The choice of treatment should be made on an individual basis after discussion between the responsible clinician and the patient, or their carers, about the advantages and disadvantages of the treatments available. If generic products are available, start treatment with the least expensive formulation, taking into account administration costs, the dose needed and the cost per dose.

Oral bisphosphonates are absorbed very poorly; therefore counselling should be given to the patient as to how and when administration is most appropriate.

All oral bisphosphonate should be taken in combination with calcium & vitamin D (see section 9.6 Vitamins), the patient should be offered the product they like the best to achieve concordance.

Prescribers are reminded to check that an annual infusion of zoledronic acid has not been given, prior to commencing oral bisphosphonates.

Please refer to formulary guidance: Management of osteoporosis

MHRA Drug Safety Update (Nov 2009): Bisphosphonates: osteonecrosis of the jaw (ONJ)

• The risk of developing osteonecrosis of the jaw with oral bisphosphonates seems to be low. The risk is substantially greater for patients receiving I/V bisphosphonates for cancer indications than for patients receiving oral bisphosphonates for osteoporosis or Paget's disease.
• There is clear evidence to suggest bisphosphonate-specific and indication-specific risk factors such as potency (highest for zoledronate); route of administration (e.g. intravenous ibandronate, pamidronate, and zoledronate); and cumulative dose. The evidence base is less robust for other proposed risk factors (e.g. duration and type of malignant disease, concomitant treatment, smoking, and comorbid conditions). However, healthcare professionals should consider these risk factors when evaluating an individual's risk.
• A history of dental disease—including invasive dental procedures, dental trauma, periodontal disease, and poorly fitting dentures—is associated with an increased risk of ONJ.
• All patients with cancer should have a dental check-up before bisphosphonate treatment.
• All other patients who start bisphosphonates should have a dental examination only if they have poor dental status.
• During treatment, patients should maintain good oral hygiene, receive routine dental check-ups, and report any oral symptoms such as dental mobility, pain, or swelling.

MHRA Drug Safety Update (June 2011): Bisphosphonates: atypical femoral fractures

• Atypical femoral fractures have been reported rarely with bisphosphonate therapy, mainly in patients receiving long-term treatment for osteoporosis.
• They are often bilateral; therefore the contralateral femur should be examined in patients who have sustained a femoral shaft fracture. Discontinuation of therapy in patients suspected to have an atypical femur fracture should be considered while they are evaluated, and should be based on an assessment of the benefits and risks of treatment for the individual.
• During treatment, patients should be advised to report any thigh, hip, or groin pain. Any patient who presents with such symptoms should be evaluated for an incomplete femur fracture.
• The optimum duration of treatment for osteoporosis has not been established. The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of bisphosphonate therapy for individual patients, particularly after 5 or more years of use.

MHRA Drug Safety Update (December 2015): Bisphosphonates: very rare reports of osteonecrosis of the external auditory canal

• Osteonecrosis of the external auditory canal has been reported very rarely (fewer than 1 in 10,000 patients) with bisphosphonates, mainly in association with long-term therapy (2 years or longer).
• The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms, including chronic ear infections, or in patients with suspected cholesteatoma.
• Possible risk factors include steroid use and chemotherapy, with or without local risk factors such as infection or trauma.
• Patients should be advised to report any ear pain, discharge from the ear, or an ear infection during bisphosphonate treatment.

Alendronic acid

• Weekly tablets 70mg (£1.22 = 4 tablets)
• Tablets 10mg (£7.50 = 28 tablets)

Indications and dose

• Treatment of postmenopausal osteoporosis, 10mg daily or 70mg once weekly
• Treatment of osteoporosis in men, 10mg daily
• Prevention and treatment of corticosteroid-induced osteoporosis in postmenopausal women not receiving hormone replacement therapy, 10mg daily

Notes

1. Alendronic acid 70mg is a 'special container' pack of four tablets. These should not be prescribed on weekly prescriptions as the pack cannot be split by the pharmacy to provide one tablet.
2. Severe oesophageal reactions (oesophagitis, oesophageal ulcers, oesophageal stricture and oesophageal erosions) have been reported; patients should be advised to stop taking the tablets and to seek medical attention if they develop symptoms of oesophageal irritation such as dysphagia, new or worsening heartburn, pain on swallowing or retrosternal pain
3. Alendronate is not recommended for patients with renal impairment, GFR less than 35mL/minute/1.73m²
4. NICE TA464: Oral bisphosphonates (alendronic acid, ibandronic acid and risedronate sodium) and intravenous bisphosphonates (ibandronic acid and zoledronic acid) are recommended, as options for treating osteoporosis in adults in accordance with the criteria outlined in the NICE TA (August 2017).

Risedronate sodium

• Weekly tablets 35mg (£1.59 = 4 tablets)
• Tablets 5mg (£20.71 = 28 tablets)
• Tablets 30mg (£155.28 = 28 tablets)

Indications and dose

• Treatment of postmenopausal osteoporosis to reduce risk of vertebral or hip fractures, 5mg daily or 35mg once weekly
• Prevention of osteoporosis (including corticosteroid-induced osteoporosis) in postmenopausal women, 5mg daily
• Treatment of osteoporosis in men at high risk of fractures, 35mg once weekly
• Paget's disease of bone (specialist), 30mg daily for 2 months; may be repeated if necessary after at least 2 months

Notes

1. At the time of writing (July 2019) risedronate sodium 5mg tablets are associated with a greater acquisition cost in comparison to alternative oral bisphosphonates licensed for both the treatment and prophylaxis of osteoporosis. In line with NICE TA 464, prescribers are reminded to consider treatments on an individual basis. If generic products are available, start treatment with the least expensive formulation. Consideration should be given to alendronic acid 10mg tablets if a once daily formulation is required.
2. Oesophageal reactions: Patients should be advised to stop taking the tablets and to seek medical attention if they develop symptoms of oesophageal irritation such as dysphagia, new or worsening heartburn, pain on swallowing or retrosternal pain
3. The use of risedronate sodium is contraindicated in patients with severe renal impairment, avoid if GFR less than 30mL/minute/1.73m²
4. NICE TA464: Oral bisphosphonates (alendronic acid, ibandronic acid and risedronate sodium) and intravenous bisphosphonates (ibandronic acid and zoledronic acid) are recommended, as options for treating osteoporosis in adults in accordance with the criteria outlined in the NICE TA (August 2017).

Ibandronic acid

• Tablets 150mg (£1.47 = 1 tablet)
• Solution for injection 1mg/ml, pre-filled syringe

Indications and dose

• Treatment of postmenopausal osteoporosis
  • Oral: 150mg once a month

Notes

1. Oesophageal reactions: Patients and carers should be advised to stop tablets and seek medical attention for symptoms of oesophageal irritation such as dysphagia, pain on swallowing, retrosternal pain, or heartburn.
2. Ibandronic acid should be used with caution in patients with renal impairment; when used for postmenopausal osteoporosis, avoid if eGFR less than 30 mL/minute/1.73 m²
3. NICE TA464: Oral bisphosphonates (alendronic acid, ibandronic acid and risedronate sodium) and intravenous bisphosphonates (ibandronic acid and zoledronic acid) are recommended, as options for treating osteoporosis in adults in accordance with the criteria outlined in the NICE TA (August 2017).

Sodium clodronate

• Capsules 400mg (£139.83 = 120 capsules)
• Tablets 520mg (£114.44 = 60 tablets)
• Tablets 800mg (£146.43 = 60 tablets)

Indications and dose

• Osteolytic lesions, hypercalcaemia and bone pain associated with skeletal metastases in patients with breast cancer or multiple myeloma
• Clodronate is eliminated mainly via the kidneys. Please refer to the manufacturers information for guidance regarding dose alterations.

Notes

1. Consultant initiation only

Pamidronate disodium

• Injection 15mg vial, 30mg vial, 60mg vial, 90mg vial

Notes

1. IV disodium pamidronate is licensed to treat hypercalcaemia, osteolytic lesions and bone pain linked to bone/ skeletal metastases and that related to Paget's disease.
2. Disodium pamidronate may be used in the treatment of osteoporosis (unlicensed). The required dose is diluted in 0.9% sodium chloride to a concentration of not more than 60mg in 250ml and given at a rate not exceeding 1mg per minute.

Zoledronic acid

• Concentrate for IV infusion 800 micrograms/ml, 5ml (4mg) vial
• IV infusion 50 micrograms/ml, 100ml bottle

Indications

• Multiple myeloma (see below)
• Osteoporosis
• Adjuvant therapy in post-menopausal women with breast cancer (unlicensed use)

Notes

1. Bisphosphonate therapy is commissioned as part of routine care of patients with symptomatic multiple myeloma. Zoledronic acid may be used as the bisphosphonate at least until disease progression if it can be provided at a negotiated contract price consistent with the financial modelling used for this decision (see Commissioning Policy for more information)
2. NICE TA464: Oral bisphosphonates (alendronic acid, ibandronic acid and risedronate sodium) and intravenous bisphosphonates (ibandronic acid and zoledronic acid) are recommended, as options for treating osteoporosis in adults in accordance with the criteria outlined in the NICE TA (August 2017)

Monoclonal antibodies

Prolia

(Denosumab)

• Solution for injection pre-filled syringe 60mg in 1ml (£183.00 = 1ml syringe)

Indications and dose

• Prevention of osteoporotic fragility fractures in postmenopausal women, in line with NICE TA204:
  • 60mg every 6 months, by subcutaneous injection into the thigh, abdomen or upper arm

Notes

1. Prescribe by brand (to prevent confusion since different products have different indications).
2. Refer to Devon wide shared care prescribing guideline
3. To avoid unnecessary out of pocket expenses, practices or pharmacies should order direct from AAH
4. NICE TA204: Denosumab (Prolia) is recommended as a treatment option for the primary prevention of osteoporotic fragility fractures only in postmenopausal women at increased risk of fractures, only if the criteria in the NICE TA are met (October 2010)
5. MHRA Drug Safety Update (October 2012) and MHRA Drug Safety Update (September 2014): Denosumab: monitoring recommended. Fatal cases of severe symptomatic hypocalcaemia, and risk of hypocalcaemia at any time during treatment.
   1. The following precautions should be followed to minimise the risk of hypocalcaemia with denosumab:
      1. Denosumab 120mg (for cancer indications) should not be used in patients with severe, untreated hypocalcaemia
      2. Denosumab 60mg (for osteoporosis indications) should not be used in patients with hypocalcaemia, regardless of severity (the contraindications vary between the two doses, because their indications are different)
   2. Refer to the MHRA alerts for further information and advice including suggested monitoring
6. MHRA Drug Safety Update (February 2013): Atypical femoral fractures have been reported rarely in patients with postmenopausal osteoporosis receiving long-term (2.5 years or longer) treatment with denosumab 60mg in a clinical trial. The risk of atypical femoral fractures also exists for denosumab 120mg (Xgeva). During denosumab treatment, patients presenting with new or unusual thigh, hip or groin pain should be evaluated for an incomplete femoral fracture. Discontinuation of denosumab therapy should be considered if an atypical femur fracture is suspected, while the patient is evaluated
7. MHRA Drug Safety Update (July 2015), MHRA Drug Safety Update (December 2015) and MHRA Drug Safety Update (June 2017):
   1. Denosumab is associated with a risk of osteonecrosis of the jaw, osteonecrosis of the external auditory canal has also been reported with denosumab
   2. Before prescribing denosumab or intravenous bisphosphonates:
      1. give patients the patient reminder card for their medicine
      2. explain the risk of osteonecrosis of the jaw, and osteonecrosis of the external auditory canal, and advise patients on precautions to take
      3. do not prescribe denosumab 120mg (cancer indication) to patients with unhealed lesions from dental or oral surgery
      4. advise patients to report any problems with their mouth or teeth, any ear pain, discharge from the ear, or an ear infection during denosumab treatment
8. MHRA Drug Safety Update (August 2020): Denosumab 60mg (Prolia): increased risk of multiple or vertebral fractures after stopping or delaying ongoing treatment
   1. an increased risk of multiple vertebral fractures has been reported in patients within 18 months of stopping or delaying ongoing denosumab 60mg treatment for osteoporosis
   2. patients with a previous vertebral fracture may be at highest risk
   3. if a patient misses a prescribed dose of denosumab, the missed injection should be administered as soon as possible
   4. patients should not stop denosumab without specialist review
   5. re-evaluate the need for continued treatment periodically, particularly after 5 or more years of use
9. MHRA Drug Safety Update (May 2022): Denosumab 60mg (Prolia): should not be used in patients under 18 years due to the risk of serious hypercalcaemia

Xgeva

(Denosumab)

• Solution for injection vials 120mg in 1.7ml (70mg/ml)

Indications and dose

• Prevention of skeletal-related events in adults with bone metastases from breast cancer and from solid tumours other than prostate, in line with NICE TA265:
  • 120mg every 4 weeks, by subcutaneous injection into the thigh, abdomen or upper arm

Notes

1. Prescribe by brand (to prevent confusion since different products have different indications).
2. NICE TA265: Denosumab (Xgeva) is recommended as an option for preventing skeletal-related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with bone metastases from breast cancer and from solid tumours other than prostate (October 2012) if:
   1. bisphosphonates would otherwise be prescribed and
   2. the manufacturer provides denosumab with the discount agreed in the patient access scheme.
   3. Denosumab is not recommended for preventing skeletal-related events in adults with bone metastases from prostate cancer.
3. MHRA Drug Safety Update (October 2012) and MHRA Drug Safety Update (September 2014): Denosumab: monitoring recommended. Fatal cases of severe symptomatic hypocalcaemia, and risk of hypocalcaemia at any time during treatment.
   1. The following precautions should be followed to minimise the risk of hypocalcaemia with denosumab:
      1. Denosumab 120mg (for cancer indications) should not be used in patients with severe, untreated hypocalcaemia
      2. Denosumab 60mg (for osteoporosis indications) should not be used in patients with hypocalcaemia, regardless of severity (the contraindications vary between the two doses, because their indications are different)
   2. Refer to the MHRA alerts for further information and advice including suggested monitoring
4. MHRA Drug Safety Update (June 2018): Denosumab (Xgeva▼) for giant cell tumour of bone: risk of clinically significant hypercalcaemia following discontinuation. Refer to MHRA alert for further information and recommendations
5. MHRA Drug Safety Update (June 2018): Denosumab (Xgeva▼) for advanced malignancies involving bone: study data show new primary malignancies reported more frequently compared to zoledronate. Refer to MHRA alert for further information
6. MHRA Drug Safety Update (February 2013): Atypical femoral fractures have been reported rarely in patients with postmenopausal osteoporosis receiving long-term (2.5 years or longer) treatment with denosumab 60mg in a clinical trial. The risk of atypical femoral fractures also exists for denosumab 120mg (Xgeva). During denosumab treatment, patients presenting with new or unusual thigh, hip or groin pain should be evaluated for an incomplete femoral fracture. Discontinuation of denosumab therapy should be considered if an atypical femur fracture is suspected, while the patient is evaluated
7. MHRA Drug Safety Update (July 2015), MHRA Drug Safety Update (December 2015) and MHRA Drug Safety Update (June 2017):
   1. Denosumab is associated with a risk of osteonecrosis of the jaw, osteonecrosis of the external auditory canal has also been reported with denosumab.
   2. Before prescribing denosumab or intravenous bisphosphonates:
      1. give patients the patient reminder card for their medicine
      2. explain the risk of osteonecrosis of the jaw, and osteonecrosis of the external auditory canal, and advise patients on precautions to take
      3. do not prescribe denosumab 120mg (cancer indication) to patients with unhealed lesions from dental or oral surgery
      4. advise patients to report any problems with their mouth or teeth, any ear pain, discharge from the ear, or an ear infection during denosumab treatment

Romosozumab

• Solution for injection in prefilled pens 90mg/1ml

Notes

1. NICE TA791: Romosozumab (EVENITY) is recommended as an option for treating severe osteoporosis in people after menopause who are at high risk of fracture (May 2022), only if:
   1. they have had a major osteoporotic fracture (spine, hip, forearm or humerus fracture) within 24 months (so are at imminent risk of another fracture) and
   2. the company provides romosozumab according to the commercial arrangement