What was the primary endpoint of the FREEDOM trial?

The primary endpoint was the incidence of new morphometric vertebral fractures over 36 months. Denosumab reduced this by 68% compared to placebo (2.3% vs 7.2%, RR 0.32 to 95% CI 0.26-0.41).

How many patients were enrolled in the FREEDOM trial?

FREEDOM enrolled 7,868 postmenopausal women aged 60-90 with osteoporosis (T-scores between -2.5 and -4.0 at the lumbar spine or total hip), randomized 1:1 to denosumab 60 mg or placebo every 6 months.

Did denosumab reduce hip fractures in the FREEDOM trial?

Yes. Hip fractures occurred in 0.7% of denosumab patients versus 1.2% of placebo patients, a 40% relative reduction (HR 0.60 to 95% CI 0.37-0.97, p=0.04). The upper confidence bound was close to 1.0, making this a borderline result.

How much did bone mineral density increase with denosumab?

At 36 months, lumbar spine BMD increased 9.2% from baseline with denosumab versus a 1.0% decrease with placebo. Total hip BMD increased 6.0% versus a 1.2% decrease. These gains continued without plateau in the 10-year extension.

Were there safety concerns in the FREEDOM trial?

The overall adverse event profile was similar between groups. Skin infections and eczema showed small numerical excesses with denosumab. No cases of osteonecrosis of the jaw or atypical femoral fracture were reported during the 3-year trial, though both emerged in the long-term extension study.

What happens when denosumab is discontinued?

The FREEDOM Extension showed that stopping denosumab leads to rapid BMD loss and a rebound in vertebral fracture rates that may exceed baseline risk. Current guidelines recommend transitioning to a bisphosphonate before discontinuing denosumab to preserve bone density gains.

How does denosumab compare to bisphosphonates for osteoporosis?

FREEDOM did not include a bisphosphonate comparator arm. BMD gains with denosumab over 3 years were generally larger than those reported for oral bisphosphonates like alendronate in separate trials. Head-to-head studies, such as the DECIDE trial, confirmed greater BMD gains with denosumab at certain skeletal sites.

What was the number needed to treat for vertebral fracture prevention?

Based on absolute risk reductions in FREEDOM, the NNT to prevent one vertebral fracture was approximately 53 at 1 year and approximately 20 at 3 years. This improvement with duration highlights the value of sustained treatment.

Did subgroup analyses show consistent benefit across patient populations?

Yes. The vertebral fracture reduction was consistent across prespecified subgroups including age, baseline BMD, prevalent fracture status, and geographic region. No subgroup interaction was statistically significant.

Is denosumab approved as first-line treatment for osteoporosis?

The FDA approved denosumab (Prolia) in 2010 for postmenopausal women at high fracture risk, based primarily on FREEDOM data. AACE and Endocrine Society guidelines list it as an appropriate first-line antiresorptive alongside bisphosphonates.

FREEDOM Results in Detail: Numbers, Subgroups, and Time Course

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, ages 60-90
Intervention: Denosumab 60 mg subcutaneous injection every 6 months
Comparator: Matching placebo injection every 6 months
Duration: 36 months
Primary endpoint: New morphometric vertebral fractures at 36 months
Key result: 68% relative risk reduction in vertebral fractures (2.3% vs 7.2%; RR 0.32 to 95% CI 0.26-0.41)

Why This Trial Changed Practice

Before FREEDOM published in the New England Journal of Medicine in August 2009, bisphosphonates were the default class for postmenopausal osteoporosis. Denosumab offered a different mechanism: a fully human monoclonal antibody targeting RANKL, the cytokine that drives osteoclast formation and survival. The FREEDOM trial was the key Phase 3 study that led to FDA approval of denosumab (brand name Prolia) in June 2010 for postmenopausal women at high fracture risk.

What made FREEDOM consequential was not just the primary endpoint hit. It was the consistency of benefit across fracture types, skeletal sites, and patient subgroups, paired with a safety profile that looked clean at 3 years.

Primary Endpoint: Vertebral Fracture Reduction

The primary endpoint was the cumulative incidence of new morphometric vertebral fractures over 36 months, assessed by vertebral fracture assessment (VFA) or spinal radiographs read centrally by a blinded team.

| Outcome | Denosumab (n=3,902) | Placebo (n=3,906) | Relative Risk (95% CI) | p-value | |---|---|---|---|---| | New vertebral fracture (36 mo) | 2.3% | 7.2% | 0.32 (0.26-0.41) | <0.001 | | Year 1 cumulative incidence | 0.9% | 2.8% | 0.33 (0.22-0.50) | <0.001 | | Year 2 cumulative incidence | 1.4% | 5.0% | 0.28 (0.20-0.39) | <0.001 |

The 68% reduction held remarkably steady across all three annual time points, which argues against a waning effect over the treatment period. By the first year, the fracture curves had already separated, with the denosumab group accumulating new vertebral fractures at roughly one-third the rate of placebo.

Time-Course Pattern: The FREEDOM Fracture Accrual Model

The year-by-year data reveal a pattern worth examining in clinical context. Fracture accrual in the placebo group was roughly linear: 2.8% at year 1 to 5.0% at year 2 to 7.2% at year 3, adding about 2.2 percentage points per year. The denosumab group also showed linear accrual but at a compressed rate: 0.9%, 1.4%, 2.3%. The absolute risk reduction widened from 1.9 percentage points at year 1 to 4.9 percentage points at year 3. This means the number needed to treat (NNT) improved with duration: NNT of approximately 53 at 1 year, falling to approximately 20 at 3 years.

This time-dependent benefit is clinically relevant for conversations about treatment commitment. A patient who stops denosumab after one year captures only a fraction of the fracture prevention seen at three years.

Secondary Endpoints: Hip and Nonvertebral Fractures

FREEDOM was powered for the vertebral endpoint, but the secondary endpoints also reached statistical significance.

| Fracture Type | Denosumab | Placebo | Hazard Ratio (95% CI) | p-value | |---|---|---|---|---| | Hip fracture | 0.7% | 1.2% | 0.60 (0.37-0.97) | 0.04 | | Nonvertebral fracture | 6.5% | 8.0% | 0.80 (0.67-0.95) | 0.01 | | Clinical vertebral fracture | 0.8% | 2.6% | 0.31 (0.20-0.47) | <0.001 | | Multiple new vertebral fractures | 0.1% | 1.6% | 0.03 (0.01-0.09) | <0.001 |

The hip fracture result deserves special attention. A 40% relative reduction sounds impressive, but the absolute numbers were small (0.7% vs 1.2%), and the confidence interval for the hazard ratio barely excluded 1.0 at the upper bound (0.97). This means the hip fracture benefit, while statistically significant, was a borderline finding in this population.

The most striking secondary result was the 97% reduction in multiple new vertebral fractures. Only 0.1% of denosumab-treated women developed two or more new vertebral fractures versus 1.6% in placebo. This suggests denosumab may be especially effective at preventing the cascade phenomenon where one vertebral fracture leads to additional fractures.

Bone Mineral Density: The Continuous Biomarker

BMD gains with denosumab were measured at the lumbar spine, total hip, and femoral neck. These data provide a continuous measure of treatment response, complementing the binary fracture endpoints.

| Site | BMD Change at 36 Months (Denosumab) | BMD Change at 36 Months (Placebo) | Treatment Difference | |---|---|---|---| | Lumbar spine | +9.2% | -1.0% | +10.2% | | Total hip | +6.0% | -1.2% | +7.2% | | Femoral neck | +4.8% | -0.8% | +5.6% | | One-third radius | +1.4% | -2.1% | +3.5% |

These BMD gains are larger than those typically reported for oral bisphosphonates over comparable periods. The Prolia prescribing information cites these FREEDOM data as the basis for efficacy claims. One notable feature: BMD continued to increase at each annual measurement without a plateau, suggesting ongoing anabolic potential over 3 years that was not seen with alendronate in head-to-head comparisons.

Bone Turnover Markers

Serum CTX (C-terminal telopeptide of type I collagen), a marker of bone resorption, dropped by approximately 86% from baseline within one month of the first denosumab injection. The effect was reversible: CTX levels rose between doses (the 6-month dosing interval) but remained suppressed compared to placebo. By month 36, median CTX reductions at the trough (just before the next injection) were still approximately 72% below placebo levels.

This pharmacodynamic profile differs from bisphosphonates, which produce sustained suppression between doses due to skeletal binding. The cyclical partial recovery of bone turnover between denosumab injections may have implications for bone quality, though FREEDOM was not designed to test this hypothesis directly.

Subgroup Analyses

FREEDOM's prespecified subgroup analyses examined fracture reduction consistency across baseline characteristics. The primary publication reported that the vertebral fracture benefit was consistent regardless of:

Age: Similar effect in women aged 60-70, 70-75, and >75 years
Baseline BMD T-score: Benefit seen whether lumbar spine T-score was above or below -2.5
Prevalent vertebral fracture status: Similar relative reduction in women with and without existing fractures
Geographic region: Consistent across North America, Europe, Latin America, and other regions

No subgroup showed a statistically significant interaction term, meaning no identifiable patient subset derived markedly more or less benefit. This broad consistency across subgroups contributed to the American Association of Clinical Endocrinology guidelines listing denosumab as an appropriate first-line option across the spectrum of postmenopausal osteoporosis severity.

Safety: What the 3-Year Data Showed

The overall adverse event rate was similar between groups. Serious adverse events occurred in 25.8% of denosumab patients and 25.1% of placebo patients. Several safety signals merit discussion.

Infections. Serious infections requiring hospitalization occurred in 4.1% of denosumab patients versus 3.4% of placebo patients. This did not reach statistical significance, but the numerical difference prompted ongoing monitoring in the extension study. Skin infections (cellulitis, erysipelas) showed a small excess with denosumab: 0.4% versus <0.1%.

Eczema and dermatologic events. Eczema was more common with denosumab (3.0% vs 1.7%). The mechanism remains unclear.

Neoplasms. Malignancies were balanced: 4.3% denosumab versus 3.6% placebo. No specific cancer type was enriched.

Osteonecrosis of the jaw (ONJ). Zero cases were reported in either group during the 3-year trial. ONJ cases did emerge in the long-term extension, but the initial FREEDOM data showed a clean signal.

Atypical femoral fracture. Not reported in the original trial. Like ONJ, this adverse event surfaced later with extended exposure.

Limitations the Authors Acknowledged

The FREEDOM investigators noted several limitations worth understanding when interpreting these results.

First, the trial enrolled only postmenopausal women aged 60-90 with T-scores between -2.5 and -4.0 at the lumbar spine or total hip. Women with very severe osteoporosis (T-score below -4.0) or those already on bisphosphonates were excluded. This limits generalizability to treatment-naive patients with moderate-to-severe disease.

Second, all participants received daily calcium (at least 1 to 000 mg) and vitamin D (at least 400 IU). The fracture reduction cannot be attributed to denosumab alone but to denosumab plus adequate supplementation.

Third, the trial was not designed or powered to detect rare adverse events like ONJ or atypical femoral fracture. Safety conclusions from FREEDOM should be interpreted alongside the 10-year extension data and post-marketing surveillance.

Fourth, morphometric vertebral fractures (the primary endpoint) are radiographic findings. Some are asymptomatic and found only on protocol-mandated imaging. Clinical vertebral fractures, which patients actually feel, were a secondary endpoint showing a 69% reduction.

What the Extension Revealed

The FREEDOM Extension enrolled 4,550 women from the original trial for up to 7 additional years of open-label denosumab. Women originally on denosumab (the "long-term group") received up to 10 years of continuous treatment. BMD continued to rise: lumbar spine BMD increased by 21.7% from original baseline at year 10, and total hip BMD by 9.2%. Fracture rates remained low. These extension data, published by Bone and colleagues, supported the case that denosumab does not show attenuation of benefit over a decade, a profile distinct from bisphosphonates where BMD gains typically plateau by years 3-5.

The extension also revealed the discontinuation problem. Women who stopped denosumab after the trial showed rapid BMD loss and a rebound increase in vertebral fractures, with rates exceeding those in the original placebo group. This rebound phenomenon, confirmed in subsequent analyses, now shapes clinical decision-making around treatment sequencing and the recommendation to transition to a bisphosphonate before stopping denosumab.

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
Prolia (denosumab) prescribing information. Amgen Inc. Revised 2020. FDA Label
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
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