The Complicated Reality of Treating Osteoporosis

Most women face the question of what to do about bone loss at some point in their lifetime. Yet decades after bone-building drugs first became available, basic questions such as who needs medication and which drug may work best remain fraught with uncertainty.

About half of U.S. women aged 50 and older have osteopenia, meaning their bones are less dense than they should be, according to a 2021 report by the U.S. Centers for Disease Control and Prevention (CDC). Another 20% have outright osteoporosis, a disease marked by fragile, weakened bones that leave people vulnerable to debilitating and even deadly fractures of the hip and spine. That’s a total of 46 million. What’s more, researchers found that between 2008 and 2018, the prevalence of osteoporosis in 50-and-older women rose by 40%.

Osteoporosis is far more common in women, who generally have smaller, lighter bones than men and experience rapid bone loss at menopause. Only 4.4% of men aged 50 and older have osteoporosis — a percentage that held fairly steady over the decade covered by the CDC report. 

Still, dangerously weakened bone is one of the most neglected conditions of aging, according to Sundeep Khosla, M.D., an endocrinologist at the Mayo Clinic in Rochester, Minn., who studies age-related bone loss. “It’s a disease that people don’t think enough about for a variety of reasons, in part, because it doesn’t happen until later in life.”

On one point, experts agree: Treatment with bone-building drugs can clearly prevent fractures in those with osteoporosis. However, when it comes to other key issues, such as which drug to use and whether the benefits of medications outweigh the risks for those with milder bone loss, recommendations conflict. 

Guidelines for screening and intervention developed by major medical organizations vary, and studies show an imbalance in treatment: many patients who could benefit go untreated, while others at low risk are prescribed drugs that may do more harm than good.

To further complicate matters, patients and physicians deciding on a medication face less-than-ideal choices that can have lifelong consequences. Once started, for example, some drugs can’t be stopped without triggering accelerated bone loss. Meanwhile, the newest, most effective medications — typically only prescribed for a couple of years — are off limits to all but those with the most severe disease, mostly due to their high cost. The Catch-22 is that those high-dollar treatments don’t work as well if you’ve already used one of the cheaper drugs, says endocrinologist and osteoporosis researcher Susan Ott, M.D., Professor Emeritus of Medicine and Metabolism, Endocrinology and Nutrition at the University of Washington. 

“It’s very frustrating,” says Dr. Ott. “The cost is driving what we do, not what would be best for the patient.”

“The cost is driving what we do, not what would be best for the patient.”

Even though uncertainties remain, the good news is that healthcare providers are better equipped than ever to detect and treat bone loss. To help you navigate the sometimes confusing and conflicting world of bone health, we interrogated experts about how to keep bones strong and what to consider when deciding whether a bone-building medication is right for you.

The Living Skeleton

It’s easy to think of your bones as inert, like a skeleton hanging in a biology classroom. But the bones inside your body are living tissue undergoing constant change. Specialized cells, called osteoclasts, remove old or damaged bone cells, releasing calcium and phosphorus into the blood, while other cells, called osteoblasts, lay down new healthy tissue. This so-called remodeling process helps keep bones strong by repairing microscopic damage from everyday activities and helps maintain healthy levels of minerals in the bloodstream.

Children and teens form bone faster than they lose it, and by their 20s, reach peak bone mass — when a human’s internal framework is strongest and most dense. By age 40, the balance shifts, and people start to lose more bone than they replace. 

That balance is heavily influenced by the sex hormones estrogen and testosterone. For women, the sharp drop of estrogen at menopause leads to the loss of up to 15% of the hard, outer cortical bone and up to 20% of the spongy, inner trabecular bone over the next decade. After that, bone loss continues, but at a slower rate.

In men, testosterone levels typically decline more gradually with age — one of the main reasons most men don’t face a significant bone loss until their 70s.

Are You Destined for Boss Loss?

How much bone you make — and keep — isn’t all up to hormones, though. Nutrition is key: Throughout life, getting adequate amounts of calcium, vitamin D, and protein is essential. Other nutrients that play a role in bone health include magnesium as well as vitamins A, C, and K. Lifestyle matters, too. Exercises like stepping, jumping, lifting, and pushing that exert force on bone tissue stimulate bone tissue to grow thicker and denser. By contrast, nicotine from cigarettes and excessive alcohol consumption both disrupt the body’s ability to build and maintain bone.

Numerous other factors increase the risk of weaker bones or fractures, including: 

• A close relative with osteoporosis
• Being White (overall, Asian, Black, and non-White Hispanic populations have lower fracture risks, although some of the evidence for ethnicity differences is three to four decades old)
• A small frame or being underweight
• Certain medical conditions: autoimmune disorders such as rheumatoid arthritis and lupus; gastrointestinal disorders such as celiac disease or inflammatory bowel disease; endocrine disorders such as diabetes, hyperthyroidism, and hyperparathyroidism; certain cancers and blood disorders such as multiple myeloma, and sickle cell disease; and neurological disorders that reduce mobility, such as stroke or Parkinson’s disease
• Medications associated with bone loss, such as steroids, anti-seizure drugs, blood thinners, diuretics, as well as certain antidepressants and drugs to reduce stomach acid

How We Got Here: A Brief History of Osteoporosis Treatment

Despite advances in therapy, older medications continue to dominate bone-loss treatment, while newer, costlier drugs remain inaccessible for many patients. And there are still uncertainties over who should be screened and treated for the condition. 

To understand how we got to this point, it helps to take a brief foray into the history of osteoporosis treatment.

The Rise and Fall of Hormone Therapy

A century ago, doctors recognized osteoporosis as a medical condition, but with no available treatments, it was widely chalked up to an inevitable consequence of aging. Then, in the 1940s, researchers made the crucial connection between the drop in estrogen levels at menopause and bone loss. Over the subsequent decades, hormone replacement therapy (HRT) — now more commonly referred to as simply hormone therapy (HT) — would become increasingly popular not just for treating menopausal symptoms, but also for preventing and treating osteoporosis. 

By the late 1990s, more than one in four postmenopausal women in America was on HT. Two decades later, that number had plummeted to one in 20. The trend reversed virtually overnight in the summer of 2002 with the publication of results from the large Women’s Health Initiative study linking HT to an increased risk of breast cancer as well as heart disease, blood clots, and stroke. 

Time and further study eased concerns by adding necessary context to those findings. Still, it remains an underused medication in younger postmenopausal women, says Dr. Ott. 

As hormone therapy was falling out of favor, attention shifted to another fast-rising osteoporosis treatment.

Bisphosphonates and Fosamax Take Over

In the late 1960s, researchers first discovered that a category of drug called bisphosphonates could affect bone metabolism. Over the next two decades, doctors began prescribing the medications off-label for bone loss, even though the U.S. Food and Drug Administration (FDA) hadn’t approved them for that specific purpose. Then, in 1995, alendronate (Fosamax) became the first bisphosphonate to win FDA approval for treating osteoporosis after studies showed that the drug could increase bone density and prevent spine and hip fractures.

With heavy promotion by its manufacturer Merck, Fosamax spawned a revolution in the diagnosis and treatment of bone loss. At the time, bone density-measuring machines were not widely available outside academic centers, but the new drug prompted the development of cheaper scanners. Merck then lobbied doctors to install the scanners in their offices and Medicare to pay for the tests. 

Before the early 1990s, osteopenia was not even an official diagnosis. But by the early 2000s, women were being diagnosed and treated for low bone mass — even if they didn’t have full-blown osteoporosis — in droves.

The hormone therapy scare of the early 2000s proved to be a huge boon for bisphosphonates. In 2007, nearly six million Americans, almost all of them women, were taking an oral bisphosphonate, according to an analysis of osteoporosis prescribing trends between 2002 and 2012. While most patients took the drugs to treat osteoporosis, starting in 2005, nearly 20% of the prescriptions were for osteopenia.

By that point, the FDA had approved three other bisphosphonates — risendronate (Actonel), ibandronate (Boniva), and zoledronic acid (Reclast) — as well as a different type of bone drug, teriparatide (Forteo). 

Still, Fosamax remained the market leader.

Merck positioned Fosamax as a safer alternative to estrogen, says Dr. Ott, summarizing the company’s reassuring promotions: “Take this wonderful non-hormonal drug that will help prevent bone fractures.” But, she adds, younger postmenopausal women with mild bone loss aren’t at risk of breaking their hip or spine: “When you’re in your 50s, you don’t have that many fractures anyway.”

Declining Sales and Lawsuits 

By 2009, sales of bisphosphonates had begun to decline as word got out that bisphosphonates caused rare but serious side effects, particularly in patients taking them for more than five years. Those adverse effects include atypical fractures in the femur (thigh bone) — the body’s strongest bone — that happen without a fall or other trauma and osteonecrosis of the jaw (ONJ), a disease that kills jawbone cells. 

Over the last two decades, disputes over whether drug companies sufficiently warned patients about the serious risks of bisphosphonates have spawned thousands of lawsuits with mixed results. In 2013, Merck paid more than $27 million to settle around 1,200 ONJ claims out of court. However, of the seven ONJ cases that went to trial, the company won five. More recently, a ruling by the U.S. Court of Appeals for the Third Circuit reinstated more than 500 femur-fracture cases that had been dismissed, and that litigation is ongoing.

Between 2007-2008 and 2017-2018, the percentage of postmenopausal women using bone drugs dropped from about 11% to 5%, mostly due to the decline in the use of bisphosphonates, according to an analysis of data from the National Health and Nutrition Examination Survey, which collects health and nutrition information from a representative sample of the U.S. population.

However, the legacy of the bisphosphonate boom is a greater reluctance to use any bone drug — sometimes warranted and, in other cases, not. 

“The decline in use of bisphosphonates is likely, in part, due to fear among women with osteoporosis regarding the risk of rare, but serious harms,” says Kristine Ensrud, M.D., M.P.H, an epidemiologist at the University of Minnesota with expertise in aging. In addition, fewer younger postmenopausal women with mild bone loss are taking the drugs. That’s “a good thing,” says Dr. Ensrud, as research shows that, compared to patients with osteoporosis, those with osteopenia benefit less from drug treatment and could face greater risks if they wind up taking them longer term. 

But the overall downturn is not without consequences. “Today, the biggest issue is the undertreatment of men and women at high risk of fractures,” says Dr. Khosla. People who’ve suffered serious breaks due to weakened bones should typically be treated with medications to prevent subsequent fractures, he points out. Yet, a 2023 analysis of health records from a large database spanning 2011 to 2019 found that fewer than 10% of patients aged 65 and older received such medications within a year of suffering a fragility fracture. “Even if we just got that fixed,” says Dr. Khosla, “that would be a huge win.”

The Gray Area of Osteoporosis Screening Before Age 65

Generally, most major medical groups agree that women aged 65 and older, as well as men and younger women who are at risk for osteoporosis or fractures, should have their bone density checked. Due to a lack of evidence on the pros and cons of screening men, guidelines vary; some advise testing the bone density of men older than 70, while others make no specific recommendations. MedShadow’s experts say that it’s reasonable to screen men with factors that put them at higher risk for fractures.

A quick, painless test called a DEXA (also referred to as a DXA) scan uses low-dose X-rays to measure bone density, usually in the spine and hip. Insurance typically covers DEXA scans for screening the groups listed above, as well as for monitoring those undergoing treatment with bone drugs.

Things get a little muddier around the question of testing postmenopausal women younger than 65, says Ensrud. In guidelines published last January, the U.S. Preventive Services Task Force, a panel of experts that makes evidence-based recommendations for preventive care, recommends a two-step process: first, identify women at higher risk (those who smoke or have a parent who broke a hip, for example), then use one of several simple assessment tools.

Two of those tools — the Osteoporosis Self-Assessment Tool, which calculates risk based on sex, age, and weight, and the Osteoporosis Risk Assessment Instrument, which is specifically designed for women and factors in estrogen use — perform fairly well in identifying osteoporosis risk in younger postmenopausal women, says Dr. Ensrud. 

The decision over when to screen women for low bone density should also take into account their age at menopause, says Mikhail Kogan, M.D., Chief Medical Officer of the GW Center for Integrative Medicine. Dr. Kogan considers screening women patients five to 10 years into menopause and male patients in their early seventies, especially if they have risk factors for osteoporosis. But he also recommends bone density testing for younger people who have a medical condition or take a medication that could weaken bones.

It’s also reasonable for a younger postmenopausal woman considering HT to get her bone density checked, as low bone mass could tip the balance in favor of therapy, says Dr. Ott. “That gives you one more important piece of information about whether to take estrogen.”

While guidelines such as the ones outlined above are good prevention steps, they shouldn’t be interpreted as hard-and-fast rules, says Dr. Kogan. “You have to take them with a grain of salt and this idea of individualization,” he notes. “Because otherwise you may be missing things.”

How to Make Sense of Your Bone Density Results

The USPSTF advises using DEXA scans to assess osteoporosis risk as the test measures bone density in the areas of most concern — the hip and spine.

Some health fairs, pharmacies, shopping centers, and even doctors’ offices offer something called a “peripheral” DEXA scan that measures bone density in the fingers, wrist, forearm, or foot. While a peripheral scan makes sense in certain circumstances — when someone has unexplained wrist fractures or can’t comfortably lie down for a hip-and-spine scan — Dr.  Khosla says that he generally prefers the regular DEXA. “Where we have the most data in terms of predicting fracture risk is with the spine and hip bone density.”

Results from DEXA scans are typically expressed as a T-score, which compares measured bone density to that of a healthy young adult. Zero indicates a bone density on par with a twentysomething; anything less is reflected with a negative number. T-scores are grouped into the following categories:

• Normal: 0 to -1
• Osteopenia (low bone mass): Between -1 and -2.5   
• Osteoporosis: -2.5 or below.

Fracture risk rises exponentially with each point below zero. Compared to a T-score of zero, a score of -1 represents roughly twice the fracture risk (although still exceeding low); a score of -2, four times the risk; -3, eight times the risk; and so on. The cutoff for osteoporosis is set at -2.5 as the risk of fracture accelerates significantly at that point. 

Conversely, the risk of breaking a bone decreases sharply as you move up the scale. So, for people with very low bone density, even small improvements make a big difference in reducing the risk of serious fractures. 

However, even though DEXA scans are considered the gold standard for measuring bone density, they are still an imprecise way to predict who will break a bone. Research suggests that more than half of serious fractures occur in people whose T-scores are not low enough to qualify as osteoporosis.

To better assess risk, researchers have developed tools that capture additional factors. The most widely used of these is the Fracture Risk Assessment Tool (FRAX), which calculates the probability of someone suffering a fracture in the next ten years. The tool provides two estimates: the risk of hip fracture and the risk of any major osteoporotic fracture — a break due to weak bone, most commonly in the hip, spine, forearm, or shoulder. FRAX incorporates the DEXA scan T-score from a part of the hip known as the femoral neck, as well as 11 other factors associated with fracture risk, such as age, sex, smoking status, and medical history. 

The tool is particularly useful for identifying patients with osteopenia who are at higher risk of fractures and may warrant drug treatment according to guidelines from the Bone Health and Osteoporosis Foundation (BHOF) and the American Association of Clinical Endocrinologists (AACE). Both groups advise considering medication for patients with 20% or higher risk of major osteoporotic fracture, or a 3% or higher risk of hip fracture, in the next 10 years. 

While helpful, FRAX is by no means perfect. It doesn’t include spine bone density, for example, allows only “yes” or “no” answers to steroid and alcohol use, and doesn’t incorporate other medical conditions associated with increased risk. Still, research shows that FRAX plus bone density provides a better estimate of risk than bone density alone.

“The sweet spot for FRAX is for people aged 65 to 80,” says Dr. Ensrud. Unfortunately, she notes, seven out of 10 fractures occur in people aged 80 and older, and the tool is less accurate in that age group. 

FRAXplus and TBS: Newer Tests for Bone Health

In 2023, researchers at the University of Sheffield in the United Kingdom released FRAXplus, which aims to improve the precision of FRAX by adjusting for additional factors such as bone density in the spine, falls in the past year, type 2 diabetes, prior fractures, and the recency of a fracture due to osteoporosis. (Users have to choose one additional factor as, according to the tool’s creators, there’s no evidence to support the accuracy of multiple adjustments.)

However, the tool’s developers note that FRAXPlus is still being refined and could be modified as more data becomes available. And while FRAX is widely incorporated into bone density results provided to clinicians, FRAXPlus is not and requires a costly subscription or license, says Dr. Ensrud. Providers also use clinical judgement to account for factors such as a patient’s fall history, she says, and there’s currently no evidence that using the newer tool leads to better outcomes for patients. Overall, while FRAXPlus may eventually replace FRAX, for now, the newer test lacks the real-world validation of the older version.

The challenge in predicting whether a bone is likely to break is that strength depends not only on bone density but also on factors such as the bone’s size, shape, internal structure, and the rate at which it’s being broken down and replaced — all of which roll up to a clinical assessment of someone’s overall bone quality. However, says Dr. Khosla, it’s difficult to evaluate bone health at the microscopic level without performing an invasive bone biopsy or using high-tech imaging equipment that is not widely available outside of research centers.

One of the factors that can be incorporated into FRAXPlus is the trabecular bone score (TBS), an inexpensive tool that shows promise for assessing bone health. The TBS analyzes DEXA images to determine the quality of spongy-looking tissue inside the bones of the spine. 

Like FRAX tools, the TBS is not a good standalone test for osteoporosis, but is intended to help predict the risk of fractures. Adjusting FRAX for TBS improves the accuracy of fracture prediction according to a 2023 review of evidence by the International Osteoporosis Foundation and the European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO). The authors concluded that the TBS could be most useful for helping guide treatment in borderline cases — patients with bone density scores on the edge of osteopenia and osteoporosis, for example. 

For Dr. Khosla, the TBS is just one more piece of evidence to consider in clinical decision-making. However, Dr. Ensrud is cautious, pointing out that as with FRAXPlus, hard evidence is lacking that incorporating TBS measurements into treatment decisions actually results in fewer broken bones.

When to Consider a Bone-Building Drug

The decision over when to treat bone loss with medication and what drug to choose is another area where guidelines differ, and where a patient’s medical history and preferences should help guide decision-making.

When Drug Therapy Is Clearly Recommended

Experts largely agree that in people with osteoporosis — as defined by a T-score of -2.5 or less, or a history of osteoporotic fracture, especially of the hip or spine — drug therapy is worthwhile because research shows that it significantly reduces the incidence of broken bones.

However, the guidelines are less clear-cut for those with osteopenia. That’s because there’s sparse evidence on the effectiveness of medication for treating osteopenia in postmenopausal women, and none at all for men.

The Uncertainty Around Treating Osteopenia

In its 2023 guidelines, the American College of Physicians (ACP) advises taking an individualized approach to treating women aged 65 and older with osteopenia. Meanwhile, 2020 guidelines from the American Association of Clinical Endocrinologists (AACE) strongly recommend medication for postmenopausal women of any age who have osteopenia and whose FRAX results indicate that they have a 3% risk of a hip fracture or 20% risk of another major osteoporotic fracture in the next decade.

However, like other clinicians, Dr. Ensrud is reluctant to start medications in someone without osteoporosis. Especially for younger women, the balance of benefits versus harms for taking a drug long-term, possibly even for the rest of their life, is unknown, she notes. “That’s why, with osteopenia or with a younger postmenopausal woman, I really stress prevention.”

“That’s why, with osteopenia or with a younger postmenopausal woman, I really stress prevention.”

Dr. Kogan is similarly conservative when it comes to drugs. FRAX predicts fracture risk over 10 years, he points out, but as risk increases with age, it’s lower at the beginning of that decade. So, someone whose FRAX score indicates a 3% risk of hip fracture actually has a very small chance of suffering such an incident over the next couple of years, he says.

“We try to assess the drivers,” explains Dr. Kogan. For example, chronic inflammation, where your body continues to send inflammatory signals even when there’s no threat, can damage healthy cells and is an underappreciated source of bone loss, he says. He works with patients to treat inflammatory conditions such as heart disease, diabetes, autoimmune conditions, and obesity, as well as address contributing lifestyle factors such as smoking, heavy drinking, and stress. 

For women with osteopenia, there’s typically time to first try non-drug measures, including exercise and supplements such as calcium and vitamin D. “I don’t rush people,” says Dr. Kogan. “There’s very solid data that drugs are not the only approach.”

If You Decide on Medication, Which Drug Is Right for You?

Medications for osteoporosis fall into two broad categories: antiresorptive agents that slow the breakdown of bone, and a newer category of drugs called anabolic agents that stimulate the body to build new bone. 

Both categories contain several drug options, and deciding which one makes sense for you should be based on several factors — the severity of your disease, other health conditions that rule out certain drugs, whether you prefer pills or periodic injections, and, unavoidably, cost.

Before you decide on a medication, it’s extremely important to talk to your provider about all your options and the long-term ramifications of each. For example, denosumab (Prolia) should be considered a lifelong drug because once you stop, bone loss actually accelerates. In addition, antiresorptive drugs, including bisphosphonates and denosumab, suppress the remodeling process that anabolic drugs rely on to lay down new bone. So, once you’ve used an antiresorptive medication, the newer anabolic drugs won’t work as well. 

It’s also important to check your health insurance, as expensive options often aren’t covered as first-line treatment. When considering cost, factor in the total price of treatment, including how much you’ll pay for the drug, any associated costs if it’s administered in a medical office, and how long your doctor expects treatment to last. In the end, the cost of a pricey intravenous drug administered annually for three years may be comparable to a five-year course of treatment with an oral medication.

Here’s a breakdown of available osteoporosis drugs.

Antiresorptive Agents to Slow Bone Loss 

The two types of medications in this category, bisphosphonates and denosumab (Prolia), work by inhibiting the processes that break down bone.

Bisphosphonates

The oldest and most well-studied of the bone drugs, bisphosphonates are recommended by major medical guidelines as first-line treatment for most people with osteoporosis, primarily because of their aforementioned track record and affordability. Unless you are at very high risk of fractures, or there’s a medical reason that you can’t take a bisphosphonate, many health insurance plans require you to try one of these drugs first. 

Research shows that bisphosphonates do offer some protection against broken bones. In general, treating postmenopausal women with bisphosphonates for three to four years reduces the risk of fractures of the hip by 36% and those of the spine by 62%, according to a comprehensive review by the American College of Physicians (ACP), the national organization for internal medicine doctors, published in 2023. Or, another way to state that benefit: Of 1,000 postmenopausal women with osteoporosis, those treated with drug therapy will suffer six fewer hip fractures and 18 fewer spinal fractures. 

One of the four bisphosphonates listed below, ibandronate, reduces the risk of spinal, but not hip, fractures. Of the remaining three drugs, there’s no clear winner when it comes to fracture prevention, although very few trials have compared the medications head-to-head.

Bisphosphonates bind tightly to minerals in the bone and linger for years. That means that the drugs continue to provide fracture protection even after patients stop taking them. In one pivotal trial, individuals who stopped alendronate (Fosamax) after five years had slightly more spine fractures than those who continued for 10, but similar rates of other fractures. Similarly, research shows that three years of treatment with zolendronic acid provides at least three additional years of benefit; risedronate provides at least a year of residual protection against bone breaks.

Side Effects

Oral bisphosphonates can cause GI problems such as heartburn, irritation of the esophagus, abdominal pain, diarrhea, constipation, or ulcers, and these are the most common reasons patients stop taking the drugs. To minimize those effects, providers typically recommend taking the drugs with a full glass of water on an empty stomach and remaining upright (not lying down) for 30 minutes afterward. 

Other rare side effects include bone, joint, or muscle pain, reported in fewer than 5% of people taking the drugs. Fewer than 1% report irritation or inflammation in the eyes. 

Up to 30% of patients receiving zoledronic acid experience flu-like symptoms, fevers, headaches, or muscle or joint pain within one to three days of their first infusion. Those side effects typically recede within a few days and lessen with subsequent doses.

Antiresorptive drugs, including bisphosphonates and denosumab (Prolia), covered below, work by inhibiting bone remodeling, which not only slows bone loss, but also bone formation and repair. Over the long term, bones can develop cracks and defects that, in rare cases, can lead to serious effects, including the atypical femur fractures (AFF) and osteonecrosis of the jaw (ONJ) that were subjects of lawsuits against the drug manufacturers in the 2010s. 

Dr. Ott compares bones to a pillar on a bridge: “Sometimes the bridge just crumbles because no one has bothered to do any maintenance and repair.”

While the risk of AFF or ONJ remains rare, it increases the longer people take an antiresorptive drug. A 10-year study of nearly 200,000 women aged 50 and older who took a bisphosphonate published in the New England Journal of Medicine demonstrates that trend. Fewer than one in 10,000 patients taking a bisphosphonate for less than three years suffered an atypical femur fracture. After three to five years, the rate of AFF rose to 2.5 cases for every 10,000 patients; after five to eight years, about 6 in 10,000; and after eight years, about 13 in 10,000.

But for perspective, the drugs are far more likely to prevent than cause a fracture. Among women treated with bisphosphonates for three to five years, for each AFF caused by the drugs, approximately 135 hip fractures will be prevented, according to a comprehensive 2018 analysis in the journal Endocrine Reviews.

The incidence of ONJ in people taking bisphosphonates for osteoporosis ranges from fewer than 1 to 10 cases per year for every 10,000 patients. (With very rare side effects, it can be difficult to pinpoint an exact number as even the largest studies only detect a few cases.) Studies suggest that zoledronic acid, the most potent bisphosphonate, carries a slightly higher risk of causing ONJ than other drugs in the class. For example, zoledronic acid was twice as likely to cause ONJ as alendronate in a 2023 French study that analyzed 10 years’ worth of data from 5.3 million osteoporosis patients. Still, the side effect remained extremely rare, affecting only 1 in 10,000 of those receiving zoledronic acid.

That study also found more than 40% of the patients who developed ONJ had an invasive dental procedure, such as getting a tooth pulled, within the previous six months. Because such treatments increase the risk of ONJ, people taking an antiresorptive drug should discuss with their doctor whether to pause the medication before dental surgery.

Minimizing Rare Side Effects

To minimize the risks of rare adverse events, experts recommend taking the drugs for only a few years. In its 2023 guidelines, the American College of Obstetricians and Gynecologists (ACOG) advises stopping oral bisphosphonates after five years and zoledronic acid after three years in patients who aren’t at very high risk of fractures. For high-risk patients, the group recommends up to 10 years of treatment with oral bisphosphonates and up to six years with zoledronic acid. In that case, the serious risk of breaks in the hip or spine outweighs the small risk of fractures due to side effects of the drug.

Unfortunately, there’s not great evidence on who would benefit most from resuming therapy or the optimal length of a drug holiday. Based on expert opinion, the ACOG guidelines say that patients can consider restarting therapy after two to four years if fracture risk increases.

Monthly costs for bisphosphonates can vary depending on your health insurance plan. Given this variability, it’s worth checking with your insurer before making a decision.

Names of Bisphosphonates

• Alendronate (Fosamax and generic) is available as pills, a liquid, and as two name-brand-only products, a dissolvable tablet called Binosto and a combination tablet with vitamin D called Fosamax Plus D. (It’s far cheaper to just take the generic and a vitamin D supplement.)  Clinicians typically recommend the once-a-week over daily dosing as it works as well and is better tolerated.

• Ibandronate (Boniva and generic) is available as a monthly pill or an injection, given every three months. The experts interviewed for this article typically don’t recommend this drug because research shows that it reduces fractures of the spine, but not the hip.

• Risedronate (Actonel, Atelvia, and generic) is available as pills taken once daily, two consecutive days monthly, or once monthly. Also available in a weekly delayed-release formulation that can be taken with food and that is less likely to cause gastrointestinal side effects.

• Zoledronic acid (Reclast and generic)is administered as an annual intravenous infusion, typically for three years. The most potent drug in this class, zoledronic acid can be more expensive than oral options due to the added cost of IV administration, and may not be covered by insurance unless you cannot tolerate or did not get results with an oral medication. If insurance covers it or you can afford to self pay, our experts note that the zoledronic can be a great option for patients who find it hard to comply with the dosing schedule of oral drugs, particularly older patients who are already having to manage multiple medications. 

Denosumab (Prolia)

Denosumab, administered as a twice-yearly injection to treat osteoporosis, is a human monoclonal antibody, a laboratory-made compound that mimics proteins in the immune system. It works by blocking specific pathways responsible for breaking down bone. (Another form of the drug, Xgeva, is administered more frequently in higher doses for treating patients whose cancer has spread to the bone.) 

At about $1,900 per dose plus costs of administering the injection, Prolia is expensive — one reason why health plans may not cover it as first-line treatment. In the last two years, the FDA has approved so-called biosimilar versions of Prolia that are generally cheaper. (Unlike with generics, drugmakers can’t produce an exact copy of the active ingredients in biologics, which are produced using living cells. Instead, they formulate highly similar versions that are not identical at the molecular level, but work the same.) 

While some studies find that Prolia increases bone density more than bisphosphonates, those gains don’t necessarily translate to fewer broken bones. In fact, a 2023 analysis of seven clinical trials that randomized 4,635 postmenopausal women with osteoporosis to either denosumab or a bisphosphonate found that the drugs worked equally well to reduce fractures.

However, unlike with bisphosphonates, large population studies run by independent researchers have not explored how well Prolia works, or how safe it is, when taken long-term.

Side Effects 

Prolia does not cause the GI side effects of bisphosphonates, but it has one major downside: It does not accumulate in bone, so if you stop taking it, bone loss accelerates. Studies show that people who stop taking denosumab lose all their bone density gains within a year or two and also face a higher risk of spinal fractures. Because of that risk, denosumab is typically considered a lifelong drug. 

However, some patients may have reason to quit: If the drug isn’t continuing to provide any benefit, for example, insurance coverage changes, or they develop adverse effects. Although Prolia is generally well-tolerated, it can occasionally cause side effects such as joint or muscle pain, skin problems such as eczema or rashes, or infections due to lowered immunity. 

And while all antiresorptive drugs interfere with bone remodeling, which in turn can reduce calcium levels in the blood, the risk of low calcium is greatest with Prolia. Because advanced kidney disease also impairs calcium regulation, the FDA issued a black box warning that the drug could cause severely low calcium in those patients. 

In addition, as with all antiresorptive drugs, Prolia carries the rare but serious risks of atypical femur fractures (AFF) and osteonecrosis of the jaw (ONJ). Results from a study sponsored by the drug’s maker, Amgen, that followed postmenopausal women with osteoporosis who chose to stay on Prolia for seven years after completing a three-year randomized trial are somewhat reassuring. Among the 1,343 women who completed 10 years of treatment, the rate of serious side effects remained low, with only seven patients developing ONJ, and one experiencing an atypical thigh bone fracture. Beyond that, there simply isn’t good safety data.

For those who need to stop Prolia, ACOG guidelines state that it’s required to start a bisphosphonate after discontinuation to avoid loss of bone density. However, there isn’t great evidence to support that strategy. A few small studies suggest that switching to intravenous zoledronic acid or oral alendronate (bisphosphonates) can help maintain bone or at least diminish bone loss. In a 2020 position statement, the European Calcified Tissue Society, the main European medical organization focused on bones and the musculoskeletal system, recommends that people who discontinue Prolia after taking the drug for 2.5 years or longer, or who have a persistently high risk of fractures, switch to zoledronic acid.

Despite those caveats, many medical guidelines recommend Prolia as a first or second-line treatment. Dr. Kogan says that it’s his “preferred drug,” because of the convenience of twice-yearly injections and lack of GI side effects. Since most of his osteoporosis patients are in their mid-70s or older, Dr. Kogan says he considers the potential long-term risks less consequential.

However, other experts are more cautious. In a recent commentary in JAMA Internal Medicine advising primary care physicians on the use of denosumab, Dr. Ensrud and colleagues write: “Since long-term efficacy and safety of denosumab are uncertain and there is an increased risk of rebound fractures after discontinuation, bisphosphonates are clearly the preferred initial treatment for fracture prevention in primary care settings.” 

Dr. Ott says she worries that serious adverse effects may become more common with long-term use of Prolia. “They’re recommending using a drug that you can’t stop without having any data on how long it’s safe,” she says. “I find that terrifying.” 

“They’re recommending using a drug that you can’t stop without having any data on how long it’s safe. I find that terrifying.” 

While all antiresorptive drugs inhibit bone remodeling, Prolia suppresses the creation of new bone more strongly than bisphosphonates. As bone health relies on replacing old, damaged bone with new tissue, Dr. Ott and others worry that slowing or stopping that process for too long could leave bones prone to atypical fractures. 

In essence, the bones become inert, says Dr. Ott. “So how long can that be good for you?” she questions. “This is messing with a natural physiologic process.”

Anabolic Drugs: the Bone Builders

The first anabolic drug for treating osteoporosis, teriparatide (Forteo), introduced in 2002, was a game changer because it actually stimulates the formation of new bone. Given as daily self-injections or monthly shots in a doctor’s office, anabolic drugs are less convenient than many other osteoporosis medications, but patients typically need them for only a year or two. After that window, the bone-building effect plateaus, and patients usually transition to a bisphosphonate for several years to maintain their gains.

Anabolics are generally more effective than drugs that only slow bone loss. Studies show that compared to osteoporosis patients taking bisphosphonates, those taking an anabolic drug realize greater gains in bone density and suffer fewer fractures.

So, why do guidelines recommend antiresorptive drugs, in particular bisphosphonates, over anabolics as a first-line treatment for most patients? One reason is convenience. Some patients prefer a weekly pill to injecting themselves every day or traveling to the doctor’s office monthly for a shot. And bisphosphonates are backed by decades of evidence on safety and efficacy, while there’s far less long-term data on anabolic drugs. 

However, the main reason anabolics aren’t more widely recommended is likely their high cost. The brand-name drugs list for $2,600 to $4,500 monthly. (Manufacturers offer cost savings to those with commercial health insurance plans, but not to people on government health plans such as Medicare or Medicaid.) 

Of the three anabolic drugs, only teriparatide is available as a generic, and even that costs about $1,200 monthly. In part, because of that high cost, most guidelines only recommend anabolic drugs for two categories of patients: those who couldn’t tolerate or didn’t respond to antiresorptive drugs and those at very high risk for fractures, including people who’ve suffered a fragility fracture or who have extremely low bone density (a T-score of -3.5 or lower). Insurance typically won’t cover an anabolic drug unless you’re in one of these groups. 

However, there’s a caveat, says Dr. Ensrud. Research shows that bone builders don’t work as well to increase bone density in people who have already taken a bisphosphonate or Prolia, she says. “But whether prior antiresorptive treatment reduces the efficacy of anabolic therapy in reducing the risk of fractures is unknown.”

If cost and insurance coverage weren’t an issue, Dr. Ott would recommend that most patients with osteoporosis use an anabolic agent to build bone for a year or two, then continue with a bisphosphonate to maintain that progress. “Because we’re limited by price right now, we’re reserving [anabolics] for the ones who have the most severe disease,” notes Dr. Ott, who says she finds the situation “infuriating.” “If you could afford it, wouldn’t you want to have the drug that worked the best?”

If you want to consider an anabolic drug, it’s a good idea to consult with a physician who specializes in treating bone disease, says Dr. Khosla. [See the box “Who to See for Treating Bone Loss.”]

Side Effects

Anabolic drugs are generally well-tolerated, most commonly causing mild side effects such as nausea, dizziness, headache, leg cramps, and high blood calcium levels. Because the initial dose of abaloparatide or teriparatide can sometimes causes a short-term drop in blood pressure, patients should administer the first dose where they can lie down if necessary.

Romosozumab, but not teriparatide or abaloparatide, is associated with rare cases of jaw osteonecrosis and atypical femur fractures. In addition, romosozumab may slightly increase the risk of heart attack or stroke. 

Both abaloparatide and teriparatide once carried a black box warning that, based on studies in mice, using the drugs for more than two years could increase the risk of bone cancer. But when that risk didn’t materialize in humans, the FDA removed the warnings. However, Dr. Ensrud notes that treatment is typically limited to two years or less anyway, as the drugs’ ability to form bone wanes after 18 to 21 months. 

For patients who remain at high risk of fractures after a course of an anabolic drug followed by a bisphosphonate, clinicians may consider trying another cycle of the drugs, says Dr. Ensrud. But currently, there’s just not good data on the long-term safety and effectiveness of that approach.

The anabolic class of medications includes three drugs:

• Abaloparatide (Tymlos) $3,000/month. Administered through daily self-injections with a prefilled autoinjector, abaloparatide is FDA-approved for use for up to two years. Studies show that abaloparatide is less likely to cause high blood calcium and increases bone density faster than teriparatide. But the two drugs work equally well in preventing fractures.
  
• Romosozumab (Evenity) $2,600/month. Administered in two injections given once a month at the doctor’s officefor a year. Unlike the other drugs in this category, romosozumab is a monoclonal antibody that both decreases bone loss and builds new bone, although there’s no good evidence that any anabolic prevents fractures better than the others. Because some studies have shown a slightly higher risk of cardiovascular events in people taking romosozumab, the drug carries an FDA black box warning recommending against its use in people who’ve had a heart attack or stroke in the last year. 

• Teriparatide (Bonsity, Forteo, and generic) $2,670 for brand-name Bonsity, $4,470/month for brand-name Forteo; $1,200/month for the generic. Administered through daily self-injections with a prefilled autoinjector, teriparatide has the longest track record in the class and is the only anabolic available as a generic. The FDA has approved the use of teriparatide for more than two years in a patient’s lifetime, although, as discussed previously, there currently isn’t solid evidence that a second course of the medication reduces fracture risk.

Preventing Bone Loss: the Overlooked Role of Estrogen

Research shows that estrogen improves bone density as well or better than a bisphosphonate and protects against fractures. Because of this, many experts feel that it’s time to rethink the use of hormone therapy in the form of estrogen alone or with progestin for preventing bone loss. 

“Most of us now feel that there was too much pushback on estrogen after the Women’s Health Initiative,” says Dr. Khosla, speaking broadly for clinicians who treat bone loss.

Several major medical organizations, including the American College of Obstetricians and Gynecologists (ACOG), the North American Menopause Society (NAMS), and the American Association of Clinical Endocrinology (AACE), now recommend HT for treating menopausal symptoms in appropriate patients. But there is a window of opportunity for HT: for women younger than 60 who are within 10 years of menopause, the benefits of the therapy for assuaging symptoms such as hot flashes and preventing bone loss can outweigh the potential harms, according to the guidelines. Older women taking HT face increased risks of serious side effects such as blood clots, heart attack, stroke, dementia, and breast cancer. 

If the goal is just to slow bone loss, the benefits don’t outweigh the risks, even in younger women, says Dr. Ensrud, echoing recommendations from ACOG and other medical organizations. But, she said, “if a woman is having bothersome menopausal symptoms, like hot flashes, and gets started on estrogen, it will be good for her bones.” 

Dr. Ott offers a contrasting perspective, saying it may be time for guidelines to reconsider estrogen to stave off bone loss in younger postmenopausal women. Unlike bisphosphonates and Prolia, which work by turning off bone resorption, she says, estrogen supports the bone’s natural physiology. “It’s giving back something that the body is missing,” says Ott. “It’s the lack of estrogen that’s really causing so much osteoporosis.

Another hormone-like drug that is approved for treating osteoporosis is raloxifene (Evista and generic), a drug that binds to estrogen receptors in the body. Raloxifene has anti-estrogen effects in the breast, which reduces the risk of the most common forms of breast cancer, and it also activates estrogen pathways in the bone that protect against bone loss. However, studies show that raloxifene reduces spinal, but not hip fracture, so its use in osteoporosis treatment is limited mostly to women at higher risk for breast cancer.

Keeping Tabs on How Well a Drug Is Working

Many guidelines recommend a DEXA scan one to two years after starting treatment. Bone density changes slowly, and it takes that long to see meaningful results. 

Dr. Ensrud notes that there’s a margin of error in bone density measurement, meaning that results could vary by a few percentage points. If you check bone density too soon after starting therapy, it can be hard to know if the changes reflect the effects of the medication or just the variability of the test results.

Thereafter, patients should be monitored every couple of years, depending on their response to therapy. Patients who are still losing bone may need more frequent monitoring, while those who have stabilized can go longer between scans. Insurance typically covers scans every two years unless there’s a medical reason (such as poor response to treatment) for more frequent tests.

Of course, increased bone density is not the ultimate goal of drug therapy. The biggest question is whether a patient has had a fracture, says Dr. Ensrud. “That’s the best way to gauge efficacy.”

Non-Drug Approaches to Strengthening Bone

When it comes to shoring up bones, the first thing that many people think of is calcium and vitamin D. But surprisingly, evidence shows supplements have only a modest benefit. 

Neither calcium nor vitamin D alone reduces the risk of fractures, according to comprehensive analyses of results from multiple studies. However, a 2019 meta-analysis of data from six randomized clinical trials involving nearly 50,000 people found that taking a combination of calcium and vitamin D for approximately six years reduced the risk of any fracture by 6% and the risk of hip fracture by 16%. The average age of study participants in individual trials ranged from the early 60s to the mid-80s. The authors note that the studies of people aged 80 and older living in institutions found the greatest reduction in fracture risk.

The best way to get your recommended daily intake of calcium (1000 mg for adults up to age 50; 1,200 mg for women 51 and older and men older than 70) is from your diet, says Dr. Ott. Because the body quickly absorbs calcium from supplements, there’s some concern that excess could build up in your arteries, she points out. Meanwhile, calcium from food is absorbed more gradually, so it’s available over a longer time for the body to use in making bone. “And food has other nutrients we need,” says Dr. Ott, citing the example of yogurt, which provides not only calcium, but also protein and bacteria that are good for your gut. 

If you do need a calcium supplement, experts recommend taking no more than 500 mg to 600 mg at once, dividing the dose between morning and evening if you take more than 600 mg daily. Or, as Dr. Ott suggests to her patients, you can chew a 500-mg calcium-carbonate antacid such as regular-strength Tums after one or two of your meals. Don’t exceed the RDA, as excess calcium can cause constipation, interfere with the absorption of other nutrients, and might increase the risk of kidney stones, prostate cancer, and heart disease.

Other than fortified foods, one of the primary sources of recommended amounts of vitamin D (600 IU for adults up to age 70; 800 IU for those 71 and older) is ultraviolet rays from sunlight, which the body uses to manufacture the nutrient. For people who don’t get much sun or who live in northern climes where, especially in the winter, sunlight is less intense, Dr. Ott recommends supplements. 

As with most supplements, it’s advisable to get your doctor’s input on adding calcium or vitamin D to your daily regimen. 

Other than nutrition, your biggest defense against bone loss is physical activity. While weight-bearing exercise strengthens bones, other forms of movement, such as swimming, help with balance and coordination, decreasing the risk of falls. 

Among all the non-drug approaches he recommends, Dr. Kogan says Tai Chi stands out. The slow, low-impact practice has strong evidence behind its bone-building effects, and he’s seen the proof firsthand. “I routinely see an 80-year-old Tai Chi master with the completely normal bones of a 25-year-old,” he says.

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