How large was the vertebral fracture reduction in FREEDOM?

Denosumab reduced new vertebral fractures by 68% compared with placebo over 36 months (2.3% vs 7.2%, p <0.001). This was the primary endpoint and the basis for FDA approval of Prolia for postmenopausal osteoporosis.

Did FREEDOM show a reduction in hip fractures?

Yes. Hip fractures were reduced by 40% (0.7% vs 1.2%, p = 0.04). While the absolute numbers were small given the moderate-risk population, the reduction was statistically significant and clinically meaningful given the high mortality associated with hip fractures.

Can denosumab be used in patients with kidney disease?

Denosumab does not undergo renal clearance and is not contraindicated in chronic kidney disease. This gives it a practical advantage over bisphosphonates, which are generally avoided when eGFR falls below 30-35 mL/min. FREEDOM did not specifically enroll patients with severe renal impairment, but post-approval data supports its use in this population.

What happens when you stop taking denosumab?

Discontinuing denosumab without transitioning to another antiresorptive leads to rapid bone loss and, in some patients, rebound vertebral fractures within 7 to 18 months. Current guidelines recommend starting a bisphosphonate immediately after or within 6 months of the last denosumab injection.

Is denosumab better than bisphosphonates for osteoporosis?

FREEDOM compared denosumab to placebo, not to bisphosphonates. Head-to-head trials are limited. Denosumab generally produces greater BMD gains than oral bisphosphonates, but fracture reduction comparisons remain indirect. The choice depends on patient factors: renal function, adherence likelihood, and willingness to commit to long-term or indefinite therapy.

How often is denosumab administered?

Denosumab (Prolia) is given as a 60 mg subcutaneous injection every 6 months. In FREEDOM, injections were administered in-clinic, which contributed to high adherence rates compared with daily or weekly oral bisphosphonate regimens.

Does denosumab cause osteonecrosis of the jaw?

ONJ was not observed during the 3-year FREEDOM trial. During the 10-year extension study, the incidence was approximately 5.2 per 10,000 patient-years, comparable to oral bisphosphonate rates at osteoporosis doses. Dental screening before initiation is recommended but not universally mandated.

Who should not start denosumab based on FREEDOM's data?

Patients unlikely to maintain regular 6-month dosing schedules or follow-up care are poor candidates because missed doses can trigger rebound bone loss. Younger postmenopausal women (under 60) may face impractically long treatment commitments. Patients with very severe osteoporosis may benefit more from anabolic agents as initial therapy.

Did the FREEDOM trial include men?

No. FREEDOM enrolled only postmenopausal women. The ADAMO trial later demonstrated BMD benefits in men with osteoporosis, and the FDA approved Prolia for male osteoporosis, but the fracture reduction evidence in men is less definitive than in FREEDOM.

How long can patients stay on denosumab?

The FREEDOM Extension provided data through 10 years of continuous use, showing sustained BMD gains and a stable safety profile. There is no established maximum duration. Unlike bisphosphonates, there is no recommended drug holiday for denosumab because discontinuation carries rebound risk.

What FREEDOM Actually Changes in Clinical Practice

Q: Did FREEDOM show a reduction in hip fractures?

Yes. Hip fractures were reduced by 40% (0.7% vs 1.2%, p = 0.04). While the absolute numbers were small given the moderate-risk population, the reduction was statistically significant and clinically meaningful given the high mortality associated with hip fractures.

Q: Can denosumab be used in patients with kidney disease?

Denosumab does not undergo renal clearance and is not contraindicated in chronic kidney disease. This gives it a practical advantage over bisphosphonates, which are generally avoided when eGFR falls below 30-35 mL/min. FREEDOM did not specifically enroll patients with severe renal impairment, but post-approval data supports its use in this population.

Q: What happens when you stop taking denosumab?

Discontinuing denosumab without transitioning to another antiresorptive leads to rapid bone loss and, in some patients, rebound vertebral fractures within 7 to 18 months. Current guidelines recommend starting a bisphosphonate immediately after or within 6 months of the last denosumab injection.

Q: Is denosumab better than bisphosphonates for osteoporosis?

FREEDOM compared denosumab to placebo, not to bisphosphonates. Head-to-head trials are limited. Denosumab generally produces greater BMD gains than oral bisphosphonates, but fracture reduction comparisons remain indirect. The choice depends on patient factors: renal function, adherence likelihood, and willingness to commit to long-term or indefinite therapy.

Q: How often is denosumab administered?

Denosumab (Prolia) is given as a 60 mg subcutaneous injection every 6 months. In FREEDOM, injections were administered in-clinic, which contributed to high adherence rates compared with daily or weekly oral bisphosphonate regimens.

Q: Does denosumab cause osteonecrosis of the jaw?

ONJ was not observed during the 3-year FREEDOM trial. During the 10-year extension study, the incidence was approximately 5.2 per 10,000 patient-years, comparable to oral bisphosphonate rates at osteoporosis doses. Dental screening before initiation is recommended but not universally mandated.

Q: Who should not start denosumab based on FREEDOM's data?

Patients unlikely to maintain regular 6-month dosing schedules or follow-up care are poor candidates because missed doses can trigger rebound bone loss. Younger postmenopausal women (under 60) may face impractically long treatment commitments. Patients with very severe osteoporosis may benefit more from anabolic agents as initial therapy.

Q: Did the FREEDOM trial include men?

No. FREEDOM enrolled only postmenopausal women. The ADAMO trial later demonstrated BMD benefits in men with osteoporosis, and the FDA approved Prolia for male osteoporosis, but the fracture reduction evidence in men is less definitive than in FREEDOM.

Q: How long can patients stay on denosumab?

The FREEDOM Extension provided data through 10 years of continuous use, showing sustained BMD gains and a stable safety profile. There is no established maximum duration. Unlike bisphosphonates, there is no recommended drug holiday for denosumab because discontinuation carries rebound risk.

By HealthRX Medical Team

Published May 25, 2026Updated May 25, 2026Last reviewed May 25, 2026

At a glance

Trial name: FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months)
N: 7,868 postmenopausal women aged 60-90
Intervention: Denosumab 60 mg subcutaneously every 6 months
Comparator: Placebo (both groups received calcium and vitamin D)
Duration: 36 months
Primary endpoint: New vertebral fractures at 36 months
Key result: 68% relative risk reduction in new vertebral fractures (2.3% vs 7.2%; p <0.001)

Why This Trial Still Matters 17 Years Later

Bisphosphonates dominated osteoporosis treatment for two decades before FREEDOM published in 2009. The trial did not just add another drug to the list. It introduced a fundamentally different mechanism, RANKL inhibition, and forced guidelines to reconsider the entire treatment algorithm for postmenopausal bone loss.

The practical question clinicians face today is not whether denosumab works. That was settled. The question is which patients benefit most from choosing denosumab over a bisphosphonate, what the consequences of stopping it look like, and how FREEDOM's enrollment criteria compare with the patients actually sitting in clinic.

Methodology Worth Examining

FREEDOM enrolled 7,868 women between 60 and 90 years old with a lumbar spine or total hip T-score between -2.5 and -4.0 at either site. Women with severe vertebral fractures (more than two moderate or any severe morphometric fractures) were excluded, as were those on prior bisphosphonate therapy within the preceding 12 months.

This exclusion matters. The trial population skewed toward treatment-naive patients with moderate, not severe, osteoporosis. Women already on bisphosphonates, the exact population clinicians most often consider switching, were largely absent.

The HealthRX Practice-Translation Framework for FREEDOM

When applying FREEDOM's results to a specific patient, three filters help clarify whether the data actually applies:

Severity filter. FREEDOM excluded the sickest patients. Women with T-scores worse than -4.0 or multiple existing vertebral fractures were not represented. Extrapolating the 68% fracture reduction to these patients requires caution, though the FREEDOM Extension and real-world registries suggest benefit persists across severity ranges.
Treatment-sequence filter. Most patients starting denosumab today are switching from a bisphosphonate, not starting de novo. FREEDOM's placebo comparison does not directly answer whether denosumab outperforms an oral bisphosphonate in a head-to-head setting.
Discontinuation filter. FREEDOM was not designed to evaluate what happens when you stop. That question became clinically urgent only after post-marketing reports of rebound vertebral fractures upon discontinuation surfaced years later.

Results Beyond the Headline

The 68% vertebral fracture reduction grabs attention, but FREEDOM's secondary endpoints tell the fuller story.

| Endpoint | Denosumab | Placebo | Relative Risk Reduction | P-value | |---|---|---|---|---| | New vertebral fracture (36 mo) | 2.3% | 7.2% | 68% | <0.001 | | Hip fracture (36 mo) | 0.7% | 1.2% | 40% | 0.04 | | Nonvertebral fracture (36 mo) | 6.5% | 8.0% | 20% | 0.01 | | BMD gain, lumbar spine (36 mo) | +9.2% | -1.2% |, | <0.001 | | BMD gain, total hip (36 mo) | +6.0% | -1.0% |, | <0.001 |

The 40% hip fracture reduction is clinically significant because hip fractures carry the highest mortality burden among osteoporotic fractures. One-year mortality after hip fracture ranges from 15% to 30% in older women. That FREEDOM demonstrated this reduction in a moderate-severity population, where hip fracture rates are lower overall, makes the absolute benefit smaller but the signal genuine.

The nonvertebral fracture reduction of 20% was statistically significant but modest. This tracks with a pattern seen across osteoporosis trials: drugs that dramatically reduce vertebral fractures often show attenuated effects at nonvertebral sites, where fall mechanics and soft-tissue factors dilute skeletal-specific interventions.

Safety Profile: What the Trial Showed and What It Missed

FREEDOM reported similar rates of adverse events between groups. Serious infection rates were not significantly different (4.1% denosumab vs 3.4% placebo, p = 0.14), though a numerical imbalance triggered ongoing surveillance. RANKL plays a role in immune cell function, making immunosuppression a biologically plausible concern.

Two safety signals emerged only after FREEDOM:

Osteonecrosis of the jaw (ONJ). No cases were reported during the 3-year trial. ONJ cases appeared during the 10-year FREEDOM Extension, with a cumulative incidence of approximately 5.2 per 10,000 patient-years. This rate is comparable to oral bisphosphonates in the osteoporosis dosing range and far below oncology-dose denosumab (120 mg monthly).

Atypical femoral fractures (AFF). Extremely rare in FREEDOM and its extension, but reported in post-marketing surveillance. The FDA label for Prolia now includes AFF as a warning, consistent with the bisphosphonate class effect, though the mechanism for RANKL inhibitors may differ.

The safety signal that changed practice most was neither ONJ nor AFF. It was the rebound fracture phenomenon after discontinuation. Multiple case series documented rapid BMD loss and clustered vertebral fractures within 12 to 18 months of stopping denosumab. This was not detectable in FREEDOM because the trial did not include a withdrawal phase.

Which Guidelines Changed, and How

Every major osteoporosis society updated its recommendations after FREEDOM, though the specific placement of denosumab varies.

The American Association of Clinical Endocrinologists (AACE) 2020 guidelines list denosumab as a first-line option for postmenopausal osteoporosis at high fracture risk, alongside bisphosphonates. For very high-risk patients (recent fracture, T-score below -3.0, or high FRAX score), AACE recommends considering anabolic agents first, with denosumab as a sequential option.

The Endocrine Society 2019 guidelines position denosumab as an alternative to bisphosphonates for initial therapy, with particular preference when renal impairment limits bisphosphonate use. Denosumab does not undergo renal clearance, a practical advantage FREEDOM's design did not specifically test but that pharmacokinetic data supports.

The National Osteoporosis Foundation (now Bone Health & Osteoporosis Foundation) incorporated denosumab into its treatment algorithm without strict hierarchical preference over bisphosphonates, leaving the choice to clinician judgment based on patient factors.

A consistent thread across all guidelines: none recommend denosumab as a time-limited therapy. The discontinuation-rebound data forced every society to add language about mandatory transition to a bisphosphonate if denosumab is stopped.

Prescribing Patterns That Actually Shifted

FREEDOM's impact on real-world prescribing followed a predictable adoption curve, but with two inflection points that went beyond the usual post-approval ramp.

First inflection: renal impairment patients (2011-2013). Clinicians quickly identified denosumab's niche for patients with eGFR below 30-35 mL/min, where bisphosphonates are contraindicated or carry elevated risk. FREEDOM did not exclude patients with moderate renal impairment, and the drug's non-renal clearance made it the default choice for this subgroup.

Second inflection: adherence-driven switching (2014-2017). Oral bisphosphonate adherence is notoriously poor. Studies estimate that 50% of patients discontinue oral bisphosphonates within one year. The twice-yearly subcutaneous injection schedule of denosumab, administered in-office, offered a structural advantage. Several real-world database analyses showed improved persistence with denosumab compared with oral alendronate or risedronate.

The countertrend emerged around 2017, when accumulating discontinuation data cooled enthusiasm. Clinicians who had been freely switching patients to denosumab began reconsidering, recognizing they were committing patients to either indefinite therapy or a carefully managed transition back to bisphosphonates.

Patients Who Differ From the Trial Population

FREEDOM enrolled postmenopausal women aged 60-90 with T-scores between -2.5 and -4.0. Several common patient profiles fall outside these boundaries.

Men with osteoporosis. The ADAMO trial extended denosumab data to men, showing similar BMD improvements. The FDA approved Prolia for men with osteoporosis, but fracture reduction evidence remains less definitive than in FREEDOM.

Glucocorticoid-induced osteoporosis. Patients on chronic corticosteroids experience bone loss through mechanisms partially distinct from postmenopausal resorption. Limited head-to-head data suggests denosumab performs comparably to bisphosphonates in this setting, but FREEDOM did not enroll these patients.

Younger postmenopausal women (50-60). FREEDOM's minimum age was 60. Women in their 50s with osteoporosis face longer treatment horizons, making the indefinite-duration commitment to denosumab more consequential. Starting a bisphosphonate with residual skeletal benefit after discontinuation may be more practical for this group.

Patients with very severe osteoporosis. The exclusion of women with T-scores below -4.0 or multiple vertebral fractures means FREEDOM's data does not directly apply to the highest-risk patients. Current guidelines recommend anabolic agents (teriparatide or romosozumab) as initial therapy for very high-risk patients, followed by an antiresorptive like denosumab.

The Discontinuation Problem FREEDOM Did Not Anticipate

No discussion of FREEDOM's clinical implications is complete without addressing discontinuation. The European Calcified Tissue Society position paper documented rapid bone turnover marker rebound, accelerated BMD loss, and clustered vertebral fractures occurring 7 to 18 months after the last denosumab injection.

The mechanism is straightforward. Denosumab suppresses osteoclast activity by binding circulating RANKL. When the drug clears (half-life approximately 26 days), the accumulated RANKL pool drives a surge in osteoclast formation that exceeds baseline resorption rates. Bisphosphonates, by contrast, incorporate into the bone matrix and continue suppressing resorption for months to years after discontinuation.

Current consensus mandates transitioning to a bisphosphonate (typically alendronate or zoledronic acid) immediately after the last denosumab dose or within 6 months. This requirement fundamentally alters the prescribing calculus. Choosing denosumab is not a standalone decision. It is a commitment to a treatment sequence.

What This Means for Clinical Decisions in 2026

FREEDOM established denosumab as effective and safe for postmenopausal osteoporosis. Seventeen years of follow-up, extension data, and real-world experience have refined that picture into a more conditional recommendation.

Denosumab remains the strongest choice when oral bisphosphonate adherence is poor, renal function limits bisphosphonate use, or in-office administration ensures compliance. It is less ideal as a first-line agent in younger postmenopausal women facing decades of treatment, or in patients likely to discontinue therapy without reliable follow-up.

The trial's lasting contribution was proving that RANKL inhibition could reduce fractures across vertebral, hip, and nonvertebral sites. Its lasting limitation was that it could not predict the clinical complexity of stopping a drug that was designed to be taken indefinitely.

Frequently asked questions

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References

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. PubMed
Bone HG, Wagman RB, Brandi ML, et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol. 2017;5(7):513-523. PubMed
Tsourdi E, Langdahl B, Cohen-Solal M, et al. Discontinuation of denosumab therapy for osteoporosis: a systematic review and position statement by ECTS. Bone. 2017;105:11-17. PubMed
Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis, 2020 update. Endocr Pract. 2020;26(Suppl 1):1-46. PubMed
FDA Prolia (denosumab) prescribing information. FDA Label
Eastell R, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2019;104(5):1595-1622. PubMed