Time Stamps

• Diagnosing Osteoporosis and Hidden Fracture Risk
• Evolution of Bisphosphonate Use in Osteoporosis Treatment
• Current Use of Bisphosphonates: Benefits, Risks, and Side Effects
• Exploring Non-Bisphosphonate Options for Fracture Prevention
• Teriparatide and Alternative Osteoporosis Medications
• Inside the Latest Bisphosphonate Clinical Trial
• Key Findings from the Zoledronate Fracture Prevention Study
• Public Health Impact of Fracture Prevention Strategies
• Final Takeaways and Expert Perspectives on Osteoporosis Care

Sponsor: Oakstone CME’s ACP MKSAP Audio Companion

Show Notes

What is osteoporosis and how do you diagnose it?

• Definition: Low bone mineral density (BMD) leading to increased risk of fractures, most frequently involving the hip, spine, humerus, and wrist.
• Risk factors:
  • Post-menopausal status
  • Female sex
  • Low BMI
  • Smoking
  • Chronic inflammatory conditions like rheumatoid arthritis
  • Chronic glucocorticoid use
• 2 ways to diagnose osteoporosis (either/or):
  • DEXA scan
    • normal T-score >-1
    • osteopenia = T-score -2.5 to -1
    • osteoporosis = T-score <-2.5
  • Presence of a fragility fracture
    • fracture that occurs with minimal trauma (like falling from a standing height)
      • Mostly occur in people with normal bone mineral density!
        • As opposed to those with osteopenia
        • Cohort study of postmenopausal women:
          • 37.6% had normal BMD, 48% had osteoporosis and 14.5% had osteoporosis
            • Women w/ osteoporosis had highest risk of fracture, BUT…
          • 26.9% of all fractures occurred in women with osteoporosis
          • 73.1% of all fractures occurred in women without osteoporosis
            • 56.5% in women with osteopenia and 16.6% in women with normal BMD
    • How can you measure 10-year risk of fragility fracture (in pts w/o osteoporosis)?
      • FRAX score
      • OST score

What are the medications we can use for osteoporosis?

• Bisphosphonates:
  • The FIT trial (ORAL):
    • Oral alendronate improved BMD
      • In women with a previous vertebral fracture, women treated with alendronate had a reduced risk of new vertebral fracture (RR 0.53 (95% CI 0.41-0.68)
    • However, oral bisphosphonates are challenging to take:
      • Instructions for patients: take once a week (usually for alendronate, can be daily) on an empty stomach, before any other medications, take with a large glass of water and sit upright for 30 minutes afterwards.
    • As such long-term compliance with oral bisphosphonates may be poor.
• The HORIZON trial (IV)
  • A once per year dose of IV zoledronic acid reduced the risk of vertebral fracture over 3 years by 70%
    • After the treatment stopped, the benefit persisted at 6-year follow-up.
  • Common side effect of IV bisphosphonate:
    • Flu-like myalgia
      • occurs in approximately 1/10 patients
      • can use acetaminophen to help this
• Two rare but dangerous side effects of bisphosphonates (Oral AND IV):
  • Osteonecrosis of the Jaw (ONJ)
    • Very rare, <0.1%
    • Risk increases with with higher doses and higher frequency of treatment
    • For routine patients, good practice to have a dental check and any required dental work performed before starting bisphosphonate
  • Atypical femoral fractures (AFF)
    • Rare- risk of about 0.1%
      • About the same as being struck by lightning!
    • Risk increases with longer duration of treatment
    • Tend to be more distal and transverse compared to ‘traditional’ neck of femur fractures
    • Can be bilateral
      • if you suspect- get imaging of both femurs (not just hips)
    • Patients can present with no or minor trauma history, may have a limp or non-specific leg pain.
      • Need to have a high index of clinical suspicion.
• Denosumab (Prolia)
  • Mechansim: RANK ligand inhibitor
  • Evidence: the FREEDOM trial –
    • In women aged 60-90 with osteoporosis, denosumab reduced the risk of new radiographic vertebral fracture by almost 70%.
  • Route/Frequency: Subcutaneous injection every 6 months
  • Side-effects:
    • ONJ
    • AFF
    • rapid BMD loss if dose is missed
  • NOTE: if you stop taking denosumab → need to switch to something else- like bisphosphonates, because BMD drops and fracture risk increases!
• Romosozumab (Evenity)
  • Mechanism: Monoclonal antibody that inhibits sclerostin
  • Evidence: FRAME trial, ARCH trial
    • In postmenopausal women with osteoporosis (T score -2.5 to -3.5) less new vertebral fractures occurred in those treated with romosozumab (6.2%) compared with oral alendronate (11.9%) at 2 years.
  • Route/Frequency: Subcutaneous injection monthly
  • Side effects:
    • Increased cardiovascular risk(stroke and MI)
      • Black box warning!
• Teriparatide (PTH analogue)
  • Mechanism: Recombinant PTH (anabolic effect)
  • Evidence:
    • Fewer new vertebral fractures with PTH compared to placebo or compared to oral alendronate
  • Route/Frequency: Subcutaneous injection daily
  • NOTE: good for vertebral osteoporosis to increase BMD, but 2-year maximum treatment course, then should switch to denosumab or bisphosphonate

Can infrequent zoledronate (IV bisphosphonate) be used as primary prevention for osteoporosis in women?

• Bolland, Fracture prevention with Infrequent Zoledronate (“FIZ”)
  • Design: Randomized control trial
  • Study Population: n=1054 women
    • Demographics: aged 50-60, from New Zealand
    • Clinical Characteristics:
      • NO osteoporosis (average T-score -0.5)
      • Few comorbidities
      • good amount of exercise
      • low rates of smoking
    • Exclusion Criteria:
      • risk factors for fractures
      • had previously used HRT or bisphosphonate.
  • Study Duration: 10-year follow up, 95% completed
  • Intervention: Zoledronate (administered in 1 of 2 ways)
    • 2 doses, one at baseline and one at 5 year OR
    • 1 dose at baseline, followed by placebo at 5 years
  • Control: Placebo at baseline and at 5 years
  • Primary Outcome: new vertebral fractures
    • Assessed using serial X-rays and patient questionnaires
  • Secondary Outcomes:
    • any fracture
    • new major osteoporotic fractures
    • fragility fracture
  • Results:
    • LOWER fracture risk in BOTH arms receiving zoledronate (vs control)
      • Primary Outcome Occurrence (new vertebral fracture)
        • 6.3% of zoledronate-zoledronate
        • 6.6% of zoledronate-placebo
        • 11.1% of placebo-placebo
      • Odds of fracture was reduced by receiving zoledronate 0.58 (95% CI, 0.38 to 0.87) compared to placebo/placebo
        • Both zoledronate groups pooled
      • Number Needed to Treat: 21 to prevent 1 vertebral fracture
      • Secondary Outcomes Occurrence
        • Any fracture:
          • Odds were reduced 0.70 (95% CI, 0.56 to 0.88) in the zoledronate/zoledronate group and 0.77 (95% CI, 0.62 to 0.97) in the zoledronate/placebo group, when compared to the placebo/placebo group.
        • NOTE: There was a higher risk of fractures overall compared to what they predicted at the onset of the study
          • 20% of participants in this study had a fracture over 10-year follow up. And in those receiving placebo only, 1 in 3 had a fracture in 10 years.
  • Adverse Events:
    • Uveitis and episcleritis (9 cases)
      • Known side effect of this drug
    • NO cases of ONJ or AFF in this study!
      • Likely because frequency of treatment was lower
        • Once or once every 5 years vs. annually, which is the usual frequency for treatment of osteoporosis

How does this trial affect our practice?

• This is a really compelling paper that should prompt us to rethink our guidance to patients who are at risk for fractures and consider primary prevention of fracture with zoledronate in patients at risk
• The threshold to treat for primary prevention (for an asymptomatic person at risk) is higher compared to treatment for secondary prevention (someone who already has the disease or symptoms, or has had a fracture)
• Guidelines have not yet changed to recommend that we treat all postmenopausal women with one dose of IV zoledronate
• There is huge potential for both cost savings and reduction of important fractures
• But the logistics of giving a once off infusion could be challenging

Take-home points

• When discussing bisphosphonate therapy, make sure to discuss the rare side effects, but also do not to overstate this risk!
  • Consider the competing (much higher) risk of fracture without treatment!
• We are under diagnosing and under treating osteoporosis and have much work to do in getting bisphosphonates to patients who could benefit most from them

Transcript

Dr. Shreya Trivedi: Welcome to Beyond Journal Club, a collaboration between Core IM and NEJM Group.

Dr. Greg Katz: The goal of Beyond Journal Club is to take landmark clinical trials and put them into context–telling the story of how we got to where we are, what it means for our patients, and how we take care of them.

Dr. Shreya Trivedi: I’m Dr. Shreya Trivedi, an internist at Beth Israel Deaconess Medical Center.

Dr. Greg Katz: I’m Dr. Greg Katz, cardiologist at NYU.

Dr Clem Lee: I’m Dr. Clem Lee, med-peds hospitalist in Boston and guest editor at NEJM.

Dr. Sarah Gorey: And I’m Dr. Sarah Gorey, a previous editorial fellow at New England Journal of Medicine and a geriatric medicine fellow at Beth Israel Deaconess Medical Center.

Dr Clem Lee: Today we’re diving into the world of bone health. And we’re going to be talking about how well do bisphosphonates prevent fractures.

Dr. Sarah Gorey: We’ll be looking at a recent trial by Bolland et al. of infrequent zoledronate therapy in patients without osteoporosis to prevent fractures, which was published in the New England Journal of Medicine, January 2025.

Dr Clem Lee: And before you all jump on me asking me this question, yes, I am very bummed that there is no cool acronym for this trial.

Dr. Shreya Trivedi: Too bad. So sad. That’s what my five-year-old would say. Too bad. So sad.

Dr. Greg Katz: And so moving on. Before we get into the study itself, we’ll discuss first how to make a diagnosis of osteoporosis, and talk about why just making that diagnosis doesn’t actually tell us everything we need to know about who should be treated with preventive medicines to reduce fracture risk.

Dr. Sarah Gorey: Then, we’ll go over what drugs we actually have in our toolkit for fracture prevention, and more importantly, what is missing and why this new bisphosphonate trial was so compelling.

Dr. Greg Katz: And finally, we’ll bring it home and discuss if this changes our practice in how we prevent fractures in our patients.

What is osteoporosis?

Dr. Sarah Gorey: We all know that osteoporosis is characterized by decreased bone mineral density and increased risk of fractures- especially at the hip, spine, humerus, and wrist. We are talking about mostly post-menopausal women. But another risk factor that we commonly see in osteoporosis is patients with chronic steroid use.

Dr. Shreya Trivedi: Yeah. I think we have all heard the scary statistics that after a hip fracture, patients are looking at a 1-year mortality as high as 28%. And, I guess, if one of the main risk factors is osteoporosis than the thought should be that we are good at diagnosing osteoporosis, hopefully we prevent some of these fractures, right?

Dr. Sarah Gorey: Well Shreya, I actually have even more disappointing news about our diagnostic tools. It turns out more than half of fragility fractures occur in patients who wouldn’t have met diagnostic criteria for osteoporosis before their fracture.

Dr. Shreya Trivedi: Wait, what?

Dr. Greg Katz: And that even may be underestimated. I mean, some of the data suggests that 3 out of 4 patients with fragility fractures either had normal bone density or osteopenia at the time of the fracture.

Dr. Shreya Trivedi: That is wild, Greg!

Dr. Greg Katz: And because of that, it’s likely they wouldn’t have really been considered candidates for preventive therapy because they didn’t have that diagnosis of osteoporosis prior to having a fracture.

Dr. Sarah Gorey: It’s such an important truth to get out there, its really unfortunate fact but its really important because this is why the study we are discussing is so relevant.

Dr. Shreya Trivedi: Yeah, I guess just so I can, like, sit with this a little better. Can you remind me, what are the diagnostic tools we do have for osteoporosis?

Dr. Greg Katz: So radiologically, you look at the DEXA scan you get that X-ray measurement of the wrist and hip, and we look at the T score, which is a measure of how dense bone is compared to that of a young, healthy person. Basically, we look at the number of standard deviations from the mean. Osteoporosis is defined as a T score <-2.5, and osteopenia is a T score between -1 and- 2.5, anything higher than -1 is considered normal, healthy bone.

Dr Clem Lee: And there is another way of getting the diagnosis of osteoporosis, and that is if you had a fragility fracture.

Dr. Sarah Gorey: And a fragility fracture is a fracture due to a minor trauma, such as a fall from a standing height.

Dr Clem Lee: Yeah, if you get one of those then you automatically earn a diagnosis of osteoporosis, regardless of what your bone density T score measures.

Dr. Sarah Gorey: And a third way where you might get treated for osteoporosis is even if you’ve never had a DEXA scan, people might use the FRAX score, which is a clinical score where you plug in people’s risk factors for osteoporosis, and it gives you an estimation of their ten-year risk of a fracture. So someone could have a really high 10 year risk for major fractures, even if your t- t-score on DEXA scan was not in the osteoporotic range.

Dr Clem Lee: So we have these various methods. We have a T score <-2.5 on a DEXA scan or a fragility fracture that can buy you a diagnosis of osteoporosis or even a high FRAX score could be an indication for treatment.

Dr. Sarah Gorey: So to recap, fractures can be absolutely devastating for patients, and while people with osteoporosis are at the highest risk, the unfortunate reality is the majority of fractures occur in patients who don’t actually have a diagnosis of osteoporosis. So there’s a significant unmet need to figure out who is actually at risk for fractures, and then an unmet therapeutic need to reduce this fracture risk.

Dr. Shreya Trivedi: That makes so sad, and I think selfishly as someone who will probably be at risk in the future for osteoporosis. I will say, you know, we did talk to a bunch of our endocrinology colleagues in prepping for this episode and, yes, they did point out we have these validated risk prediction tools and we have come so far in the last few decades in that these prediction tools are helping us pick up those at greatest risk but it sounds like similar to most things in medicine we still have more to do and still have this unmet diagnostic need.

Dr Clem Lee: Wait, Shreya, hold on to that thought. Let’s put a pin on that unmet diagnostic need and look through the meds we actually have to prevent fractures, but I promise we’re going to circle back if we even need to diagnose osteoporosis in the first place.

Medications to prevent fracture

Dr Clem Lee: So the story of treating osteoporosis actually starts in the 1940s, when estrogen treatment was shown to improve markers of bone density in postmenopausal women. But then hormone replacement therapy, or HRT became kind of controversial, so investigators look for other targets.

Dr. Shreya Trivedi: The bisphosphonate story starts with the Fracture Intervention Trial (aka FIT – Clem, I think that’s a good acronym, Clem) published in JAMA and the Lancet in the late 1990s. The best decade. The headline was that there was a significant reduction in fractures with alendronate therapy in one of the studies in women with low bone density and the other studies with a history of osteoporotic fractures.

Dr Clem Lee: The challenge with alendronate is that it’s tough to actually go through the mechanics of treatment – you have to take the medication once a week (which is tough to remember), you need to take it on an empty stomach since food reduces its bioavailability, and then you need to take with a full glass or water and sit upright for 30 minutes after taking it to reduce the likelihood of esophagitis.

Dr. Greg Katz: But there were two additional problems here: (1) many of the fractures that were prevented were just incidental fractures seen on imaging, not necessarily clinically symptomatic, and (2) some concern arose in the early 2000s about the rare side effects of jaw osteonecrosis and atypical femoral fractures. These are really rare but can be totally devastating, and the press that they got dissuaded many people from taking bisphosphonate therapy.

Dr Clem Lee: So summarizing so far — alendronate reduces fracture risk – at least as measured on x-rays, but it’s tough to take, and isn’t as effective at reducing clinically symptomatic fractures, which is what most of our patients care about.

Dr. Sarah Gorey: Luckily, that wasn’t the end of the bisphosphonate story. FIT trial set the stage for HORIZON, the first big zoledronic acid study, which showed a 70% reduction in the risk of vertebral fracture over 3 years in women taking once yearly zoledronic acid. What was really important with this study was that IV zoledronic acid reduced clinically significant fractures.

Dr. Shreya Trivedi: So that was big news – a once-a-year drug that reduces the type of fractures our patients care about.

Dr. Sarah Gorey: And some of that benefit persisted for 6 years in the HORIZON extension study, even in patients who stopped getting zolendronic acid after 3 years.

Dr Clem Lee: That durable benefit is because bisphosphonates have a long half-life, so they have long treatment effects- but this also means you need to surveil them long term for those rare side effects.

Dr. Greg Katz: And the complexity of the those impacts makes the risk/benefit discussion with a patient important. On one hand, the risk of atypical femoral fractures is really low – by most estimates about 0.1% incidence. But then on the other hand, if you have one of the effects it could be totally devastating.

Dr. Sarah Gorey: And on top of it the hard part about atypical fractures is that you have to have a high index of suspicion for them clinically. They won’t always present with trauma – sometimes patients just present with hip or leg pain.

Dr. Shreya Trivedi: That’s really frustrating, just leg or hip pain and they have an atypical fracture.

Dr. Sarah Gorey: Yeah. And the thing with atypical fractures, they are more distal and transverse so you need a femur x-ray and not just a hip x-ray to make the diagnosis. Also about a third of these can be bilateral so you should image both sides.

Dr. Shreya Trivedi: Wow. That sucks! And I think the big thing that kept coming up when we talked to endocrinologists, was actually how rare these side effects are compared to the amount of attention that it gets.

Dr. Ole-Petter R. Hamnvik: Hi, I’m OP Hamnvik. I’m an endocrinologist at Brigham and Women’s Hospital in Boston, where I’m also an associate professor of medicine at Harvard Medical School, and I am the Education editor for NEJM group. Osteonecrosis of the jaw and the atypical femoral fractures are real side effects. Studies find it fairly consistently, but they’re so extremely rare. And that is the take home to me, and I looked up at some point the likelihood of someone being struck by lightning, or the likelihood of someone knowing someone who has been struck by lightning, and it is in the same order of magnitude as your likelihood of having an atypical femur fracture or osteonecrosis of the jaw as a result of treatment with these agents, at least at the doses that we use in osteoporosis treatment, I think the story is different when you start to talk about the higher doses that we use for oncologic indications. So just like any medication has side effects, so do these. But it is so rare that it shouldn’t preclude their use to prevent these adverse outcomes.

Dr. Sarah Gorey: And one promising thing about these atypical femoral fractures is that the risk is proportional to the duration and also the frequency of treatment, and the risk decreases back to baseline when you stop the drug.

Dr. Shreya Trivedi: And that risk being proportional to the frequency of treatment will come up really nicely in the study we’ll talk about in a second. But say your patient is still concerned about the side effects of bisphosphates. There are a few other agents you might see your patients on, and we’re going to highlight 3 of the major ones.

Dr. Greg Katz: The first one is denosumab, or as my patient’s call it — Prolia, a rankL inhibitor that decreases bone breakdown. In the FREEDOM trial, Prolia was really impressive, with a 40% reduction in hip fractures and a 70% reduction in fractures overall compared to placebo in women with osteoporosis.

Dr Clem Lee: The advantage of Prolia/denosumab is that it’s subQ and it’s only given every 6 months and doesn’t stick around in bone for years.

Dr. Sarah Gorey: However, unfortunately, in the follow-up of the FREEDOM trial we learned that even though denosumab maintained bone mineral density, at 5 years investigators had identified 8 cases of osteonecrosis of the jaw and 2 atypical femoral fractures among 4,550 women that were treated.

Dr. Shreya Trivedi: Oh, so now we know that these rare side effects you know, jaw necrosis atypical femoral fractures are not specific to bisphosphonates! And I think my brain just want to, like, compare, the two, right? We said point 1% for bisphosphates. It looks like, you know, the with the numbers you gave, it’s point 0.2% with denosumab, developing osteonecrosis the jaw and point zero 0.4% atypical femoral fractures with denosumab.

Dr. Sarah Gorey: Exactly, and with longer term follow-up studies, and wider use, another important limitation of denosumab became apparent. That is, once you stop using it, you’re bone mineral density begins to drop. So if you stop the drug, you have to switch to something else, usually a bisphosphonate.

Dr. Shreya Trivedi: I think the scenario just reinforces that theme, right? But like treatment with osteoporosis, like many things that are chronic diseases, it’s a long run marathon.

Dr Clem Lee: And the next osteoporosis treatment option that we have is romosozumab, or as your patients may call it, Evenity, this is a subcutaneous once-a-month drug that works upstream of osteoblasts to increase bone formation and to a lesser extent, inhibit bone resorption.

Dr. Sarah Gorey: In the FRAME trial, romosozumab reduced both vertebral fractures and nonvertebral fractures and that was included in the secondary endpoint.

Dr. Greg Katz: Unfortunately, Evenity comes with a black-box warning about increased cardiovascular risk because of a signal in the ARCH trial for a 2-fold increase in major adverse cardiovascular events in post menopausal women. I can’t tell you how many patients I’ve seen asking for cardiac clearance before they start Evenity for their osteoporosis, almost like if they’re wishing we had a crystal ball to see who’s going to have these cardiovascular events.

Dr. Sarah Gorey: Gosh, it’s a tough life for those cardiologists.

Dr. Shreya Trivedi: I think geriatricians have a harder job, and maybe arguably the most important job. I am such a Geri fan.

Dr. Greg Katz: I agree with it.

Dr. Sarah Gorey: Okay lets round out our tour of the non-bisphosphonate treatments that reduce fracture risk in osteoporosis, we have teriparatide, which is a parathyroid hormone analogue that also reduces fracture risk and increases bone density in patients with osteoporosis.

Dr. Shreya Trivedi: Yeah. they unfortunate thing about teriparatide is it’s a daily injection. It’s an anabolic hormone, so patients can’t be on it indefinitely. It’s recommended to take only for two years, and after that, switch to either denosumab or a bisphosphonate.

Dr. Sarah Gorey: Okay! So to recap, we have 4 classes of drugs to use in patients with osteoporosis – bisphosphonates, denosumab, romosozumab, and teriparatide – each have some clear evidence that they lower fracture risk, but each also have individual risk/benefit tradeoffs.

Dr. Shreya Trivedi: Yes, so with bisphosphates and denosumab, we get the worry of atypical femoral fracture with Evenity. There’s an increased cardiac risk both with teriparatide and denosumab. It’s a short duration of therapy, and then switching over to another treatment is required.

Fragility Fractures

Dr. Greg Katz: So we talked about the diagnosis and treatment and my big concern is that the metrics that we use to decide treating osteoporosis to prevent fracture aren’t all that useful for any given person. They’re population-based. And so even though an individual with osteoporosis is at higherindividual risk, I am still so struck by the fact that the vast majority of fragility fractures occur in people do not meet the diagnostic criteria for osteoporosis. And even if you use osteopenia plus a risk calculator, you still miss a fair number of people.

Dr Clem Lee: Yeah, it’s really unfortunate. Everything we have which includes T-score, FRAX score, and even fancy bone turnover markers are imperfect and then on top of that we are not able to predict who is going to have a bad complication once they start treatment.

Dr. Sarah Gorey: Yeah, that is the gap. We have these good drugs that reduce fracture risk but we just are not great at figuring out who should be treated and when. And this brings us to our newest study, which is called “Fracture Prevention with Infrequent Zoledronate in Women 50 to 60 Years of Age” by Bolland et al, published in the New England Journal of Medicine in January 2025.

Dr Clem Lee: Whew, that was a marathon. We’re definitely gonna need an acronym for that. Greg, can I task you, as a cardiologist, to come up with something?

Dr. Greg Katz: Clem? I thought you were the acronym connoisseur. But what about if we go with “FIZ” Fracture prevention with Infrequent Zoledronate?

Dr Clem Lee: I love it.

Dr. Shreya Trivedi: From FIT to FIZ!

Fracture Prevention with Infrequent Zolendronate

Dr. Sarah Gorey: So the investigators of this new study asked a pretty simple question: what if we just treat some postmenopausal women with intermittent bisphosphonates instead of waiting until they develop osteoporosis to start treatment?

Dr. Shreya Trivedi: I think that’s a great question, right? If our current predictive models aren’t good at figuring out who is actually going to get these fractures, then this is a pretty compelling trial from like, a public health perspective, a public health intervention, right? If we could just give this treatment to more people, and maybe everyone, will we prevent fractures?

Dr Clem Lee: Yeah. So what the researchers did here is that they sent letters to invite 53,000 women aged 50 to 60 who were registered to vote in New Zealand to participate in the trial. They eventually enrolled 1,054 patients and followed them for 10 years.

Dr. Sarah Gorey: It’s important to say that none of these women had a diagnosis of osteoporosis. Their T-scores were not < -2.5. And they were randomized equally into 3 groups.

Dr. Shreya Trivedi: And so who were these 3 groups? One group received zoledronate at the start of the study and then again at 5 years – and just to make it easier, we’re going to call this the zoledronate/zoledronate group. The second group received zoledronate at the start and then a placebo 5 years later – so we’re going to call this the zoledronate/placebo group. And then the third and last group received placebo at both time points – and we’ll call that the placebo/placebo group.

Dr. Greg Katz: And overall, this was a pretty healthy group with only a slightly low bone mineral density! The average age was 56, more than 80% were of European ancestry, average BMI was 27, the average T score was -0.5, basically none of the patients smoked.

Dr. Shreya Trivedi: Yeah, and then they also had a decent amount of physical activity, not a ton of comorbidities. This is exactly the population we want to study. Let’s see can we prevent a lot of fractures?

Dr Clem Lee: And to avoid confounders participants were excluded on the basis of things that either substantially raise or lower fracture risk. For example, they weren’t allowed to have taken a bisphosphonate, hormone replacement therapy, or glucocorticoids.

Dr. Shreya Trivedi: And the primary endpoint was a new vertebral fracture seen on x-ray, but the investigators also looked at all fractures, fragility fractures, and quote, unquote, “major osteoporotic fractures” which means any fracture of the wrist, spine, shoulder, hip, or pelvis.

Dr. Sarah Gorey: I thought the tracking for this study was pretty onerous. The study participants had to fill out questionnaires every 6 months on fractures, adverse events, and any changes in medications. They had formal clinical assessments and x-rays at time 0 and then at 5 years and 10 years. And 95% of participants completed follow up. So it was a really motivated group who did their homework twice a year for 10 years.

Dr Clem Lee: And I also give the radiologists an A plus, because the radiologists assessing fractures on those images used a semi-quantitative scale that actually covers a spectrum of bone issues from deformity and loss of vertebral height to different severity of fractures. So, it really wasn’t just a binary yes or no – they assessed fractures on a continuum.

Dr. Shreya Trivedi: It sounds like an impressive trial protocol – with long-term evaluation, some sophisticated assessments, to answer the question at hand – do bisphosphonates prevent fractures even in people who aren’t at elevated fracture risk with their current scores?

Dr. Greg Katz: So now that we’ve gone through those methods – Sarah, do you want to do the honor of telling everyone the results?

Dr. Sarah Gorey: Sure – I looked at this design trial, and I was pretty skeptical, to be honest. I was thinking these results are going to be neutral. It’s a low risk healthy population, and we all know how hard it is to show benefit in a primary prevention trial, but I was pleasantly surprised, both the zoledronate/zoledronate and zoledronate/placebo groups had a lower risk of vertebral fracture compared to placebo-placebo groups.

Dr Clem Lee: Yeah and the absolute risk reduction for vertebral fractures was actually pretty impressive, about 5% absolute reduction in both zoledronate groups compared to placebo. That means we could prevent one vertebral fracture just by treating 20 fairly low risk women.

Dr. Greg Katz: And all of the secondary endpoints were positive too – there were fewer fragility fractures, major osteoporotic fractures, and fractures of all kinds, and there was a pretty consistent reduction between 30 and 40% across all of those secondary endpoints.

Dr. Shreya Trivedi: This all sounds great, but Sarah you lived and breathed in this research. Even brought this to the writer’s pitch. I’m curious. Anything else that stood out for you?

Dr. Sarah Gorey: What really hits me Shreya about this is just how many fractures there were! So the investigators predicted that this group of fairly low-risk women without osteoporosis would have on average a 9% risk of fracture over 10 years, but by the end of the trial a whopping 20% of patients had a major osteoporotic fracture – so instead 9 in 100 women having fracture, its 20 in 100 women having a fracture! It’s a huge increase!

Dr Clem Lee: I think that just reinforces the fact even people who look low-risk on paper still have fracture risk – that’s why our predictions are so hard to make.

Dr. Sarah Gorey: Right, and another thing that stood out to me — if we just look at the placebo group, 1 out of 3 patients who didn’t get any zoledronate at all had at least one fracture by the end of the 10-year study.

Dr. Shreya Trivedi: What! A third of healthy middle aged women who were engaged enough to respond to a letter in the mail were getting fractures. That just seems really unfair.

Dr. Greg Katz: Yeah, to emphasize that point, people who self-select to join a study may also be the ones who are taking vitamins and exercising and taking good care of themselves, but that’s making assumptions, because these are people who responded to an invitation in the mail to enroll in a study. But it does speak to a certain level of diligence and engagement, and the fact that this is probably not the least healthy living group that you’ll see.

Dr. Shreya Trivedi: I need to switch the conversation now to side effects, right? I feel like once you see an atypical femoral fracture or jaw osteonecrosis, you’re so kind of burned by that, and we’ve talked about it before. So I’m curious, did we see any in this trial?

Dr. Sarah Gorey: So I was really relieved when I looked at the supplementary appendix that there actually weren’t any of either of those events in either the zoledronate groups. Yes, I suppose the study only had 1,000 patients, so it’s relatively small, but it’s still a reassuring piece of information.

Dr Clem Lee: You know, something that caught my eye in the supplementary appendix is that I see that there are 6 deaths in the zoledronate/zoledronate group and three in the zoledronate/placebo group. I don’t know what do you guys make of that.

Dr. Greg Katz: The confusing thing about that stat to me is, what did these people die from? There may be a small signal with four cases of melanoma in the zoledronate/zoledronate group, but not for other cancers. And the theoretical mechanism I would worry about here would be cardiovascular death, but there are no cardiovascular events, and so there’s this tiny number of bad events. I think it’s really tough to draw any conclusions about that, rather than just chalking it up to chance.

Dr. Sarah Gorey: So to recap – infrequent zoledronate – in this study either a one-time dose or two doses over a 10-year period – reduced vertebral fractures, major osteoporotic fractures, fragility fractures, and actually fractures of all kinds in a fairly healthy group of women in their 50s. So overall, it was a pretty impressive result for the bisphosphonates.

Dr. Shreya Trivedi: Yeah, and the fact that these people didn’t get an atypical femoral fracture or jaw osteonecrosis was also good news.

Take Aways

Dr. Shreya Trivedi: Now, I think, onto the most important part of beyond journal club. What should we take away from this study in terms of how we think about how we take care of patients?

Dr. Sarah Gorey: For me, what was really impressive about this trial is that primary prevention is really hard to show a benefit in, and this trial pushes bisphosphonates into the primary prevention space, which is a whole new idea, like the idea of giving the drug before the patient is even diagnosed with osteoporosis.

Dr Clem Lee: Yeah, but we were prepping for this podcast, there were a couple of ongoing themes we kept coming back to, and the first was that the bar to treat in primary prevention is different than the bar for secondary prevention treatment. When we’re talking about an intervention for an asymptomatic person who is just at risk of a bad outcome, there should be a different threshold before we start to medicalize a person and turn them into a patient.

Dr. Shreya Trivedi: But didn’t we clear that bar. Look at what happened to the placebo group. One in three women had a fracture over a 10 year period who didn’t get any treatment. Right?

Dr. Greg Katz: That fracture incidence is such a good point. If you told a relatively healthy 55 year old woman we have to talk about starting medicine to prevent fractures. And by the way, I just checked your T score, it’s normal. I think that patient would look at me like I’m crazy, but lo and behold, look at what happened in the placebo arm this trial, one out of three women had a fracture over 10 years.

Dr. Sarah Gorey: Yeah. So the most optimistic read of this evidence is that you should just treat every postmenopausal woman with at least one dose of zoledronate – that’s kind of what the editorial accompanying the trial said – it would be a small individual benefit but a huge population benefit.

Dr. Greg Katz: And that comes to the second idea we kept coming back to, which is that public health officials are going to look at a question like primary prevention of fractures very differently than a doctor who takes care of individual patients.

Dr Clem Lee: Yeah, public health officials might see a huge public health impact with this, because hip fractures cost about $30 billion every year in the US, whereas one dose of zoledronic acid is less than $100, so I kind of wonder if it’s gonna make it into like the USPSTF or The Endocrine Society guidelines.

Dr. Greg Katz: And so, you can see that signal for low numbers of those alarming side effects and it’s really great news, but how confident are we that that signal is gonna remain the same if this type of study makes its way into USPSTF guidelines and we really expand the use of bisphosphonate therapy for primary prevention? Do we really know what will happen with a high degree of certainty if we start giving bisphosphonates to millions of women across the United States?

Dr. Sarah Gorey: I do want to point out that the jaws osteonecrosis, and the atypical femoral fractures are a dose and duration-independent risks. So I wonder whether giving this q5 year infrequent dosing schedule that we saw in this trial would reduce that risk, since the frequency is not the same as would normally be in other trials.

Dr Clem Lee: Yeah, that’s a good point. I mean, I think if the risk of the side effects is proportional to how often you’re getting a drug, then I say, let’s just offer a one-time shot, because then this chance of having a bad event with one single dose is probably very low.

Dr. Greg Katz: So to me, this is such an attractive strategy. We can give you a shot at 50, and your fracture risk reduces by 30% over the next 10 years. And so you’re telling me, my mom can go for her flu shot, be hooked up to IV zoledronate for 30 minutes, and then her fracture risk is lower, even though she doesn’t do anything else to prevent fractures.

Dr. Shreya Trivedi: So let’s see what some of our other experts and people who live and breathe osteoporosis would do, and whether they would give this drug to their mom.

Dr. Annie Garment: Hi, my name’s Dr. Annie Garment. I am the Chief of General Internal and hospital medicine at Bellevue Hospital here in New York City. So I’m on “Team Yes,” we should do this in an ideal world. I think for me, the kicker is not my concern about the medication in and of itself. I actually have great confidence in bisphosphonates and very little fear. For me, it’s just the fact that it’s an infusion. I think that’s gonna be what you know is gonna make it logistically, really challenging to roll this out on any sort of population wide level. But if you said to me that there was this same trial with a pill, I would say, with the same side effect profile and outcomes and whatnot. I would say, no, no concerns for me. I would absolutely encourage my mom to do this.

Dr. Shreya Trivedi: Okay, it sounds like we have a strong two thumbs up from Dr. Annie Garment.

Dr. Ole-Petter R. Hamnvik: For my patients, now, I am not quite ready to say that a patient with a normal bone density who is in this age group, who’s postmenopausal, should receive one or several doses of zoledronic acid. I like to see the data out there for a little bit longer, see the reactions of the community, see guidelines get updated, potentially, and I think it probably will in the next several years as the results have a chance to deep into our consciousness, and you know, experts discuss and present their take on it. So I think I probably will be considering these results. I think it’s always difficult to tell a patient who feels well, who has normal numbers on the measurement that you need to take a medication. It’s the same for my patients with diabetes who have, quote, normal cholesterol or LDL numbers, but we don’t want it to be just normal. We want it to be extra normal, so they should take a statin. It’s a little bit the same thinking of you have a totally normal bone density, but we know that you’re at risk of fracturing, and therefore we’re still going to recommend a treatment. While that is true, I think it’s going to be a challenge to have those conversations with patients, especially due to some of the concerns that patients may have read about when it comes to the bisphosphonates.

Dr. Annie Garment: And this is one of them, where the potential benefits are so huge, the prevalence of falls as we get older and osteoporotic fractures is so high, and the risk of these agents is incredibly low, and I think that with all medicines, most people are more afraid of the side effects than they are afraid of what’s going to happen if I don’t take the medicine. And that’s not specific to primary prevention, right? But you think of all the conversations you have in your clinic exam room where patients say, I’m worried about XYZ side effects, even though those are so much less likely to happen than the bad things that could happen if you don’t take the medicine. But that’s just human nature, right? You have confidence in the future until you don’t. And so I think that I can understand why the instinct is quite literally, if it ain’t broke, don’t fix it.

Dr. Shreya Trivedi: Oh man, if it ain’t broke, don’t fix it. It’s so humbling to just think about this topic as a whole, let alone the meds. I think there are just so many parts of it that are underappreciated, misunderstood, not just by patients, but also by clinicians.

Dr. Greg Katz: Going into the pre-work for this episode, I’m not sure that we were all thinking about it correctly, and I’ve come around to the idea that it’s probably not the right way to think about this to ask, does this person have osteoporosis? But instead, I think it makes sense to ask, is this person at risk for a fragility fracture? Because the fragility fracture is the outcome that people care about. They don’t really care about what their T score is. They care if they have a broken bone or not.

Dr. Shreya Trivedi: That actually reminds me, like the conversation I had with one of our endocrinologist colleagues, like, maybe we seem to like re-frame all of this, and maybe instead of calling it a fragility fracture, we make it like a more of a layman’s term, we just call it a bone attack, right? Like similar to a heart attack?

Dr. Greg Katz: Oh, I love that. That’s a brilliant analogy. And calling a fragility fracture a bone attack is going to introduce an urgency to the issue and really make us step up our prevention game. And you know, there’s some similarities between a bone attack and a heart attack, like this underlying disease, just like atherosclerosis, Osteoporosis is a slowly progressive chronic disease that shows signs on imaging long before it causes a problem, and then all of a sudden, boom, you have this urgent, almost catastrophic event in people’s lives that totally can change their course. And just like with atherosclerosis, just like with heart attacks, we have treatments to prevent fragility fractures, to prevent bone attacks, and I’m excited to teach more people about the opportunities to use them.

Dr. Shreya Trivedi: Yeah, I’m excited to also see what our listeners think, right, like, how can we move the needle on the multiple areas we need to make headway on? You know, is re-framing it like a bone attack, kind of taking notes from the cardiology world. Is that going to help? Maybe there’s some other good ideas out there, and welcome any thoughts, and please write in.

Dr Clem Lee: And with that, it’s a wrap for today…..

Dr. Greg Katz: If you found this episode helpful, please share with your team and colleagues and give us a rating on Apple Podcasts or whatever podcast app you use. It really does help people find us.

Dr. Shreya Trivedi: Thank you to Dr. Jimin Hwang for the accompanying graphic and to nurse Kathreene Gala for the audio editing.

Dr Clem Lee: If you have any feedback, please email us at [email protected].

Dr. Sarah Gorey: Opinions expressed are our own and do not represent the opinions of any affiliated institutions.

References

• Pasco JA, Seeman E, Henry MJ, Merriman EN, Nicholson GC, Kotowicz MA. The population burden of fractures originates in women with osteopenia, not osteoporosis. Osteoporos Int. 2006;17(9):1404-1409.
• Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998;280(24):2077-2082.
• Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet. 1996;348(9041):1535-1541.
• Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356(18):1809-1822.
• Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 2012;27(2):243-254.
• Lo JC, Huang SY, Lee GA, et al. Clinical correlates of atypical femoral fracture. Bone. 2012;51(1):181-184.
• Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756-765.
• Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab Treatment in Postmenopausal Women with Osteoporosis. N Engl J Med. 2016;375(16):1532-1543.
• Fatoye F, Smith P, Gebrye T, Yeowell G. Real-world persistence and adherence with oral bisphosphonates for osteoporosis: a systematic review. BMJ Open. 2019;9(4):e027049. Published 2019 Apr 14.
• Saag KG, Petersen J, Brandi ML, et al. Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis. N Engl J Med. 2017;377(15):1417-1427.
• Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344(19):1434-1441.
• Saag KG, Shane E, Boonen S, et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med. 2007;357(20):2028-2039.
• Bolland MJ, Nisa Z, Mellar A, et al. Fracture Prevention with Infrequent Zoledronate in Women 50 to 60 Years of Age. N Engl J Med. 2025;392(3):239-248.

The post Bisphosphonates and Fracture Prevention Trial: Beyond Journal Club with NEJM Group appeared first on Core IM Podcast.