Overview
- Pyrophosphate analogues that bind bone mineral and inhibit osteoclast resorption
- Nitrogen agents (alendronate, risedronate, zoledronic acid) inhibit farnesyl pyrophosphate synthase
- Used for osteoporosis, Paget’s disease, osteogenesis imperfecta, hypercalcaemia of malignancy and bone metastases
- Long term use linked to atypical femoral fractures, often with prodromal thigh pain
- Also osteonecrosis of the jaw, oesophageal irritation and acute phase reactions
Western Health Orthopaedic Registrar presentation – The Orthopaedic Implications of Diphosphonate Therapy by Dr Andrew Salipas
Definition
- Pyrophosphate analogues with a P-C-P backbone binding hydroxyapatite at active remodelling sites
- Non-nitrogen agents such as etidronate form non-hydrolysable ATP analogues causing osteoclast apoptosis
- Nitrogen agents inhibit farnesyl pyrophosphate synthase in the mevalonate pathway
- Poor oral absorption, skeletal half-life of years and renal excretion
Management
- Unsuitable for heterotopic ossification prophylaxis, since mineralisation proceeds once stopped
- NSAIDs or radiotherapy preferred for heterotopic ossification
- Zoledronic acid weeks after hip fracture repair reduced fractures and mortality without impairing healing
- Reduce periprosthetic bone loss after hip and knee arthroplasty
- Drug holiday after about 5 years oral or 3 years intravenous therapy in lower risk patients
- Denosumab needs bisphosphonate transition when stopped, because of rebound multiple vertebral fractures
Complications
- Atypical femoral fracture lies between the lesser trochanter and supracondylar flare
- ASBMR definition needs four of five major features
- Major features are minimal trauma, transverse lateral cortex origin, complete or incomplete pattern, minimal comminution and beaking
- Stop the drug, image the contralateral femur and consider teriparatide
- Cephalomedullary nail for complete fractures
- Consider prophylactic nailing for painful incomplete fractures
- Osteonecrosis of the jaw is exposed bone persisting beyond 8 weeks
- Jaw risk is very low at osteoporosis doses, and dental review beforehand reduces it
- Oesophagitis, acute phase reaction, hypocalcaemia and ocular inflammation
Reviewed by Professor Phong Tran, Head of Orthopaedic Surgery, Western Health. Last updated 10 October 2026.