Bisphosphonates

Bisphosphonate regimens

Bisphosphonates slow bone loss and improve bone mineral density (BMD) by inhibiting osteoclasts. They reduce vertebral, nonvertebral and hip fracture rates.

Suitable regimens are:

Oral bisphosphonates (except enteric-coated formulations) must be taken on an empty stomach, and at least 2 hours apart from calcium, iron, magnesium and antacids, which can limit efficacy by significantly reducing absorption.

Throughout therapy, ensure the patient’s calcium intake is sufficient and they are vitamin D replete.

Zoledronic acid can cause hypocalcaemia, particularly in patients with risk factors for hypocalcaemia such as vitamin D deficiency, kidney disease or a malabsorption disorder. Before the first dose, measure kidney function, serum corrected calcium concentration and serum 25-hydroxyvitamin D concentration. In patients at risk of hypocalcaemia, these parameters should also be measured before each subsequent dose. Intravenous administration of zoledronic acid in primary care is safe provided that:

• serum 25-hydroxyvitamin D concentration is greater than 50 nanomol/L
• serum calcium concentration corrected for albumin is in the normal range (2.10 to 2.60 mmol/L)
• estimated glomerular filtration rate (eGFR) is greater than 35 mL/min/1.73 m²
• the patient is well hydrated.

Intravenous zoledronic acid can cause transient influenza-like symptoms. This most often occurs after the first dose and is less likely to occur with subsequent doses. To reduce the severity of the reaction, advise patients to take paracetamol before and for several days after the infusion.

Less frequent administration of zoledronic acid may be considered with specialist advice. In a study of women aged over 65 years with osteopenia, administration of zoledronic acid every 18 months reduced the incidence of fractures compared to placebo².

Duration of bisphosphonate therapy

Bisphosphonates are retained in the skeleton after treatment withdrawal. The beneficial effects on BMD persist for several years after stopping alendronate and zoledronic acid. In contrast, BMD decreases within one year of stopping risedronate.

Long-term bisphosphonate therapy has been linked to an increased risk of skeletal adverse effects such as osteonecrosis of the jaw and atypical fracture of the femur, although the absolute risk remains low. Limiting the duration of bisphosphonate therapy may reduce the incidence of these effects.

In patients not at high risk of minimal-trauma fracture, consider stopping therapy after 5 years of an oral bisphosphonate or 3 years of an intravenous bisphosphonate. Bisphosphonate treatment can be continued for up to 10 years (oral) or 6 years (intravenous) for patients at high risk of minimal-trauma fracture, including patients:

• age 75 years and older
• with a previous hip or vertebral fracture
• who had minimal-trauma fracture after starting treatment (after exclusion of other causes of fracture)
• with hip T-score of –2.5 or lower.

Evidence to guide oral bisphosphonate treatment beyond 10 years is not available, so treatment needs to be individualised according to patient needs. Consider specialist input.

After stopping treatment, consider measuring BMD after 2 to 3 years—treatment can be restarted if BMD has decreased significantly (eg decreased by 5% or by 0.05 grams/cm² at lumbar spine, hip or femoral neck). Treatment can also be restarted if the patient has a minimal-trauma fracture after stopping treatment, or has new or worsening risk factors for fracture (eg increased falls risk).

For information about monitoring therapy, see here.