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If you’ve recently been diagnosed with osteoporosis or osteopenia, chances are your doctor has mentioned bisphosphonates. Or perhaps you’ve just finished a course of EVENITY or Prolia, and your doctor is recommending a bisphosphonate as your next step.

Either way, you want to understand: is a bisphosphonate the right choice for me?

In many cases, pharmaceutical intervention, in combination with an evidence-based osteoporosis exercise program, is an appropriate course for individuals at elevated risk of fracture. To help you have an informed conversation with your physician, this post sets out to provide a clear, current understanding of where bisphosphonates fit in your osteoporosis or osteopenia treatment plan.

The treatment landscape has changed significantly in recent years. Guidelines have been updated, new medications have entered the picture, and our understanding of treatment sequencing has evolved. This post reflects the latest evidence, including the 2023 American College of Physicians (ACP) guidelines and the American Association of Clinical Endocrinologists (AACE) recommendations.

Important Disclosures

This post is for information purposes only and does not constitute medical advice. Always consult with your physician. 

MelioGuide has no relationship, commercial or otherwise, with any pharmaceutical manufacturers including the products discussed in this post. Dr. Rubin also has no commercial relationship with any pharmaceutical manufacturer.

Medical Review

This post on bisphosphonates for osteoporosis and osteopenia was reviewed by Dr. Janet Rubin. Dr. Rubin is an endocrinologist and the Sarah Graham Kenan Distinguished Professor of Medicine and Vice Chair for Research at the University of North Carolina Department of Medicine.

What Are Bisphosphonates?

Bisphosphonates are a class of medications that reduce the risk of osteoporotic fractures by inhibiting bone resorption, the process by which old bone is broken down. They are among the most widely prescribed osteoporosis treatments, with an estimated 4 million women in the United States taking them as of 2008. (1)

The first bisphosphonate used medically was etidronate (Didronel), given in 1967 to treat myositis ossificans. It was later used for Paget disease of bone, but its use was limited to six months because prolonged treatment caused osteomalacia, a softening of the bone due to impaired mineralization. The addition of a nitrogen atom to the molecule dramatically increased potency and led to the second generation: the amino-bisphosphonates. These include alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), and zoledronic acid (Reclast). Unlike etidronate, the amino-bisphosphonates do not inhibit mineralization at clinical doses. (1)

How Do Bisphosphonates Work?

At the molecular level, bisphosphonates inhibit an enzyme called farnesyl pyrophosphate synthase, which is essential for the formation of the osteoclast cytoskeleton. This effectively shuts down osteoclast activity, the cells responsible for resorbing bone. While bisphosphonates do not directly inhibit osteoblasts (the bone-building cells), they substantially reduce bone formation indirectly because bone remodeling is a coupled process. (1)

When a bisphosphonate is introduced, osteoclasts stop resorbing bone, but osteoblasts continue filling existing resorption pits. This produces a modest initial increase in bone volume and densit

Do Bisphosphonates Increase Bone Density?

According to Dr. Susan Ott, Professor Emeritus at Division of Metabolism, Endocrinology and Nutrition at the University of Washington Medical School, bisphosphonates do not “build” bone. Dr. Ott states that they preserve existing bone by preventing its breakdown.

Over time, the existing bone matrix becomes more densely packed with mineral crystals, which is reflected in rising bone density scores, particularly during the first three years. After that, femoral bone density typically plateaus, which is the expected pattern and not a sign that the medication has stopped working. (1)

I discussed bisphosphonates and other osteoporosis medications with Dr. Ott in an extensive interview. Dr. Ott covers bisphosphonates and bone density at 10:47 in the video below.

Where Bisphosphonates Fit in Today's Treatment Landscape

Bisphosphonates are medications that slow bone loss by reducing the activity of osteoclasts, the cells that break down bone. They’ve been used to treat osteoporosis since the 1990s and remain the most widely prescribed class of osteoporosis medication.

In 2023, the American College of Physicians issued updated guidelines that reinforced bisphosphonates as the clear first-line treatment for most people with osteoporosis. This was a notable change from their 2017 guidance, which treated bisphosphonates and denosumab (Prolia) as roughly equivalent initial options. The updated position states: for postmenopausal women and men with primary osteoporosis, start with a bisphosphonate (2).

The one major exception is for individuals at very high risk of fracture, those with severe osteoporosis, multiple prior fractures, or very low bone density. For these patients, current guidelines recommend starting with an anabolic agent like EVENITY (romosozumab) or teriparatide (Forteo) for one to two years, followed by a bisphosphonate to preserve the bone gains (3).

So whether bisphosphonates are your starting point or your follow-on medication, they will almost certainly be part of your treatment at some stage.

Bisphosphonates as First-Line Treatment: Who Should Start

Not everyone with low bone density needs a bisphosphonate. The decision depends on your overall fracture risk, not just your bone density score.

When to Start Bisphosphonates: FRAX Score

The World Health Organization’s FRAX tool estimates your 10-year probability of fracture by combining your bone density with other risk factors including age, weight, fracture history, family history, smoking, alcohol use, and steroid use.

In the United States, treatment guidelines generally recommend considering bisphosphonates when your 10-year hip fracture risk exceeds 3% or your major osteoporotic fracture risk exceeds 20%. In Canada, pharmaceutical intervention is typically considered when your major fracture risk exceeds 20%, with those in the moderate range (10-20%) evaluated on a case-by-case basis depending on additional risk factors.

Bisphosphonates for Osteopenia

Are bisphosphonates recommended for osteopenia?

The answer depends on your complete risk profile. A T-score between -1 and -2.5 (the osteopenia range) doesn’t automatically mean you need a bisphosphonate. However, the 2023 ACP guidelines suggest that for women over 65 with low bone mass, clinicians should take an individualized approach, and if treatment is initiated, a bisphosphonate should be used (2).

The most important study on this question is the 2018 HORIZON trial extension, which showed that zoledronic acid (Reclast) significantly reduced fractures even in women with osteopenia, not just those with full osteoporosis (3). This was a landmark finding because most earlier bisphosphonate trials had focused exclusively on people with T-scores below -2.5.

The patients who benefit most from bisphosphonate treatment in the osteopenia range are those with additional risk factors: a previous fracture, a strong family history of hip fracture, long-term steroid use, or a history of falls. If your only finding is mild osteopenia with no other risk factors, your doctor may instead recommend monitoring, adequate calcium and vitamin D, and a targeted exercise program.

Bisphosphonates After EVENITY or Forteo

If you’ve just completed a 12-month course of EVENITY or up to two years of Forteo (teriparatide), transitioning to a bisphosphonate is not optional, it’s essential.

Anabolic medications like EVENITY build new bone during the treatment period, but once you stop taking them, those gains begin to reverse. Research by Reid from the FRAME trial shows that without follow-on antiresorptive therapy, patients can lose the majority of their bone density gains within 12 months of completing anabolic treatment (5). (These findings come from the FRAME trial participants who received romosozumab for one year then denosumab for two years.)

A bisphosphonate slows down the osteoclasts (the bone-removing cells), preserving the new bone created during your anabolic treatment phase.

Which Bisphosphonate After EVENITY?

Both oral alendronate and intravenous zoledronic acid (Reclast) have been used as follow-on therapy after EVENITY. The ARCH trial used alendronate and demonstrated significantly lower fracture risk with the romosozumab-to-alendronate sequence than alendronate alone (6).

Zoledronic acid (Reclast) is also commonly chosen because its once-yearly dosing may improve long-term adherence.

Timing the Transition

Current practice typically involves starting the bisphosphonate approximately one to two months after your final EVENITY injection. Your doctor should arrange a DEXA scan around the time of your transition to measure the bone density gains from EVENITY and establish a new baseline. Bone turnover markers (like P1NP and CTx) may also be monitored at 6 and 12 months after the switch.

Does Treatment Sequence Matter?

Yes, significantly. Research has consistently shown that starting with an anabolic agent (EVENITY or Forteo) followed by a bisphosphonate produces greater total bone density gains than the reverse sequence (7). This is an important conversation to have with your doctor if you’re at very high risk of fracture and being offered a bisphosphonate as your very first treatment. Instead, the anabolic-first approach may be more appropriate for you.

For a complete discussion of EVENITY, including its mechanism of action, side effects, and the latest research on repeating treatment courses, see our detailed post: EVENITY (Romosozumab): A Physician’s 2026 Review for Patients.

Bisphosphonates After Prolia

If you’re on Prolia (denosumab) and your doctor is recommending a transition, this section is critical.

Unlike bisphosphonates, Prolia cannot simply be stopped. When Prolia is discontinued without follow-on therapy, bone turnover rebounds dramatically, bone density drops rapidly, and the risk of multiple vertebral fractures increases significantly, sometimes within months of the last missed injection (8). The AACE guidelines explicitly state that Prolia treatment should not be discontinued without starting a subsequent antiresorptive or other therapy to prevent this rebound effect (3).

A bisphosphonate is the most common bridge medication when transitioning off Prolia. Both oral bisphosphonates (such as alendronate) and intravenous zoledronic acid have been used for this purpose, though the optimal regimen and duration are still being studied.

If you’re currently on Prolia and considering any changes to your treatment, please discuss this thoroughly with your physician before making any decisions. For a comprehensive discussion of Prolia, its side effects, and the challenges of discontinuation, see our detailed post: How Long Can You Take Prolia Injections.

Bisphosphonate Drug Holiday: Updated Guidelines

The concept of a bisphosphonate drug holiday, a planned, temporary break from bisphosphonate treatment, is now well-established in clinical practice, but the specifics depend on your individual fracture risk.

The rationale for drug holidays is twofold.

  1. First, bisphosphonates accumulate in bone tissue and continue to exert some protective effect even after you stop taking them, unlike medications like Prolia whose effects reverse quickly.
  2. Second, rare but serious side effects, specifically atypical femoral fractures and osteonecrosis of the jaw, appear to be associated with longer durations of use (9). A planned break may reduce these risks while maintaining fracture protection.

Bisphosphonate Holiday Guidelines

Based on the most current guidelines from the ACP, AACE, and the Endocrine Society, here is how drug holidays are generally approached:

  1. Low Fracture Risk. If you are at low fracture risk and were started on a bisphosphonate for reasons that may no longer be relevant (e.g., temporary steroid use), treatment can be discontinued with monitoring. You would only need reassessment if you experience a new fracture or your risk factors change.
  2. Moderate Fracture Risk. If you are at moderate fracture risk (which includes many individuals diagnosed with osteoporosis by DEXA), the general recommendation is to take oral bisphosphonates for five years (or intravenous zoledronic acid for three years), then reassess. If your fracture risk has decreased, for example, your T-score has improved to above -2.5 and you’ve remained fracture-free, a drug holiday of two to four years is reasonable. During the holiday, your doctor should reassess your fracture risk every two to four years using DXA and FRAX, and consider restarting treatment if bone density declines significantly or you experience a new fracture (2, 3).
  3. High Fracture Risk. If you are at high fracture risk, for example, you have a T-score at or below -2.5 at the femoral neck after treatment, a history of vertebral or hip fracture, or multiple fragility fractures, guidelines recommend continuing oral bisphosphonates for up to 10 years (or zoledronic acid for up to 6 years) before considering a shorter holiday of one to two years. The AACE recommends that even after the holiday, treatment should be restarted promptly if there is any decline in bone density or a new fracture (3).
  4. Very High Fracture Risk. If you are at very high fracture risk, your doctor may recommend continuous treatment without a holiday, or a very short break with close monitoring.

What Happens During a Bisphosphonate Drug Holiday?

When you stop a bisphosphonate, bone density at the spine typically stays relatively stable for the first one to three years. Hip bone density may decline slightly. P1NP and CTx bone turnover markers gradually trend toward pre-treatment levels over one to two years, though they generally don’t reach full baseline. Studies suggest that alendronate provides more residual protection during a holiday than risedronate, likely because alendronate binds more tightly to bone (10).

A 2025 review in the Journal of Clinical Endocrinology & Metabolism emphasized that one size does not fit all when it comes to drug holidays. The initial bisphosphonate used, treatment duration, and each patient’s individual characteristics all affect what happens during the break, and how long it can safely continue (9). This is why regular reassessment during a holiday is essential.

When Do You Restart Bisphosponates After a Drug Holiday?

Your doctor should consider restarting bisphosphonate treatment if any of the following occur during your drug holiday:

  • Significant decline in bone mineral density on your DXA scan
  • New fragility fracture
  • Meaningful increase in bone turnover markers
  • Changes to your risk profile (e.g., starting steroid therapy, a fall resulting in injury)

Do Bisphosphonates Reduce Bone Quality?

Clients worry is that bisphosphonates produce denser but lower quality brittle bone, bone that looks better on a DEXA scan but is actually weaker and more prone to fracture.

I put this question directly to Dr. Janet Rubin, an endocrinologist specializing in bone and mineral diseases at the University of North Carolina and someone with no commercial ties to any pharmaceutical company. Her response was both direct and reassuring.

Dr. Rubin acknowledges that the concern has some historical basis. The very first bisphosphonate, etidronate, which came out of Switzerland in the early 1990s, was associated with potentially poor bone quality. But every bisphosphonate prescribed since alendronate (Fosamax) was developed in the late 1990s has consistently demonstrated fracture prevention in large clinical trials.

Her logic is straightforward: if these drugs produced bad bone, they would cause fractures, not prevent them. Why would doctors prescribe a medication to millions of people who haven’t yet had a fracture if it were going to cause fractures? The clinical evidence over more than two decades shows the opposite, these medications reliably reduce fracture risk.

One of the early concerns among researchers was whether bisphosphonates might interfere with fracture healing, since they slow down bone remodeling. That concern has also been put to rest. Bisphosphonates can be given immediately after a hip fracture without impairing healing.

The Real Issue: Bisphosphonate Therapy Duration

Dr. Rubin explained that the actual problem was not the medications themselves, but how they were prescribed. Because bisphosphonates seemed so safe, patients were often put on them and left on them indefinitely, sometimes for decades. That is where the risk of rare but serious side effects, particularly atypical femoral fractures, comes in.

The risk of atypical femoral fracture builds with the number of years you are continuously on the medication. In Dr. Rubin’s clinical experience, that risk starts to meaningfully increase around the four-year mark. She aims to get most of her patients to a drug holiday by that point. (Some clinicians initiate holidays as early as four years, while guidelines generally suggest reassessment at five years for oral bisphosphonates.)

The good news is that the risk resets during a holiday. Large registry studies from Scandinavian countries show that after approximately one year off a bisphosphonate, your risk of atypical femoral fracture returns to near-baseline. When you restart the medication, you essentially begin with a clean slate from a side-effect perspective.

This is why the cyclical approach to bisphosphonate treatment, treat for a defined period, take a monitored holiday, restart when needed, has become the standard of care. You are not committing to a lifetime of continuous medication. You are using the drug strategically, in cycles, to keep your fracture risk low while minimizing the risks associated with prolonged use.

Tailoring Bisphosphonate Treatment to Your Stage of Life

Dr. Rubin takes a practical, age-stratified approach with her patients. She describes the 65-to-75 age range as “young-old” and the 75-to-85 range as “middle-old.” For patients in these groups, the goal is to cycle through treatment and holidays, monitoring bone density and fracture risk at each stage.

For older patients who are becoming frail, the calculation changes. In those cases, Dr. Rubin may keep a patient on denosumab (Prolia) continuously rather than cycling through bisphosphonate holidays or opt for EVENITY.

The key principle is that your treatment should evolve as you do. What’s right for you at 67 may not be right at 82, and a good clinician will adjust the plan as your risk profile changes.

What Dr. Rubin Sees in Practice

Perhaps the most reassuring part of our conversation was what Dr. Rubin said about her own patients: the women she treats with bisphosphonates and other osteoporosis medications through their 70s and early 80s are simply not fracturing. That’s the clinical reality she observes, and it aligns with what the research shows.

We know that over half of untreated women over 50 will experience a fragility fracture in their lifetime. Exercise, nutrition, and fall prevention all help but Dr. Rubin is candid that even with the best lifestyle interventions, some women will fracture as they age. The medications we have today, used wisely and in the right sequence, have genuinely changed that trajectory.

If your primary care provider has recommended a bisphosphonate and you’ve been hesitant because of concerns about bone quality, I’d encourage you to bring this information to your next appointment. The bone quality concern applied to a drug that hasn’t been in use for decades. The bisphosphonates prescribed today have a strong track record, and when used with appropriate holidays, the risk profile is very manageable.

Bisphosphonates Side Effects in Context

No medication is without risk, and bisphosphonates are no exception. However, it’s important to weigh these risks against the very real danger of osteoporotic fractures, which carry their own significant consequences for health and quality of life.

Common side effects include gastrointestinal discomfort with oral bisphosphonates (heartburn, nausea, esophageal irritation) and flu-like symptoms after the first IV infusion of zoledronic acid. These are usually manageable and tend to decrease with subsequent doses.

Atypical Femoral Fractures

Atypical femoral fractures are an unusual type of thigh bone fracture associated with long-term bisphosphonate use (generally beyond five years). They are rare, the incidence is estimated at approximately 3-50 per 100,000 person-years of bisphosphonate use. To put this in perspective, bisphosphonates prevent far more fractures than the atypical fractures they may cause. The risk appears to decrease after stopping bisphosphonates (11).

Osteonecrosis of the Jaw (ONJ)

Osteonecrosis of the jaw (ONJ) is a condition where the jawbone fails to heal, usually following dental surgery. In osteoporosis patients taking standard bisphosphonate doses, the incidence is very low, approximately 0.01% to 0.06%. The risk is substantially higher in cancer patients who receive much larger doses of intravenous bisphosphonates (9). A dental check-up before starting bisphosphonate treatment is a sensible precaution.

If you are concerned about the side effects of any particular bisphosphonate, discuss the alternatives with your doctor. In some cases, switching from an oral to an intravenous formulation (or vice versa) can resolve issues.

The Role of Exercise Alongside Bisphosphonates

Whether you’re at low, moderate, or high fracture risk, exercise should be part of your bone health strategy. This is true regardless of whether you take a bisphosphonate.

A well-designed osteoporosis exercise program doesn’t just build bone density. It improves balance, builds the muscle strength needed to reduce fall risk, and supports the posture changes that protect your spine from compression fractures. These benefits complement, they don’t replace, what bisphosphonates do, and bisphosphonates don’t replace what exercise does.

I’ve developed a free, seven-day email course called Exercise Recommendations for Osteoporosis that covers the essential principles of safe, effective exercise for bone health. It’s a good starting point whether or not you’re currently on medication.

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Bisphosphonate Reference Guide

Your doctor will recommend a specific bisphosphonate based on your medical history, tolerance, and treatment goals. Here is a brief overview of the four main options:

  1. Alendronate (Fosamax) is the most widely prescribed bisphosphonate. It’s taken as a weekly oral tablet and has the most extensive long-term safety data. It reduces the risk of vertebral, non-vertebral, and hip fractures. It’s often the default first choice for most patients and is the most common follow-on after anabolic treatment in clinical trials.
  2. Risedronate (Actonel) is available as a weekly or monthly oral tablet. It also reduces vertebral and non-vertebral fractures. It may have a slightly faster onset of fracture protection than alendronate, and some patients tolerate it better. However, its residual effect during a drug holiday may be shorter than alendronate’s.
  3. Ibandronate (Boniva) can be taken as a monthly oral tablet or quarterly IV infusion. It has been shown to reduce vertebral fractures, but the evidence for non-vertebral and hip fracture reduction is less robust than for alendronate, risedronate, or zoledronic acid.
  4. Zoledronic acid (Reclast) is given as a once-yearly IV infusion. It reduces vertebral, non-vertebral, and hip fractures. It avoids the gastrointestinal side effects of oral bisphosphonates entirely, making it a good option for patients who cannot tolerate oral formulations or have absorption issues. It’s increasingly favoured as the follow-on after EVENITY due to its potent antiresorptive effect and the convenience of annual dosing.

When to Take a Bisphosphonate

All oral bisphosphonates must be taken first thing in the morning on an empty stomach with a full glass of plain water, and you must remain upright for at least 30 minutes afterward without eating or drinking anything else. This can be inconvenient, but it is essential for both absorption and to protect your esophagus.

Conclusion

Bisphosphonates remain the backbone of osteoporosis treatment in 2026. Whether they’re your first medication after a diagnosis or your essential follow-on after EVENITY, Forteo, or Prolia, understanding when and why they’re the right choice puts you in a stronger position to work with your physician.

FAQs: Bisphosphonates

This section addresses common questions individuals have regarding bisphosphonates for osteoporosis or osteopenia. The answers are based on published guidelines. Always discuss your questions with your physician.

Bisphosphonates for Osteoporosis and Osteopenia: Key Takeaways

  • Bisphosphonates are confirmed as first-line treatment for most people with osteoporosis
  • If you’re at very high risk, an anabolic agent first (EVENITY or Forteo) followed by a bisphosphonate is the optimal sequence
  • Never stop Prolia without transitioning to a bisphosphonate or other antiresorptive therapy
  • Drug holidays are appropriate after 3-5 years for many patients, but the timing depends on your individual fracture risk
  • Exercise is essential alongside any medication strategy
  • If you have specific questions about your situation, bring this information to your next appointment and discuss it with your physician. The right choice depends on your unique medical profile, fracture history, and treatment goals.

Further Readings

References

  1. Ott, S. M. (2011). What is the optimal duration of bisphosphonate therapy? Cleveland Clinic Journal of Medicine, 78(9), 619–630. doi:10.3949/ccjm.78a.11022
  2. Qaseem A, et al. Pharmacologic treatment of primary osteoporosis or low bone mass to prevent fractures in adults: a living clinical guideline from the American College of Physicians. *Annals of Internal Medicine*. 2023;178(1):79-94.
  3. Camacho PM, et al. American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis — 2020 update. *Endocrine Practice*. 2020;26(Suppl 1):1-46.
  4. Reid IR, et al. Fracture prevention with zoledronate in older women with osteopenia. *New England Journal of Medicine*. 2018;379(25):2407-2416.
  5. Reid IR, et al. Bone loss after romosozumab/denosumab: effects of bisphosphonates. *Calcif Tissue Int*. 2018;102:1-7.
  6. Saag KG, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis (ARCH trial). *New England Journal of Medicine*. 2017;377(15):1417-1427.
  7. Cosman F, et al. Romosozumab and antiresorptive treatment: the importance of treatment sequence. *Osteoporosis International*. 2022;33:1243-1256.
  8. Cummings SR, et al. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. *Journal of Bone and Mineral Research*. 2018;33(2):190-198.
  9. Tsourdi E. Drug holidays with bisphosphonates in osteoporosis treatment: one size does not fit all. *Journal of Clinical Endocrinology & Metabolism*. 2025;110(3):e899-e900.
  10. Black DM, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX). *JAMA*. 2006;296(24):2927-2938.
  11. Adler RA, et al. Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a Task Force of the American Society for Bone and Mineral Research. *Journal of Bone and Mineral Research*. 2016;31(1):16-35.

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