Bisphosphonates

Bisphosphonates 

Clinical pharmacology

Bisphosphonates are used in the treatment of osteoporosis, Paget's disease, symptomatic hypercalcaemia, hypercalcaemia of malignancy, and for the reduction of adverse skeletal events (eg fractures) in patients with multiple myeloma and bone metastases (see Table 5.32). They slow bone loss by reducing bone resorption. In addition, they bind strongly to bone mineral, thus forming a depot from which they are released as the bisphosphonate-containing bone is remodelled. In high doses, etidronate is the only bisphosphonate that can inhibit the mineralisation of bone. The doses at which effects on mineralisation occur are not related to antiresorptive potency. There is wide variation between the bisphosphonates in terms of their potency in inhibiting bone resorption relative to their potency in inhibiting mineralisation. 

The first bisphosphonate to be available was etidronate. Newer agents approved for osteoporosis (alendronate and risedronate) are more potent inhibitors of bone resorption but have less significant effects on bone mineralisation. Alendronate and risedronate show a reduction in vertebral fracture risk of 40% to 50%, and in risk of hip fracture by 40% to 60%; however, this fracture risk has only been demonstrated in trials of daily therapy. Weekly administration produces the same beneficial effects on bone mineral density (BMD) and markers of bone turnover; however, fracture prevention trials have not been performed with this dose.

The bisphosphonate drugs are the major pharmacological agents for the management of hypercalcaemia of malignancy and for the reduction of adverse skeletal events (eg fractures) in patients with multiple myeloma and bone metastases from breast, prostate and other solid tumours. They act as inhibitors of osteoclastic bone resorption. They have proven efficacy in breast cancer and myeloma (and possibly in prostate cancer) in the management of bone pain. Parenteral bisphosphonates give the most rapid results in malignant hypercalcaemia; however, oral formulations may be more convenient for maintenance.

Bisphosphonates have been shown to delay the onset of skeletal complications in patients with osteolytic bone metastases. There is also a possible role in the management of refractory bone pain.

Due to poor oral absorption of bisphosphonates, food, drink (apart from water) and medications should be avoided before and after administration according to the product information for each drug. Calcium salts, iron and magnesium supplements, and antacids inhibit absorption and so should not be taken within 2 hours of bisphosphonates. 

A number of case reports have linked bisphosphonate use with osteonecrosis of the jaws; the risk of this is possibly aggravated by dental extractions. It is recommended that, if possible, dental treatment be attended to before bisphosphonate therapy is commenced. For further information, and advice from the Therapeutic Goods Administration.

Alendronate

Alendronate has been developed to improve the ratio between dosages that inhibit resorption and dosages that inhibit mineralisation. Alendronate does not appear to interfere with mineralisation at antiresorptive doses and can be used continuously. 

Like all bisphosphonates, alendronate is poorly absorbed from the intestine, and absorption is further reduced in the presence of food, calcium supplements, antacids and other medications. Calcium supplements should not be administered at the same time as alendronate, but should preferably be taken in the evening. The most common adverse effects of alendronate are abdominal pain (usually mild and transient), nausea, dyspepsia, constipation, diarrhoea, and musculoskeletal pain. Oesophagitis is a potential adverse effect with alendronate. Uncommonly, it can cause severe oesophageal and chest pain, including ulceration. Be wary in patients with active, or a definite history of upper gastrointestinal disorders who generally should not receive alendronate. To minimise the potential for this adverse effect (and to allow adequate absorption), alendronate should be taken in the morning, after an overnight fast, with a full glass of water and the patient should remain upright and take nothing else by mouth for at least 30 minutes. These precautions do not completely prevent the possibility of the adverse effect. The potential for oesophageal irritation may be reduced by weekly rather than daily dosing—a schedule that is often more convenient for patients. 

Disodium pamidronate

Disodium pamidronate has properties similar to those of etidronate. It inhibits bone resorption, but has less effect on bone mineralisation than etidronate. Only parenteral disodium pamidronate is available in Australia. After intravenous administration, it is about 50% bound to plasma proteins and approximately 50% is excreted in the urine unchanged within 72 hours.

Adverse effects include a transient exacerbation of bone pain, a usually asymptomatic fall in serum calcium concentration and a transient lymphopenia. Pyrexia and flu-like symptoms such as myalgias and arthralgias are common particularly after the initial treatment, but generally resolve spontaneously. Uveitis has occasionally been reported. 

Severe local reactions and thrombophlebitis have followed administration of disodium pamidronate as a bolus injection; therefore it should be given by slow intravenous infusion (less than 60 mg/hour). It should be used with caution in patients with renal impairment. If creatinine clearance is less than 30 mL/minute, disodium pamidronate should be avoided unless there is life-threatening hypercalcaemia. With less severe renal impairment, the rate of infusion should be reduced to less than 20 mg/hour.

Etidronate

Etidronate inhibits mineralisation at doses similar to those required to inhibit resorption. Doses above 10 mg/kg/day are associated with defective mineralisation, which may lead to bone pain and fractures. Defective mineralisation appears more likely to occur with prolonged therapy, approximately 5 years. Etidronate is given as a cyclical regimen based on the idea of blocking resorption, then allowing a drug-free period for bone formation. 

When they occur, gastrointestinal adverse effects usually are mild. It is vital that etidronate is taken carefully as recommended to optimise drug bioavailability. Etidronate should be taken with a full glass of water—food, other drinks or medications should not be taken within 2 hours.

Etidronate may be used as an alternative agent for individuals with osteoporotic fractures who are intolerant to either alendronate or risedronate. 

Risedronate

Risedronate is more potent than most other bisphosphonates and has low bioavailability. To avoid gastrointestinal adverse effects (and to allow adequate absorption), risedronate should be taken first thing in the morning with a full glass of water and the patient should remain upright and take nothing else by mouth for at least 30 minutes. Administration of divalent cations (eg calcium supplements) should be at different times during the day. Risedronate is excreted unchanged by the kidney. Dosage adjustment is unnecessary in mild to moderate renal impairment. Common adverse effects include headache, nausea, dizziness, diarrhoea and myalgia. This drug is also now available as either a daily or weekly tablet. 

Sodium clodronate is the only oral bisphosphonate drug licensed in Australia for the treatment of hypercalcaemia of malignancy and osteolytic bone metastases in multiple myeloma and breast cancer. In concentrations that induce inhibition of bone resorption, sodium clodronate has no effect on the normal mineralisation process in bone tissue. Its therapeutic effect is achieved by inhibition of abnormal bone destruction. This reduces elevated serum and urine calcium levels.

The gastrointestinal absorption of oral sodium clodronate is low and there is great inter- and intra-individual variation. It has a strong affinity for calcium and other divalent cations of food, so its absorption is negligible when given with food. It should not be taken within 2 hours of food, and concomitant administration with milk and drugs containing divalent cations should be avoided. 

Common adverse effects are nausea and vomiting, diarrhoea and epigastric pain. It may also result in the elevation of parathyroid hormone, alkaline phosphatase, lactate dehydrogenase and aminotransferases. Reversible proteinuria, elevations of serum creatinine and renal dysfunction have been reported after intravenous treatment. Severe renal damage may occur after rapid infusion of high doses.

Tiludronate

Tiludronate has a greater effect on biochemical markers of bone turnover than etidronate and does not cause mineralisation defect. Tiludronate should be used with caution in patients with renal impairment. It should not be taken within 2 hours of food. Mild gastrointestinal disturbance is a potential adverse effect of tiludronate. In Australia tiludronate has only been approved for the treatment of Paget's disease. 

Zoledronic acid

Zoledronic acid is a potent bisphosphonate used for the treatment of hypercalcaemia of malignancy and to reduce skeletal-related events in the setting of bone metastases. In clinical trials, zoledronic acid 4 mg by intravenous infusion was more effective than disodium pamidronate 90 mg for malignant hypercalcaemia. There was a higher incidence of hypocalcaemia and hypophosphataemia with zoledronic acid therapy. In other aspects, adverse events were similar with the two treatments. A major advantage of zoledronic acid is the short infusion time of 15 minutes.

Zoledronic acid is prescribed as a monthly infusion. However, monthly serum creatinine measurements are required in view of the reports of drug-induced renal failure.

Annual doses of 4 mg of zoledronic acid increase bone mineral density in postmenopausal women. Studies are currently in progress to assess the antifracture efficacy of this dose as treatment for postmenopausal osteoporosis.

Comparative table of clinical uses and doses for bisphosphonates (Table 5.32)

Drug	Clinical uses/doses
	osteoporosis (treatment)	Paget’s	symptomatic hypercalcaemia	hypercalaemia of malignancy
alendronate	10 mg daily/ 70 mg weekly (long-acting)	40 mg daily for 6 months
disodium pamidronate		30 to 60 mg IV every 2 to 12 months	30 to 90 mg IV	30 to 90 mg IV every 2 to 6 weeks
etidronate (with calcium carbonate)	400 mg daily for 14 days then calcium for 76 days
risedronate	5 mg daily/ 35 mg weekly (long-acting)	30 mg daily for 2 months
sodium clodronate				2.4 to 3.2 g daily, reduce to 1.6 g daily
tiludronate		400 mg daily for 3 months
zoledronic acid			4 mg IV	4 mg IV every 2 to 6 weeks