ago, is a longtime medical writer (not a doctor) and shares his commentary with Gumshoe readers once or twice a month. He does not generally write about the investment prospects of topics he covers, but has agreed to our trading restrictions.  Past Doc Gumshoe columns are available here.]