# Bone-modifying agents (bisphosphonates, denosumab)

Source: https://onco.cc/technologies/bone-modifying-agents/  
OnCo record `bone-modifying-agents` (Technology). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Zoledronic acid and denosumab reduce fractures, spinal cord compression and bone pain from bone metastases and myeloma, prevent treatment-induced bone loss, and in postmenopausal breast cancer modestly reduce recurrence in bone.

## Summary

Pamidronate (1995, myeloma) and zoledronic acid (2002) reduce skeletal-related events by ~30-40%; denosumab (anti-RANKL, 2010) is superior to zoledronic acid for delaying SREs in solid tumours and non-inferior in myeloma, without renal dosing. Adjuvant bisphosphonates reduce bone recurrence and breast cancer mortality in postmenopausal women (EBCTCG 2015 meta-analysis: 3.3% absolute mortality reduction) and are guideline-recommended; denosumab did not improve disease outcomes adjuvantly (D-CARE). De-escalated dosing (12-weekly zoledronic acid, CALGB 70604) is standard. Osteonecrosis of the jaw (1-2%; dental review), hypocalcaemia, atypical femoral fractures and rebound vertebral fractures after stopping denosumab are the key harms. Also used for hypercalcaemia of malignancy and cancer-treatment-induced bone loss (aromatase inhibitors, ADT).

## Fields

- Kind: Technology
- Status: standard-of-care
- Last checked: 2026-09-08
- Tags: gap-fill; supportive
- Principle: Inhibit osteoclast-mediated bone resorption (bisphosphonates via farnesyl pyrophosphate synthase in osteoclasts; denosumab by neutralising RANKL) to reduce the vicious cycle between tumour cells and bone turnover.
- Since: 1995
- Strengths: Large reductions in fractures and cord compression; Adjuvant survival benefit in postmenopausal breast cancer; Generic zoledronic acid is cheap; 12-weekly dosing
- Limitations: Osteonecrosis of the jaw; Denosumab discontinuation rebound; Optimal duration unknown

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Bisphosphonate
- EBCTCG adjuvant bisphosphonates (Lancet 2015): https://doi.org/10.1016/S0140-6736(15)60908-4
- ASCO bone-modifying agents guideline: https://doi.org/10.1200/JCO.2017.75.4614

## Connected records

- cancers: [HR-positive / HER2-negative breast cancer](https://onco.cc/cancers/breast-hr-positive/), [Metastatic cancer (cancer that has spread)](https://onco.cc/cancers/metastatic-cancer/), [Multiple myeloma](https://onco.cc/cancers/multiple-myeloma/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Parathyroid carcinoma](https://onco.cc/cancers/parathyroid-carcinoma/), [Prostate cancer](https://onco.cc/cancers/prostate/), [Renal cell carcinoma](https://onco.cc/cancers/rcc/)
- fronts: [Recovery & Rejuvenation](https://onco.cc/fronts/rejuvenation/), [Supportive Care & Survivorship](https://onco.cc/fronts/supportive-care/)
- technologies: [Bone after childhood cancer: peak bone mass, osteonecrosis and what rebuilds](https://onco.cc/technologies/rejuv-paed-bone/), [Bone loss caused by cancer treatment, and what rebuilds it](https://onco.cc/technologies/cancer-treatment-bone-loss/), [Cancer pain management](https://onco.cc/technologies/pain-management/), [Palliative radiotherapy](https://onco.cc/technologies/palliative-radiotherapy/), [Survivorship care and late-effects surveillance](https://onco.cc/technologies/survivorship-care-plan/)
- drugs: [Denosumab](https://onco.cc/drugs/denosumab/), [Ibandronic acid](https://onco.cc/drugs/ibandronic-acid/), [Pamidronate](https://onco.cc/drugs/pamidronate/), [Radium-223 dichloride](https://onco.cc/drugs/radium-223/), [Zoledronic acid](https://onco.cc/drugs/zoledronic-acid/)
- companies: [Outperform Cancer](https://onco.cc/companies/outperform-cancer/)
- key papers: [Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials](https://onco.cc/key-papers/paper-early-breast-cancer-trialists-collaborative-group-ebctcg-lancet/), [Role of Bone-Modifying Agents in Metastatic Breast Cancer: An American Society of Clinical Oncology-Cancer Care Ontario Focused Guideline Update](https://onco.cc/key-papers/paper-van-poznak-j-clin-oncol/)
- terms: [Bone metastases and skeletal-related events](https://onco.cc/terms/bone-metastases/)
- pathways: [Organ tropism: seed and soil](https://onco.cc/pathways/organ-tropism-seed-soil/)
- targets: [RANK ligand (RANKL)](https://onco.cc/targets/rankl/)
- trials: [A Trial of SHR-2017 Injection in Patients With Bone Metastases From Solid Tumors](https://onco.cc/trials/nct07028268/)

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