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Research · Medication

Denosumab

In the FREEDOM trial, denosumab injections cut new spine fractures from 7.2% to 2.3% against placebo in women with osteoporosis, and lowered hip fractures. Against bisphosphonates it raised bone density more, with fracture results that disagree. Stopping it brought spine fractures back, often several at once. Severe low calcium in dialysis patients carries an FDA boxed warning.

Add to Bio HackChecked 2026-11-14
Status
Prescription biologic in the US, injected under the skin. Prolia (60 mg every 6 months) is FDA-approved for postmenopausal women with osteoporosis at high risk for fracture, to increase bone mass in men with osteoporosis, for osteoporosis caused by steroid medicines, and for bone loss in men on androgen deprivation for prostate cancer and women on aromatase inhibitors for breast cancer. Prolia carries an FDA boxed warning, added in January 2024, for severe low calcium in advanced chronic kidney disease. Xgeva (120 mg every 4 weeks) is approved to prevent skeletal-related events in multiple myeloma and bone metastases from solid tumors, for giant cell tumor of bone, and for high calcium from cancer that did not respond to bisphosphonates.
Also called
Prolia, Xgeva, denosumab biosimilars, RANKL inhibitor, RANK ligand antibody, osteoporosis injection, bone metastasis injection
Taken for
osteoporosis, preventing fractures, spine fracture, hip fracture, bone density, bone loss from steroids, bone loss from prostate or breast cancer treatment, bone metastases, giant cell tumor of bone

Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on

Shown to help6

Reported risks9

What people take it for, and what was found

Shown to help6

ModerateStudied in women

Fractures in postmenopausal women with osteoporosis

Shown to cut new spine fractures by 68%, from 7.2% to 2.3% over 3 years, and hip fractures by 40% against placebo in women with osteoporosis.

Compared with placebo injections [1]; placebo, in a network of trials [2]

The numbers and sources
Effect
Over 36 months of 60 mg under the skin every 6 months, new spine fractures on x-ray occurred in 2.3% on denosumab and 7.2% on placebo (RR 0.32, 95% CI 0.26 to 0.41). Hip fractures were 0.7% against 1.2% (HR 0.60, 95% CI 0.37 to 0.97) and other nonvertebral fractures 6.5% against 8.0% (HR 0.80). Cancer, infection, heart disease, delayed fracture healing and low calcium did not rise, and there was no jaw osteonecrosis [1]. A network meta-analysis of 107 trials found denosumab lowered hip, nonvertebral and spine fractures against placebo, among the largest relative reductions with teriparatide, abaloparatide and romosozumab [2].
Population
7,868 women aged 60 to 90 with a bone density T-score below -2.5 [1]; 193,987 postmenopausal women in 107 trials [2].
Sources
[1], [2]
Caveats
The network abstract does not give denosumab's effect sizes [2]. All women took calcium and vitamin D [3].
LimitedStudied in women

Ten years of treatment

One open-label extension found yearly spine fractures stayed at 0.9 to 1.9% and spine bone density rose 21.7% over 10 years of denosumab in women with osteoporosis.

Compared with before treatment, in the same women, and a projected placebo group [4]

The numbers and sources
Effect
Yearly new spine fractures ranged from 0.90% to 1.86% and nonvertebral fractures from 0.84% to 2.55%, similar to the first 3 years of FREEDOM and lower than a projected long-term placebo group. Bone density rose 21.7% at the spine and 9.2% at the total hip from FREEDOM baseline. Serious adverse events stayed at 11.5 to 14.4 per 100 participant-years [4].
Population
4,550 women who completed FREEDOM, 2,626 of whom finished the 7-year extension [4].
Sources
[4]
Caveats
No placebo group after year 3, and women who stayed were those who tolerated the drug. Funded by Amgen [4].
LimitedStudied in men

Spine fractures in men on hormone therapy for prostate cancer

One trial found new spine fractures fell from 3.9% to 1.5% over 3 years against placebo in men on androgen deprivation for prostate cancer.

Compared with placebo injections [8]

The numbers and sources
Effect
At 36 months, new spine fractures occurred in 1.5% on denosumab 60 mg every 6 months and 3.9% on placebo (RR 0.38, 95% CI 0.19 to 0.78). Spine bone density rose 5.6% against a 1.0% loss at 24 months. Adverse events were similar [8].
Population
1,468 men on androgen deprivation for nonmetastatic prostate cancer [8].
Sources
[8]
Caveats
One trial. Fracture was a secondary end point [8].
Why limited
This rests on one trial, of 1,468 people. Strength counts independent studies that agree, so one trial is limited at any size.
LimitedStudied in women

Fractures in women on aromatase inhibitors for breast cancer

One trial found clinical fractures halved against placebo in postmenopausal women taking aromatase inhibitors for early breast cancer, with no jaw osteonecrosis.

Compared with placebo injections [9]

The numbers and sources
Effect
Time to first clinical fracture was delayed on denosumab 60 mg every 6 months (HR 0.50, 95% CI 0.39 to 0.65), with 92 fractures against 176 on placebo. The effect held with normal or low bone density at the start. Adverse and serious adverse events did not differ, and no jaw osteonecrosis was found [9].
Population
3,420 postmenopausal women with early hormone receptor-positive breast cancer on aromatase inhibitors [9].
Sources
[9]
Caveats
One trial.
Why limited
This rests on one trial, of 3,420 people. Strength counts independent studies that agree, so one trial is limited at any size.
Limited

Bone loss from steroid medicines

One trial found denosumab raised spine and hip bone density more than oral risedronate over 2 years in people on steroid medicines, with similar fractures.

Compared with oral risedronate, double-dummy [10]

The numbers and sources
Effect
At 24 months, spine bone density rose 6.2% on denosumab and 1.7% on risedronate in people starting steroids, and 6.4% and 3.2% in those continuing them. Total hip density rose 3.1% against 0.0% and 2.9% against 0.5%. Adverse events, serious infections and fractures were similar [10].
Population
795 adults on glucocorticoids, 74% of whom completed 24 months [10].
Sources
[10]
Caveats
Fractures were not the primary outcome [10].
Moderate

Skeletal events with bone metastases

Shown to delay a first fracture, spinal cord compression, or bone radiation or surgery by about 8 months against zoledronic acid in cancer spread to bone, with similar survival.

Compared with intravenous zoledronic acid [11][12]

The numbers and sources
Effect
Pooling three double-blind trials, Xgeva delayed the first skeletal-related event by a median 8.21 months and lowered its risk by 17% against zoledronic acid (HR 0.83, 95% CI 0.76 to 0.90). Disease progression and overall survival were similar. Low calcium was more common on denosumab, and jaw osteonecrosis was similar [11]. A meta-analysis of the same three trials found fewer skeletal events (OR 0.84, 95% CI 0.74 to 0.95), with no significant difference in pathological fractures alone (OR 0.78) [12].
Population
Patients with breast cancer, prostate cancer, other solid tumors or multiple myeloma with bone involvement, 4,050 in 3 RCTs [11][12].
Sources
[11], [12]
Caveats
Both analyses pool the same three trials [11][12].

Mixed results1

Strong

Compared with bisphosphonates

Mixed results: denosumab raised bone density 1 to 2% more than bisphosphonates in head-to-head trials, while reviews disagree on whether it also lowered fractures.

Compared with bisphosphonates, mostly oral alendronate [5][6][7]

The numbers and sources
Effect
Across 10 head-to-head trials, denosumab raised bone density more than bisphosphonates at 12 months (spine 1.42%, total hip 1.11%) and 24 months (spine 1.74%). Fractures did not differ at 12 months, and one trial found fewer osteoporotic fractures than alendronate at 24 months (RR 0.51, 95% CI 0.27 to 0.97) [5]. A review of 23 trials in people not treated before found no fracture difference (RR 0.99, 95% CI 0.62 to 1.57) [6]. A review of harms in 11 trials found fewer spine fractures on denosumab (RR 0.54, 95% CI 0.31 to 0.93) and fewer withdrawals for side effects (RR 0.49) [7].
Population
5,361 participants in 10 RCTs [5]; 6,680 patients in 23 RCTs [6]; 11 RCTs in primary osteoporosis [7].
Sources
[5], [6], [7]
Caveats
Most trials were powered for bone density, not fractures [5]. All trials in [7] had a risk of bias. More findings on bisphosphonates are on their page.

Doses studied

Prolia's trials and label use 60 mg under the skin once every 6 months, with calcium of at least 1,000 mg and vitamin D of at least 400 IU a day [1][3]. FREEDOM ran 3 years [1] and its open-label extension a further 7 [4]. The prostate and breast cancer bone-loss trials used the same 60 mg every 6 months [8][9]. Xgeva's trials used 120 mg under the skin every 4 weeks [13]. D-CARE used 120 mg every 3 to 4 weeks for about 6 months, then every 12 weeks to 5 years [14].

Risks

Reported risks9

LimitedVery common

FDA boxed warning: severe low calcium in advanced kidney disease

FDA states Prolia raises the risk of severe low calcium in advanced kidney disease, mostly on dialysis, with deaths. One cohort found it in 41% within 12 weeks.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
FDA added the boxed warning in January 2024 after its review found severe hypocalcemia in patients with advanced chronic kidney disease, particularly on dialysis and with mineral and bone disorder, with hospitalization, life-threatening events and death. Most cases arose 2 to 10 weeks after an injection [15]. In female dialysis patients aged 65 and older, severe low calcium within 12 weeks occurred in 41.1% after denosumab against 2.0% after oral bisphosphonates (weighted RR 20.7), and very severe low calcium in 10.9% against 0.4% [16]. The label applies the warning to eGFR below 30 mL/min/1.73 m2 [3].
Population
Medicare patients reviewed by FDA [15]; 1,523 women on dialysis given denosumab and 1,281 given oral bisphosphonates [16].
Sources
[15], [16], [3]
Caveats
Observational data. Severe was a corrected calcium below 7.5 mg/dL or emergency care [16].
ModerateVery common

Common side effects

Back pain, limb pain and muscle pain were very common on Prolia and about as common on placebo. Raised cholesterol was reported in 7.2% against 6.1%.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
In FREEDOM, back pain occurred in 34.7% on Prolia and 34.6% on placebo, pain in a limb in 11.7% against 11.1%, musculoskeletal pain in 7.6% against 7.5%, high cholesterol in 7.2% against 6.1%, and cystitis in 5.9% against 5.8%. Pancreatitis occurred in 0.2% against 0.1%. Severe, sometimes disabling bone, joint or muscle pain has been reported after approval [3].
Population
3,886 women on Prolia and 3,876 on placebo [3].
Sources
[3]
Caveats
Label table of reactions more common than placebo [3].
ModerateCommon

Low calcium in people without advanced kidney disease

Shown to lower calcium below normal in 1.7% against 0.4% on placebo in osteoporosis, and severely in 3.1% on Xgeva against 1.3% on zoledronic acid.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
In FREEDOM, calcium fell below 8.5 mg/dL at any visit in 1.7% on Prolia and 0.4% on placebo, lowest about 10 days after a dose [3]. In the cancer trials, severe low calcium (below 7 mg/dL) occurred in 3.1% on Xgeva and 1.3% on zoledronic acid, and a third of those had two or more episodes [13]. In D-CARE, low calcium was 7% against 4% on placebo [14].
Population
7,762 women in FREEDOM [3]; patients with bone metastases in three trials [13]; 4,459 women with early breast cancer [14].
Sources
[3], [13], [14]
Caveats
All trial participants took calcium and vitamin D [3].
ModerateStudied in womenCommon

Rebound spine fractures after stopping

Shown to let spine fractures return after stopping, from 1.2 to 7.1 per 100 women a year, with 61% of those who fractured having several at once.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
In 1,001 women who stopped denosumab in FREEDOM or its extension, spine fractures rose from 1.2 per 100 participant-years on treatment to 7.1 off it, similar to 8.5 after stopping placebo. Of those with a fracture off treatment, 60.7% had multiple spine fractures against 38.7% after placebo, a 3.4% and 2.2% risk. Past spine fracture raised the odds 3.9 times [17]. The label states 6% of women who stopped developed new spine fractures and 3% multiple, starting 7 to 43 months after the last dose, and that bone density returns to pretreatment values within 18 months [3].
Population
1,001 women who stopped denosumab and 470 who stopped placebo, followed at least 7 months [17]; FREEDOM participants [3].
Sources
[17], [3]
Caveats
A post hoc analysis [17]. The label states that patients who stop are to be moved to another antiresorptive drug [3].
ModerateCommon

Jaw osteonecrosis

Shown to cause jaw osteonecrosis in about 2 to 5% at cancer doses, rising with years of use, and in 13 of 4,550 women over 10 years at osteoporosis doses.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
In the bone metastasis trials, jaw osteonecrosis was confirmed in 1.8% on Xgeva and 1.3% on zoledronic acid. In a 7-year trial in prostate cancer, the yearly rate reached 7% after the second year. In multiple myeloma it was 4.1% against 2.8% [13]. In D-CARE it was 5% on denosumab 120 mg and under 1% on placebo [14]. At the osteoporosis dose, 13 cases occurred in 4,550 women over up to 10 years [4]. Most cases followed tooth extraction, poor oral hygiene or a dental appliance [13].
Population
Patients with bone metastases, prostate cancer and myeloma [13]; 4,459 women with early breast cancer [14]; 4,550 women with osteoporosis [4].
Sources
[13], [14], [4]
Caveats
Rates at the 60 mg osteoporosis dose are much lower than at the 120 mg cancer dose.
ModerateCommon

Serious infections and skin reactions

Shown to raise serious infections slightly, 4.0% against 3.3% on placebo, and skin reactions such as eczema, 10.8% against 8.2%, in women with osteoporosis.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
In FREEDOM, nonfatal serious infections occurred in 4.0% on Prolia and 3.3% on placebo. Skin infections leading to hospital, including cellulitis, were 0.4% against under 0.1%, and endocarditis occurred in 3 women on Prolia and none on placebo. Dermatitis, eczema and rashes occurred in 10.8% against 8.2% [3]. Against bisphosphonates, infections were slightly more common (RR 1.14, 95% CI 1.02 to 1.27) [7].
Population
7,808 women in FREEDOM [3]; 11 head-to-head trials [7].
Sources
[3], [7]
Caveats
Deaths from infection were 0.2% in both groups [3].
LimitedRare

Atypical thigh bone fractures

The label warns of atypical low-trauma fractures of the thigh bone shaft. Two occurred in 4,550 women over up to 10 years.

The numbers and sources
How common
Rare: fewer than 1 in 1,000 people.
Effect
One atypical femoral fracture occurred in each group during the 7-year extension [4]. The label states these fractures were reported as early as 2.5 years into treatment, may affect both legs, often follow weeks of thigh pain, and also occur in untreated people with osteoporosis [3].
Population
4,550 women with osteoporosis [4]; trial and postmarketing reports [3].
Sources
[4], [3]
Caveats
The label states causality has not been established [3].
LimitedHow often is not known

Heart events against bisphosphonates

One review linked denosumab to about twice the major cardiovascular events of bisphosphonates in head-to-head trials. The authors call it a finding to confirm.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Against bisphosphonates, denosumab was associated with more five-point major adverse cardiovascular events (RR 2.05, 95% CI 1.03 to 4.09) and more cardiovascular adverse events (RR 1.61, 95% CI 1.07 to 2.41) [7]. In FREEDOM, cardiovascular disease did not rise against placebo [1].
Population
11 head-to-head RCTs in primary osteoporosis [7]; 7,868 women [1].
Sources
[7], [1]
Caveats
All trials had a risk of bias, and cardiovascular events were not primary outcomes [7].
LimitedHow often is not known

Use in pregnancy

The label states Prolia is contraindicated in pregnancy. In monkeys, high doses raised fetal loss and stillbirth and stopped lymph node formation.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Human data are too few to assess risk. Monkeys given 50 times the human dose through pregnancy had more fetal loss, stillbirths and infant deaths, absent lymph nodes, abnormal bone growth and dental dysplasia [3].
Population
Cynomolgus monkeys and RANKL knockout mice [3].
Sources
[3]
Caveats
Animal data [3].

Claims tested and not found

  1. That denosumab prevents breast cancer from spreading to bone. In D-CARE, bone metastasis-free survival did not differ from placebo (HR 0.97, 95% CI 0.82 to 1.14) [14].
  2. That denosumab extends survival in cancer spread to bone. Overall survival was similar to zoledronic acid [11].

Related

Bisphosphonates

Sources

  1. Cummings SR, San Martin J, McClung MR, et al. Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis. New England Journal of Medicine. 2009. https://doi.org/10.1056/nejmoa0809493
  2. Barrionuevo P, Kapoor E, Asi N, et al. Efficacy of Pharmacological Therapies for the Prevention of Fractures in Postmenopausal Women: A Network Meta-Analysis. The Journal of Clinical Endocrinology & Metabolism. 2019. https://doi.org/10.1210/jc.2019-00192
  3. US Food and Drug Administration. Prolia (denosumab injection) prescribing information, revised July 2026. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=49e5afe9-a0c7-40c4-af9f-f287a80c5c88
  4. 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. The Lancet Diabetes & Endocrinology. 2017. https://doi.org/10.1016/s2213-8587(17)30138-9
  5. Lyu H, Jundi B, Xu C, et al. Comparison of Denosumab and Bisphosphonates in Patients With Osteoporosis: A Meta-Analysis of Randomized Controlled Trials. The Journal of Clinical Endocrinology & Metabolism. 2019. https://doi.org/10.1210/jc.2018-02236
  6. Li M, Ge Z, Zhang B, et al. Efficacy and safety of teriparatide vs. bisphosphonates and denosumab vs. bisphosphonates in osteoporosis not previously treated with bisphosphonates: a systematic review and meta-analysis of randomized controlled trials. Archives of Osteoporosis. 2024. https://doi.org/10.1007/s11657-024-01447-7
  7. Kobayashi T, Morimoto T, Ito K, Mawatari M, Shimazaki T. Denosumab vs. bisphosphonates in primary osteoporosis: a meta-analysis of comparative safety in randomized controlled trials. Osteoporosis International. 2024. https://doi.org/10.1007/s00198-024-07118-0
  8. Smith MR, Egerdie B, Toriz NH, et al. Denosumab in Men Receiving Androgen-Deprivation Therapy for Prostate Cancer. New England Journal of Medicine. 2009. https://doi.org/10.1056/nejmoa0809003
  9. Gnant M, Pfeiler G, Dubsky PC, et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. The Lancet. 2015. https://doi.org/10.1016/s0140-6736(15)60995-3
  10. Saag KG, Pannacciulli N, Geusens P, et al. Denosumab Versus Risedronate in Glucocorticoid-Induced Osteoporosis: Final Results of a Twenty-Four-Month Randomized, Double-Blind, Double-Dummy Trial. Arthritis & Rheumatology. 2019. https://doi.org/10.1002/art.40874
  11. Lipton A, Fizazi K, Stopeck AT, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. European Journal of Cancer. 2012. https://doi.org/10.1016/j.ejca.2012.08.002
  12. Zhang Z, Pu F, Shao Z. The skeletal-related events of denosumab versus zoledronic acid in patients with bone metastases: A meta-analysis of randomized controlled trials. Journal of Bone Oncology. 2017. https://doi.org/10.1016/j.jbo.2017.09.003
  13. US Food and Drug Administration. Xgeva (denosumab injection) prescribing information, revised July 2026. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=628f0998-1206-4001-aeee-18133aa9f3bf
  14. Coleman R, Finkelstein DM, Barrios C, et al. Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial. The Lancet Oncology. 2020. https://doi.org/10.1016/s1470-2045(19)30687-4
  15. US Food and Drug Administration. FDA adds Boxed Warning for increased risk of severe hypocalcemia in patients with advanced chronic kidney disease taking osteoporosis medicine Prolia (denosumab). Drug Safety Communication. 2024. https://www.fda.gov/drugs/drug-safety-communications/fda-adds-boxed-warning-increased-risk-severe-hypocalcemia-patients-advanced-chronic-kidney-disease
  16. Bird ST, Smith ER, Gelperin K, et al. Severe Hypocalcemia With Denosumab Among Older Female Dialysis-Dependent Patients. JAMA. 2024. https://doi.org/10.1001/jama.2023.28239
  17. Cummings SR, Ferrari S, Eastell R, 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. https://doi.org/10.1002/jbmr.3337

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