Prevention of skeletal-related events in cancer patients

 NB: Onset of treatment effect of zoledronic acid may be 2 to 3 months from initiation of therapy.
† Adjuvant bisphosphonates are only recommended for use in women who are postmenopausal, unless the adjuvant/neoadjuvant treatment plan includes ovarian suppression therapy (i.e. GnRH agonist) or oophorectomy. Consultant decision.
*Non-formulary approval will be required.

1. Give a single oral dose of 100,000iu colecalciferol prior to starting treatment. Unless patient is already taking vitamin D supplements. Remember to check for prescribed and over-the-counter supplements.
2. Measure serum adjusted calcium levels. Correct pre-existing hypocalcaemia before starting treatment.
3. Assessment of dental health. All (except edentulous) patients must attend for a dental check-up before commencing therapy with a bisphosphonate or denosumab. Therapy must be postponed until healing from any remedial dental work is complete.
4. Evaluation of renal function.

• See drug information below
• At each clinic appointment all patients must be asked about any dental problems (including pain, swelling or numbness in the mouth) and any ear problems (pain, discharge or infection)
• Correct electrolyte abnormalities as per Electrolyte Working Group Guidelines.

If a patient develops hypocalcaemia despite being prescribed recommended doses of calcium and vitamin D supplementation:

• Check that the patient is taking the supplements as prescribed
• Consider whether there are factors which may affect the absorption of calcium supplements (eg administration with food)
• Check, and if necessary, correct magnesium levels.

If there are no issues identified and the patient is asymptomatic, consider increasing the calcium supplementation. Contact local Biochemist or Endocrinologist for advice if patients have asymptomatic hypocalcaemia resistant to treatment.
If the patient is symptomatic (usually occurs when calcium < 1·9 mmol/L) contact Biochemist or Endocrinologist urgently due to potential risk of dysrhythmia and seizure. Symptoms of hypocalcaemia include: perioral and digital paraesthesiae, positive Trousseau’s and Chvostek’s signs, tetany and carpopedal spasm, laryngospasm, ECG changes (prolonged QT interval) and arrhythmia, seizure. Note: Severe symptomatic hypocalcaemia (including fatal cases) have been reported with denosumab. 

a.   Osteonecrosis of the jaw
Patients with cancer are at higher risk for osteonecrosis of the jaw (ONJ). The risk is increased not only by the disease itself but by concurrent treatments. Bisphosphonates and denosumab increase the risk of ONJ. Tyrosine kinase inhibitors (TKIs) and anti-angiogenic systemic anticancer treatments (SACT) also increase the risk of ONJ. Patients should be advised of the risk of ONJ and counselled on appropriate precautions:

• Maintenance of good oral hygiene
• Routine dental check-ups during treatment
• Advising doctor/dentist that they are receiving a bisphosphonate or denosumab, particularly if dental treatment or surgery is required
• Reporting immediately any problems with mouth or teeth during treatment (eg loose teeth, pain, swelling, non-healing sores, or discharge)

b.   Osteonecrosis of the external auditory canal
Osteonecrosis of the external auditory canal has been very rarely reported with (mainly long-term) bisphosphonate or denosumab use. Other risks include steroid use, chemotherapy and other local factors such as infection or trauma. The possibility should be considered in patients who present with ear symptoms including chronic ear infections.

c.   Atypical femoral fractures
Bisphosphonates and denosumab have been reported to be associated with an increased risk of atypical femoral fractures. Patients should be advised to report any thigh, hip or groin pain.

d.   Gastro-intestinal irritation
Oral bisphosphonates can cause local irritation of the upper gastrointestinal mucosa. Caution should be used when oral bisphosphonates are given to patients with active upper gastrointestinal problems e.g. Barrett’s oesophagus, dysphagia, other oesophageal diseases, gastritis, duodenitis or ulcers. Patients must be advised to comply with dosing instructions and instructed to discontinue the bisphosphonate and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.

• Patients receiving NSAIDs in addition to bisphosphonates have developed renal dysfunction.
• Additional risk of gastrointestinal irritation. Avoid/reduce if possible.
• Caution with concomitant aminoglycosides due to risk of additive hypocalcaemia.
• (Oral only) Impaired absorption with divalent metal ions: avoid administration with food, antacids and mineral supplements. See administration instructions.

• Ensure pre-treatment requirements have been met.
• Prescribe ibandronic acid 50mg tablets once daily (or at reduced frequency depending on renal function) as per specialist letter (duration of treatment stated on letter).
• Ensure any other bisphosphonate, eg weekly alendronate or risedronate is stopped whilst patient is taking ibandronic acid.
• Review current non-steroidal anti-inflammatory drugs (NSAIDs) use (increased risk of gastro-intestinal side-effects and potentially increased risk of renal dysfunction).
• Review annually:
  • Medication review to check compliance; potential side-effects; tolerability of ibandronic acid; ensure patient and/or carer understands how to administer tablets; check oral hygiene advice is being followed.
  • Annual blood tests: renal function and serum adjusted calcium. Calculated creatinine clearance should be calculated for patients with BMI less than 20 since eGFR may overestimate renal function.
• If ibandronate tablets are not tolerated or patient is unable to comply with dosing instructions, refer back to specialist for consideration of IV zoledronic acid 6 monthly as an alternative.
• Inform consultant if ibandronate is discontinued for any reason.

This information is not comprehensive. Refer to individual SPCs for further information.

 AdjCa – adjusted calcium; Mg – magnesium; Phos – phosphate.

• Supply Patient Information Leaflet for adjuvant breast cancer patients
• Maintain adequate fluid intake
• Risk of osteonecrosis of the jaw:
  • maintain good oral hygiene and attend regularly for review at dentist
  • report mouth/dental symptoms promptly
  • avoid invasive dental procedures – discuss with prescriber
• Risk of atypical fracture of femur: report thigh, hip or groin pain
• Risk of osteonecrosis of the auditory canal: report any ear pain, discharge from the ear or ear infections
• Importance of adherence to administration advice for oral bisphosphonates
• Risk of GI irritation with oral bisphosphonates: seek medical attention if GI symptoms develop or worsen
• Continue with calcium and vitamin D supplementation unless advised otherwise.

Guidelines adapted from WOSCAN Clinical Guidelines

1. Healthcare Improvement Scotland and NHS Scotland, 2016. Scottish Palliative Care Guidelines. Hypercalcaemia. [online] Edinburgh: Scottish Partnership for Palliative Care. Available from: http://www.palliativecareguidelines.scot.nhs.uk/guidelines/palliative-emergencies/Hypercalcaemia.aspx (last updated 17 Feb 2016; accessed 14/8/17)
2. Wang-Gillam A et al, 2008. Evaluation of vitamin D deficiency in breast cancer patients on bisphosphonates. The Oncologist, 13, pp821-7. doi:10.1634/theoncologist.2008-0013
3. Himelstein AL et al, 2017. Effect of longer-interval vs standard dosing of zoledronic acid on skeletal events in patients with bone metastases: a randomized clinical trial. JAMA, 317(1), pp48-58. doi:10.1001/jama.2016.19425
4. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), 2015. Adjuvant bisphosphonate treatment meta-analyses of individual patient data from randomised trials. Lancet, 386, pp1353-61. doi:10.1016/S0140-6736(15)60908-4
5. Hadji P et al, 2016. Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European Panel. Ann Oncol, 27(3), pp379-90. doi: 10.1093/annonc/mdv617
6. Electrolytes Working Group, NHS Highland, 2014. Guidelines for the treatment of low electrolytes. [online] Available from: https://tam.nhsh.scot/home/therapeutic-guidelines/fluid-and-electrolytes/treatment-of-low-electrolytes/ (accessed 11/9/18)
7. Datapharm, 2017. Zoledronic Acid Accord 4 mg/5 ml concentrate for solution for infusion, last updated 9 Aug 2017. [online] Available from: http://www.medicines.org.uk/emc/medicine/28673 (accessed 14/8/17)
8. Datapharm, 2017. Bonefos [sodium clodronate] tablets, last updated 23 Jun 2016. 
9. Datapharm, 2017. XGEVA [denosumab], last updated 28 Jun 2017. [online] Available from: http://www.medicines.org.uk/emc/medicine/24755 (accessed 14/8/17)