Anti-resorptive | Inhibit osteoclasts | First-line for osteoporosis | Watch for atypical femoral fracture and jaw osteonecrosis
TWO CLASSES BY CHEMISTRY
Critical Must-Knows
- Anti-resorptive: bisphosphonates bind hydroxyapatite at sites of active remodelling and are taken up by osteoclasts, where they impair function and trigger apoptosis - bone resorption falls and bone density rises
- Nitrogen-containing agents (alendronate, zoledronate) inhibit farnesyl pyrophosphate synthase in the mevalonate pathway, blocking prenylation of GTPases the osteoclast needs to survive and ruffle its border
- First-line for osteoporosis and proven to cut fractures: zoledronic acid reduced vertebral fractures by about 70 percent and hip fractures by about 41 percent
- Atypical femoral fracture (AFF): subtrochanteric or diaphyseal, transverse, with lateral cortical thickening - prodromal thigh pain warrants radiographs of BOTH femurs
- Osteonecrosis of the jaw (MRONJ): higher risk with intravenous and oncology-dose therapy and after dental extraction - arrange dental review before starting where possible
Clinical Pearls
- "Oral dosing must be taken on an empty stomach with a full glass of water, staying upright for 30 to 60 minutes - this prevents pill oesophagitis
- "Correct vitamin D and calcium and check renal function first - avoid zoledronate if eGFR is less than 35
- "A first intravenous dose often causes a flu-like acute phase reaction - warn the patient
- "AFF risk rises with longer treatment duration, which is the rationale for the drug holiday
Clinical Imaging
Atypical Femoral Fracture - the radiographs to recognise
Critical Bisphosphonate Exam Points
Mechanism
Bisphosphonates are pyrophosphate analogues that bind bone mineral and are swallowed by osteoclasts during resorption. Nitrogen-containing agents then inhibit farnesyl pyrophosphate synthase, the osteoclast loses its ruffled border and undergoes apoptosis, and resorption falls. This is the classic basic-science viva answer.
Atypical Femoral Fracture
Subtrochanteric or diaphyseal, transverse fracture with lateral cortical thickening (beaking), often a medial spike, frequently bilateral, and preceded by thigh pain. New thigh pain on a bisphosphonate means radiograph BOTH femurs.
Osteonecrosis of the Jaw
Exposed necrotic jaw bone for more than 8 weeks in a patient on an antiresorptive with no prior jaw radiotherapy. Risk is far higher with intravenous / oncology dosing and after dental extraction - dental review before starting.
Before You Prescribe
Check and correct calcium and vitamin D (hypocalcaemia risk), assess renal function (avoid zoledronate if eGFR less than 35), and counsel on oral administration to avoid oesophagitis.
Memory aids
GROANBisphosphonate Complications
| G | GI / oesophagitis Oral agents - administration matters |
| R | Renal impairment Avoid IV zoledronate if eGFR low |
| O | Osteonecrosis of the jaw IV and dental work raise risk |
| A | Atypical femoral fracture Subtrochanteric, transverse, thigh-pain prodrome |
| N | Need calcium check (and acute phase reaction) Correct calcium and vitamin D, warn of the first-dose flu-like reaction |
| G | GI / oesophagitis Oral agents - administration matters | A | Atypical femoral fracture Subtrochanteric, transverse, thigh-pain prodrome |
| R | Renal impairment Avoid IV zoledronate if eGFR low | N | Need calcium check (and acute phase reaction) Correct calcium and vitamin D, warn of the first-dose flu-like reaction |
| O | Osteonecrosis of the jaw IV and dental work raise risk |
Hook:Patients GROAN about bisphosphonates - GI, Renal, Osteonecrosis of jaw, Atypical fracture, Need calcium check.
STAMPAtypical Femoral Fracture Features
| S | Subtrochanteric / diaphyseal Location below the lesser trochanter to the shaft |
| T | Transverse fracture line Starts at the lateral cortex |
| A | Antecedent thigh pain Prodrome for weeks to months |
| M | Medial spike With minimal comminution |
| P | Pointy lateral beaking (and bilateral) Focal lateral cortical thickening, image both sides |
| S | Subtrochanteric / diaphyseal Location below the lesser trochanter to the shaft | M | Medial spike With minimal comminution |
| T | Transverse fracture line Starts at the lateral cortex | P | Pointy lateral beaking (and bilateral) Focal lateral cortical thickening, image both sides |
| A | Antecedent thigh pain Prodrome for weeks to months |
Hook:STAMP out atypical fractures - thigh pain plus a transverse subtrochanteric line with lateral beaking means image both femurs.
WAVESafe Oral Dosing
| W | Water - full glass Plain water only |
| A | After waking, before food Empty stomach for absorption |
| V | Vertical - stay upright 30 to 60 minutes to avoid oesophagitis |
| E | Everything else waits No food, calcium, or other drugs for 30 to 60 minutes |
| W | Water - full glass Plain water only | V | Vertical - stay upright 30 to 60 minutes to avoid oesophagitis |
| A | After waking, before food Empty stomach for absorption | E | Everything else waits No food, calcium, or other drugs for 30 to 60 minutes |
Hook:Ride the WAVE - Water, After waking, Vertical, Everything else waits.
Overview
Bisphosphonates are the most widely used anti-resorptive drugs in orthopaedic and metabolic bone practice. They reduce bone turnover by inhibiting osteoclasts, which slows bone loss, raises bone mineral density, and lowers fracture risk. They are first-line treatment for osteoporosis and are also used in Paget disease, hypercalcaemia of malignancy, bone metastases and multiple myeloma, and paediatric osteogenesis imperfecta.
For the exam, three threads matter and recur throughout this topic: how they work (a clean basic-science mechanism), what they prevent (fractures, with strong randomised evidence), and what can go wrong (the rare but heavily examined complications of atypical femoral fracture and osteonecrosis of the jaw, and the drug-holiday concept that follows from them).
Mechanism of Action
Bisphosphonates are stable synthetic analogues of pyrophosphate, in which the central oxygen is replaced by a carbon atom (the P-C-P backbone). That carbon makes them resistant to enzymatic breakdown, and two side chains determine behaviour: one side chain (usually a hydroxyl) gives high affinity for bone mineral, while the second side chain determines anti-resorptive potency.
How they reach and act on the osteoclast:
- After absorption, bisphosphonates rapidly bind hydroxyapatite at sites of active bone remodelling, where mineral is exposed.
- During resorption the osteoclast ingests bone mineral and, with it, the bound bisphosphonate.
- Inside the osteoclast the drug disrupts function, the ruffled border is lost, and the cell undergoes apoptosis.
- Net effect: osteoclast-mediated resorption falls, the remodelling space closes, secondary mineralisation continues, and bone mineral density rises.
Two chemical classes with different intracellular targets:
Non-nitrogen vs Nitrogen-containing Bisphosphonates
| Feature | Non-nitrogen (older) | Nitrogen-containing (modern) |
|---|---|---|
| Examples | Etidronate, clodronate, tiludronate | Alendronate, risedronate, ibandronate, zoledronate |
| Intracellular target | Incorporated into non-hydrolysable ATP analogues that poison the osteoclast | Inhibit farnesyl pyrophosphate synthase in the mevalonate pathway |
| Downstream effect | Direct cytotoxicity to the osteoclast | Loss of GTPase prenylation (Ras, Rho, Rac), so the osteoclast cannot ruffle or survive |
| Potency / current use | Lower potency, largely historical | High potency, first-line agents today |
The mevalonate-pathway step is the high-yield detail: nitrogen-containing bisphosphonates block farnesyl pyrophosphate synthase, so the small GTPases that the osteoclast depends on are never prenylated (lipid-anchored to the membrane). Statins act on the same pathway higher up (HMG-CoA reductase), which is a favourite linking question.
Agents, Potency and Routes
Common Bisphosphonates
| Agent | Class | Typical route and dose | Notes |
|---|---|---|---|
| Alendronate | Nitrogen-containing | Oral 70mg weekly | Most widely used first-line oral agent |
| Risedronate | Nitrogen-containing | Oral 35mg weekly | Alternative oral agent, similar efficacy |
| Zoledronic acid | Nitrogen-containing | IV 5mg once yearly (osteoporosis) | Most potent, useful if oral not tolerated |
| Pamidronate | Nitrogen-containing | IV infusion | Paget disease, hypercalcaemia, paediatric osteogenesis imperfecta |
| Etidronate | Non-nitrogen | Oral | Older agent, can impair mineralisation if used continuously |
Relative potency runs zoledronate greater than risedronate greater than ibandronate greater than alendronate greater than etidronate, reflecting both binding affinity for bone mineral and how strongly each inhibits the target enzyme.
Indications
Osteoporosis
Postmenopausal, male, and glucocorticoid-induced osteoporosis - the commonest indication and first-line pharmacological therapy for fracture prevention.
Paget Disease of Bone
Reduce pain and disordered bone turnover. A single zoledronic acid infusion gives durable suppression of the elevated alkaline phosphatase.
Malignancy
Hypercalcaemia of malignancy, and reduction of skeletal-related events in bone metastases and multiple myeloma (usually higher, more frequent dosing than in osteoporosis).
Paediatric
Osteogenesis imperfecta - cyclical intravenous pamidronate reduces fracture rate and bone pain in moderate to severe disease.
Clinical Relevance
Bisphosphonates appear across every part of the exam and daily practice. In fracture clinic and fracture liaison services they are the backbone of secondary prevention after a fragility fracture. In basic-science vivas the mevalonate-pathway mechanism is a classic ask. In trauma and arthroplasty the recognition and management of atypical femoral fractures, and the dental implications of osteonecrosis of the jaw, are common scenarios. Knowing when to start, when to pause (drug holiday), and what to warn patients about is the practical core that examiners probe.
Evidence for Fracture Prevention
Once-Yearly Zoledronic Acid Reduces Fractures (HORIZON-PFT)
- Double-blind RCT, 7765 postmenopausal women, annual 5mg zoledronic acid infusion vs placebo over 3 years
- Morphometric vertebral fracture reduced by about 70 percent (3.3 vs 10.9 percent)
- Hip fracture reduced by about 41 percent (1.4 vs 2.5 percent)
- Serious atrial fibrillation occurred more often with zoledronic acid (50 vs 20 patients)
Alendronate as the Standard Active Comparator (ARCH)
- RCT in 4093 high-risk postmenopausal women using oral alendronate 70mg weekly as the active comparator
- Confirms alendronate as an effective, guideline-standard anti-resorptive for fracture prevention
- Romosozumab followed by alendronate lowered new vertebral fracture by 48 percent versus alendronate alone
- Adjudicated osteonecrosis of the jaw and atypical femoral fracture were rare events in both arms
Complications
Bisphosphonate Complications
| Complication | Who and when | Key point |
|---|---|---|
| Pill oesophagitis | Oral agents, poor administration | Empty stomach, full glass of water, stay upright 30 to 60 minutes |
| Acute phase reaction | First IV dose | Flu-like fever and myalgia for 1 to 3 days - warn and pre-hydrate |
| Hypocalcaemia | Vitamin D deficient or untreated | Correct calcium and vitamin D before starting |
| Renal impairment | IV zoledronate | Avoid if eGFR is less than 35, infuse slowly, ensure hydration |
| Atypical femoral fracture | Long-duration use | Subtrochanteric or diaphyseal, transverse, thigh-pain prodrome |
| Osteonecrosis of the jaw | IV / oncology dosing, dental work | Exposed necrotic jaw bone for more than 8 weeks |
Atypical Femoral Fracture (AFF)
AFFs occur in the subtrochanteric region or femoral diaphysis and have a characteristic look: a transverse or short-oblique fracture line that begins at the lateral cortex, focal thickening (beaking) of that lateral cortex, a medial spike, minimal comminution, and frequent bilateral involvement. Many patients describe prodromal thigh or groin pain for weeks to months. The absolute risk is low and the fracture-prevention benefit greatly outweighs it for most patients, but the risk rises with treatment duration.
Clinical Pearl
New or worsening thigh pain in a patient on a bisphosphonate is an atypical femoral fracture until proven otherwise - image BOTH femurs (full-length views). An incomplete AFF with pain often needs prophylactic intramedullary nailing; a complete fracture needs fixation.
Medication-Related Osteonecrosis of the Jaw (MRONJ)
MRONJ Definition and Management (AAOMS Position Paper, 2022 Update)
- MRONJ: exposed jaw bone, or bone probed through a fistula, persisting for more than 8 weeks
- Occurs in a patient on antiresorptive or antiangiogenic therapy with no history of jaw radiotherapy
- Risk is markedly higher with intravenous and oncology-dose therapy and after dental extraction
- Prevention centres on dental assessment and treatment before starting therapy where feasible
The Drug Holiday
Because the rare complications (AFF and MRONJ) are linked to cumulative duration, while the fracture benefit persists for a time after stopping (bisphosphonate stays bound to bone), guidelines suggest reassessing after about 3 to 5 years of oral therapy or 3 years of intravenous therapy:
- Lower risk patients (good bone density gain, no recent fracture): consider a drug holiday and reassess every 1 to 3 years.
- Higher risk patients (previous hip or vertebral fracture, very low bone density, ongoing steroids): continue treatment, as the fracture-prevention benefit dominates.
- The holiday is a pause with planned review, not permanent cessation - bone density and fracture risk are reassessed and treatment restarted when indicated.
Exam Viva Scenarios
Use these scenarios to practise clinical reasoning and management decisions
Mechanism and Monitoring (~3 min)
"A 68-year-old woman with postmenopausal osteoporosis is started on weekly alendronate. The examiner asks you to explain how it works and what you would check and counsel before prescribing."
Mechanism: Alendronate is a nitrogen-containing bisphosphonate. It binds hydroxyapatite at sites of active remodelling and is taken up by osteoclasts, where it inhibits farnesyl pyrophosphate synthase in the mevalonate pathway. The osteoclast cannot prenylate the GTPases it needs, loses its ruffled border, and undergoes apoptosis, so resorption falls and bone density rises.
Before prescribing: I would confirm and correct vitamin D and calcium to avoid hypocalcaemia, check renal function, and ask about upper gastrointestinal disease and recent dental problems.
Counselling: Take it on an empty stomach with a full glass of water, remain upright for 30 to 60 minutes, and take nothing else in that window. I would warn about the rare risks of atypical femoral fracture and jaw osteonecrosis and tell her to report new thigh pain.
Thigh Pain on Long-Term Bisphosphonate (~4 min)
"A 74-year-old woman on alendronate for 8 years reports several weeks of dull right thigh pain with no injury. She is still walking but the pain is worse on weight-bearing. How do you proceed?"
Concern: Long-duration bisphosphonate use plus new thigh pain is an atypical femoral fracture until proven otherwise.
Assessment: Focused history and examination, then full-length AP and lateral radiographs of BOTH femurs - AFFs are frequently bilateral and an incomplete lesion on the other side is easily missed. I look for a transverse lucency at the lateral cortex with focal cortical beaking. If radiographs are normal but suspicion is high, I would obtain MRI or a bone scan.
Management: Stop the bisphosphonate and optimise calcium and vitamin D. A complete fracture needs fixation, typically a cephalomedullary nail. An incomplete fracture with pain usually warrants prophylactic intramedullary nailing because progression to complete fracture is common; an incomplete painless lesion may be trialled with protected weight-bearing and close review.
Other side: I would manage a contralateral incomplete AFF on its own merits, with a low threshold for prophylactic fixation.
BISPHOSPHONATES
Clinical summary
Mechanism
- •Pyrophosphate analogues - bind hydroxyapatite, taken up by osteoclasts
- •Nitrogen-containing: inhibit farnesyl pyrophosphate synthase (mevalonate pathway)
- •Non-nitrogen: form toxic ATP analogues
- •Net effect: less resorption, higher bone mineral density
Key Efficacy
- •Zoledronic acid: vertebral fracture down about 70 percent, hip about 41 percent
- •Alendronate: guideline-standard oral first-line agent
- •First-line for osteoporosis fracture prevention
Before Prescribing
- •Correct calcium and vitamin D
- •Check renal function - avoid zoledronate if eGFR less than 35
- •Oral: empty stomach, full glass of water, upright 30 to 60 minutes
- •Arrange dental review where feasible
Red Flags
- •Thigh pain on long-term therapy - image both femurs for AFF
- •Exposed jaw bone for more than 8 weeks - MRONJ
- •First IV dose flu-like acute phase reaction
- •Reassess for a drug holiday at 3 to 5 years
Guidelines, Registries and Global Practice
- Osteoporosis guidelines (for example AAOS/AOA bone-health initiatives, NICE/NOGG in the UK, and endocrine society guidance) consistently place bisphosphonates as first-line pharmacological therapy for fracture prevention, with intravenous zoledronate favoured where oral agents are not tolerated or adherence is poor.
- Fracture liaison services and bone-health programmes worldwide use bisphosphonates as the backbone of secondary fracture prevention after a fragility fracture.
- The drug holiday concept is endorsed across major guidelines as a way to balance long-term fracture benefit against the duration-dependent risks of AFF and MRONJ, with high-risk patients continued on therapy.
- MRONJ guidance (AAOMS position paper) standardises the definition, staging, and the emphasis on pre-treatment dental optimisation across settings.