Up to 30% of osteoporosis cases in postmenopausal women are caused by external factors like medications, rather than simply the decrease in estrogen that occurs around menopause. That’s according to a Mayo Clinic report from more than 20 years ago.
In pre-menopausal women and men, that number is up around an astonishing 50%.
Those are sobering statistics, given that Americans are some of the most medicated people in the world, and that many commonly prescribed drugs have damaging effects on bone.
Many people—and their physicians—are ignorant of the detrimental effects a lot of common medications have on bone.
In 2018 alone, Americans filled nearly six billion prescriptions, according to a Medscape review posted in 2019. More than two-thirds of those were for just two illnesses—diabetes and hypertension. According to CDC stats, about 50% of all Americans use at least one prescription drug, and doctors write prescriptions in three-quarters of all appointments.
All medications come with risks, including nausea, drowsiness, dry mouth, rashes, diarrhea, or more serious complications such as liver damage, heart attacks, and strokes. But many people—and their physicians—are ignorant of the detrimental effects a lot of common medications have on bone.
Acid blockers and some antidepressants are especially problematic, but other types of drugs can also contribute to osteopenia, osteoporosis, and increased risk of fractures.
A thorough medication review should be routine in the assessment of any patient showing signs of, or risk factors for osteoporosis.
Acid Blockers
Acid blockers, including proton pump inhibitors (PPIs) and histamine 2-receptor antagonists (H2RAs) have consistently been shown to increase risk of falls and fracture.
PPIs include esomeprazole (Nexium), omeprazole (Prilosec, “the little purple pill”), pantoprazole (Protonix), lansoprazole (Prevacid) and rabeprazole (Aciphex). The H2RAs include Famotidine (Pepcid) and cimetidine (Tagamet).
Both types of acid blockers are associated epidemiologically with increased fracture risk. In 2010, the FDA warned that PPIs increase the risk for hip, spine or radius fractures. The earliest study that looked at this issue goes all the way back to 2006, when researchers determined that people taking any type of acid blocker had increased fracture risk of up to 82%, compared to people not taking these drugs (Yang YX et al. JAMA, 2006).
There are several potential physiological mechanisms that could account for the observed correlations.
Gastric acid plays a role in facilitating the release of ionized calcium from food, so drugs that block acid may interfere with absorption of dietary calcium. Reductions in calcium absorption can trigger release of parathyroid hormone, and elevated levels of this hormone can stimulate bone resorption as a compensatory mechanism to maintain blood calcium levels. There’s also some evidence to suggest PPIs may directly impact the bone remodeling process.
FDA requires osteoporosis/fracture risk warning labels on prescription acid blockers, but not on the OTC versions. Back in 2011, the agency reasoned that because the OTC products are low-dose and marketed only for short 14-day courses, they’re unlikely to be problematic.
Not only do PPIs weaken bones, they also raise the risk of falls. A 2019 metanalysis of data from over 350,000 patients found that PPIs increased the overall risk of falls by 27%
It is true that the risk of adverse effects with PPIs and H2RAs does increase with dose and duration. Of the two types of acid-blocking medications, PPIs appear to be the most detrimental to bone. Among people using PPIs for four years, the risk of hip fracture increases by a shocking 217% compared with non-users. In this analysis, when the researchers focused only on patients with heartburn, the fracture risk from PPIs was even higher—350% greater (Yang YX et al. JAMA, 2006).
Not only do PPIs weaken bones, they also raise the risk of falls. A 2019 metanalysis of data from over 350,000 patients found that PPIs increased the overall risk of falls by 27%, and the risk of falls leading to hospitalization by 61% (Lapumnuaypol K, et al. QJM, 2019).
Vitamin B12 deficiency may be a factor in this as well. PPIs hinder absorption of B12, which is essential for healthy nervous system function, and muscle strength. B12 deficiency often shows up as numbness in the extremities, impaired balance, and muscle weakness. It does not take too much imagination to see how this might increase the risk of falling.
Long-term PPI use also depletes magnesium, which is important for muscle function. It’s also possible that the drugs could also have direct CNS effects. There’s some research to suggest that in some people PPIs can trigger dizziness, visual disturbances, and cognitive impairment, all of which would increase the risk of falling, especially among vulnerable elderly people.
Antidepressants
Approximately 11% of all US adults took prescription drugs for treatment of depression in 2023, the most recent year for which the National Center for Health Statistics has data. That’s one in nine individuals over the age of 18. And, as has been seen in many earlier surveys, there’s a marked gender disparity. More than 15% of US women took antidepressants, versus 7.4% of men.
Almost 14% of all US adults took antidepressants in 2018, and that was before the pandemic turned everyone’s world upside down.
Antidepressants may indeed be helpful for ameliorating the psychosocial impact of depression, but they can be very bad news for bone.
As with so many other things, the older people get, the greater the risk for depression. Nearly 25% of all women 60 years old and older took an antidepressant in 2018. But this is obviously not just a problem in older people. According to a 2024 study of dispensing patterns published in the journal, Pediatrics, the monthly rate of antidepressant prescriptions for teens and young adults rose 64% more rapidly during the pandemic compared to the pre-pandemic years.
Antidepressants may indeed be helpful for ameliorating the psychosocial impact of depression, but they can be very bad news for bone.
In a Canadian study that tracked patients for 10 years, researchers found that taking either an SSRI or an SNRI was associated with a 68% increase in fracture risk. Another study showed that women taking SSRIs lost bone at a rate more than 1.6 times faster than women who weren’t on these meds.
Two studies evaluated how many patients would have to take SSRIs before one of them experienced a fracture. One of these studies came to the conclusion that gender or age didn’t matter; the fracture risk was the same. Statistically, for every 42 patients taking an SSRI, one of them would be expected to break a hip, wrist or forearm.
The researchers working on the second study evaluated their data a little differently. They looked at the risk of fractures based on duration of SSRI use. They found that even taking an SSRI for just one year or less still increased fracture risk. For every 85 patients on the drugs for a year or less, one would be expected to break a bone (Khanassov V, et al. Int J Geriatr Psychiatry, 2018).
Researchers found that taking either an SSRI or an SNRI was associated with a 68% increase in fracture risk. Women taking SSRIs lost bone at a rate more than 1.6 times faster than women who weren’t on these meds.
The risk got even worse the longer people took the drugs. For every 19 patients taking an antidepressant for one to five years, one would be expected to break a bone.
These patterns are alarming, given that nearly 25 million adults have been on antidepressants for more than two years. Another 15.5 million have been on the drugs for at least five years, and many people find it extremely difficult to discontinue them.
Androgen-Deprivation Therapy
The category of androgen deprivation therapy (ADT) includes drugs such as leuprolide (Lupron, Eligard), goserelin (Zoladex), triptorelin (Trelstar) and histrelin (Vantras, Supprelin LA).
In women, ADT is used to treat polycystic ovarian syndrome (PCOS), endometriosis, uterine myomas and premenopausal breast cancer. In men, ADT drugs are used to treat prostate cancer.
In both men and women, these drugs create osteoporosis by increasing inflammation and stimulating osteoclast activity, resulting in bone resorption (Bellido T, et al. J Clin Invest. 1995; Kim TJ, et al. Cancers (Basel), 2020).
Bone loss has been detected in patients as young as 29 years old, after only three months of ADT treatment (Waibel-Treber S, et al. Hum Reprod.1989). The loss of testosterone (in men and women) also leads to muscle wasting, decreased strength, and increased risk for falls and fractures (Lee CE, et al. Curr Oncol, 2011).
According to a 2010 study by researchers at the University of Melbourne, men undergoing prostate cancer treatment typically lose about 5% of their bone mass within one year of starting ADT. An earlier study showed that 43% of prostate cancer patients developed osteoporosis after two years on ADT drugs. By 4 years, that number was up to 50%. By year 10, it was 81%.
And what about fractures? Compared with men not taking ADT drugs, those on ADT had a 21% increased risk for any type of fracture, and a 30% risk elevation for a hip fracture, according to a cohort study of nearly 4,000 men. The older the man, the greater his risk. In men 81-85 years old, there was a 42% increase, and in men over 85, there was a 48% increase compared to men in the 61-71 year age bracket. In one study of records from over 50,000 ADT-treated men, researchers reported that nearly 20% had broken a bone within five years.
Men undergoing prostate cancer treatment typically lose about 5% of their bone mass within one year of starting ADT.
None of this is news. Researchers have published studies showing these patterns and correlations for decades. But with all the myriad pressures of today’s clinical practice, it’s easy to overlook the role these drugs play in the osteoporosis equation.
Aromatase Inhibitors
Bone loss in women with breast cancer is a major concern.
Up to 80% of all breast cancer patients lose bone (Gross GJ, et al. Oncol Nurs Forum, 2002; Chen Z, et al. Cancer, 2005). And this is definitely linked to poor outcomes. According to a 2014 study of over 9,500 breast cancer patients, those who were hospitalized with a fracture had an 83% higher risk of dying compared to those who did not break a bone.
By suppressing estrogen, AIs also trigger a series of events that increase reactive oxygen species (ROS), which contribute to inflammation, cell and tissue damage, and unhealthy changes in the bone microenvironment.
Aromatase inhibitors (exemestane (Aromasin), letrozole (Femara), and anastrozole (Arimidex)) block estrogen production and are among the top-prescribed drugs for post-menopausal women with the estrogen receptor positive types of cancer. Once a woman is prescribed an AI, it’s common for her to take it for many years.
By suppressing estrogen, AIs also trigger a series of events that increase reactive oxygen species (ROS), which contribute to inflammation, cell and tissue damage, and unhealthy changes in the bone microenvironment. AI-induced estrogen deficiency not only boosts osteoclast formation, it also prolongs how long osteoclasts remain active in breaking down bones. The result is rapid bone loss and a higher risk of fractures.
After five years on an AI, one in every five patients—an alarming 20%—suffered a bone fracture (Hadji P, et al. Ann Oncol. 2011). That’s a troubling number, indeed.
All of the drugs I’ve covered here have their place. Judiciously prescribed, they can be life-changing and even life-saving. But it is very important to consider their impact on bone. Osteoporosis is not a minor concern. It can have profound—even life threatening—impact on patients’ lives. To the extent we can, it’s vital that we recognize the risks and do all we can to mitigate them.
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John Neustadt, ND, is Founder and President of the dietary supplement company Nutritional Biochemistry, Inc. (NBI, nbihealth.com) and NBI Pharmaceuticals. Dr. Neustadt started NBI in 2006 when he couldn’t find products with the doses of nutrients he needed for his patients. He received numerous US FDA Orphan Drug Designations for potentially treating rare diseases using natural products through his company, NBI Pharmaceuticals. Dr. Neustadt hosts the “Delivering Health” podcast. He is a Bone Health and Osteoporosis Foundation Corporate Advisory Roundtable member, was North American Medical Advisor to the international JCCA Maccabi Games, and was Vice President and Treasurer of the California Naturopathic Doctors Association (CNDA). Dr. Neustadt has written four books and over 100 research reviews and was recognized by Elsevier as a Top Ten Cited Author in the world for his work. His latest book is Fracture-Proof Your Bones: A Comprehensive Guide to Osteoporosis.
