Bisphosphonates
Bisphosphonate drugs are the standard anti-osteolytic treatment for myeloma bone disease and are offered to all patients with symptomatic myeloma. They work by binding to mineralised bone and inhibit osteoclast activity, thereby reducing or preventing further bone destruction although they are not able to repair existing bone damage. Their mechanism of action is summarised in Figure 4.
In the UK, bisphosphonate treatment is recommended for all patients with symptomatic myeloma whether or not they have evidence of myeloma bone disease. This is because bisphosphonate treatment has several potential beneficial effects including:
- Preventing or reducing further bone breakdown
- Alleviating bone pain and the need for analgesia
- Preventing and correcting hypercalcaemia
- Reducing the need for radiotherapy or other invasive procedures
- Reducing the risk of pathological fractures
- Improving quality of life, particularly by relieving pain and maintaining mobility
- Improving the chances of healing and recovery of strength of bone
Currently, three bisphosphonates are approved for the treatment of myeloma bone disease (Table 1). The choice of treatment depends on individual clinical factors, local practice and patient/doctor preferences.
Table 1: Bisphosphonates used in myeloma
| Generic name | Generic name | Method and frequency of administration | Dose adjustment for renal impairment |
|---|---|---|---|
| Sodium clodronate | Bonefos® Loron® | Oral tablets, taken once or twice per day | Half dose if creatinine clearance 10–30 ml/min Contraindicated if <10 ml/min |
| Pamidronate disodium | Aredia® | Intravenous infusion over 60 – 90 minutes, monthly | Slower infusion rate (20 mg/h) if renal impairment; not recommended if creatinine clearance <30ml/min except in life-threatening hypercalcaemia |
| Zoledronic acid | Zometa® | Intravenous infusion over 15 minutes, monthly | Check creatinine before each infusion, ensure hydration. Not recommended if creatinine clearance <30ml/min. Reduced dosing recommended in patients with creatinine clearance 30-60 ml/min |
Following results of the Myeloma IX trial, zoledronic acid is the current first-line treatment for myeloma patients. The optimum duration and frequency of treatment should be guided by individual factors such as remission status, extent of myeloma bone disease and patient preference. In most cases, bisphosphonate treatment is given monthly for at least two years.
Intravenous bisphosphonates are also important in the treatment of moderate to severe hypercalcaemia (corrected calcium 2.9mmol/L) and are given in conjunction with intravenous saline rehydration. It is important to ensure patients have adequate urinary output and in some cases, diuretics may be necessary to prevent volume overload and to promote urinary calcium excretion. A further dose of bisphosphonates may be given after 72 hours if calcium levels remain high.
Bisphosphonates are generally well tolerated. However, nausea, vomiting, diarrhoea and/or abdominal pain may occur with oral bisphosphonates. These may improve with twice daily instead of once daily administration and taken with water at least one hour before or after food. Fever and flu-like symptoms (including bone pain, myalgia, malaise and rigors) can occur after infusion of intravenous bisphosphonates but usually resolve within several days. Hypocalcaemia is another potential side effect, so nursing staff must be vigilant for signs such as neuromuscular irritability, confusion and mood changes and alert the medical team. To try and prevent this, oral supplements with calcium and vitamin D are generally prescribed for patients on zoledronic acid.
All bisphosphonates should be used with caution in renal impairment. Renal function should be monitored regularly and creatinine levels checked prior to intravenous bisphosphonate infusion. Depending on the degree of renal impairment it may be necessary to dose-reduce or stop bisphosphonate treatment as outlined in Table 1. Although not routinely funded for use in myeloma, in some cases where patients with renal impairment are not able to receive bisphosphonates, the use of denosumab may be granted.
A rare but potentially very serious side-effect of intravenous bisphosphonate treatment is a condition known as osteonecrosis of the jaw (ONJ). ONJ is a condition in which areas of the jaw bone are not covered by the gum and become exposed to infection, causing the bone to die (Figure 4). The condition must last more than eight weeks for it to be classified as ONJ and most often develops in myeloma patients after invasive dental procedures such as dental extraction. Symptoms of ONJ include jaw pain or inflammation, non-healing gums, loosening teeth, or a feeling of numbness or heaviness in the jaw.
Although the incidence of ONJ is low, specific recommendations for the prevention and management of ONJ should be followed by all patients receiving bisphosphonate treatment. It is important patients understand they:
- Let their dentist know if they are about to start or are on bisphosphonate treatment
- Have a dental examination and appropriate preventative dentistry before starting bisphosphonate treatment
- Have regular dental check-ups whilst on bisphosphonate treatment
- Avoid invasive dental procedures wherever possible
- Are managed by an experienced oral maxillofacial surgeon if they develop ONJ
For those requiring dental procedures, it is not known whether temporarily discontinuing bisphosphonate treatment can reduce the risk of ONJ. Bisphosphonate may remain active within bone for many months after it has been discontinued and the management plan of each patient should be based on individual benefit/risk.
In most cases, a modified dosing schedule or preventative measures can greatly reduce the incidence and/or severity of side-effects of bisphosphonates. Read more about the use of bisphosphonates for the treatment of myeloma bone disease in our myeloma nurse guide.