Bisphosphonates

Alendronate

Alendronate is an aminobisphosphonate with general properties similar to those of the other bisphosphonates. It inhibits bone resorption and is used in osteoporosis and Paget’s disease of bone. It has also been used in the treatment of bone metastases and hypercalcemia of malignancy.

Clodronate

Clodronate is a bisphosphonate that has demonstrated efficacy in patients with a variety of disorders of enhanced bone resorption, including Paget’s disease, osteolytic bone metastases, and hypercalcemia of malignancy [ , ]. In preclinical studies, clodronate prevented bone loss during immobilization [ ].

Etidronate

Etidronate, an alkylbisphosphonate, was the first to be introduced for the management of bone resorption disorders. Subsequently, a cyclic regimen of etidronate followed by calcium supplementation was established in the treatment of osteoporosis.

Pamidronate

Pamidronate in the disodium form, a second-generation bisphosphonate, has an intermediate antiresorptive activity; its continuous administration produces rapid suppression of bone resorption. Unlike etidronate, it does not impair bone mineralization at therapeutic dosages in patients with Paget’s disease. Pamidronate inhibits osteoclast activity primarily by binding with hydroxyapatite crystals in the bone matrix, preventing the attachment of osteoclast precursor cells. Other mechanisms of action of matrix-bound pamidronate may include direct inhibition of mature osteoclast function, promotion of osteoclast apoptosis, and interference with osteoblast-mediated osteoclast activation. In patients with osteoporosis, pamidronate increased bone mineral density by 6.8% over 2.2 years [ ]. The frequently observed adverse effects with pamidronate therapy were gastrointestinal: gastritis due to either a local reaction when a high concentration of the drug stays in the mucus or by chelation with calcium ions [ ].

Risedronate

Risedronate is a pyridinylbisphosphonate with potent antiresorptive properties. In animal studies it was about 1000 times more potent than etidronate and 3–5 times more potent than alendronate [ ], which enables the use of a lower dose and a shorter treatment regimen, with consequent potential minimization of adverse effects. In a randomized, double-blind, multicenter study of the efficacy, safety, and tolerability of risedronate in 62 patients taking oral risedronate for Paget’s disease of bone, adverse effects were recorded in 29 patients [ ]. Twelve had upper gastrointestinal adverse events, of which three were moderate to severe. Four other patients withdrew because of adverse events, but one only was considered to be possibly drug-related (mild colitis). There was a transient reduction in serum calcium and phosphorus concentrations, greatest at 1 month after the start of treatment, and followed by a gradual return toward baseline concentrations.

Comparative studies

In 72 postmenopausal women (mean age 65 years) with established osteoporosis who took elemental calcium 1.0 g/day and vitamin D 400 U/day, etidronate and hormones were compared [ ]. The Hormone Replacement Therapy (HRT) group (n = 18) took cyclical estrogen and progesterone; the etidronate group (n = 17) took intermittent cyclical etidronate; and the combined therapy group (n = 19) took both HRT and etidronate. Three patients in the HRT group and two patients in the combined therapy group withdrew owing to estrogen-related adverse effects. One patient each from the control group and the etidronate group withdrew because of inability to tolerate the medications. Two patients each from the control and combined therapy groups, and one from the etidronate group withdrew owing to other medical problems. There was one death due to myocardial infarction in the etidronate group, and one patient in the control group was lost to follow-up. Six patients complained of nausea after etidronate, but symptoms improved with time.

In 32 women treated for postmenopausal osteoporosis for 2 years with either pamidronate or with oral fluoride, adverse effects were a transient fever with influenza-like symptoms in five patients after the first infusion of pamidronate, and rigors and mild phlebitis in one patient [ ].

Placebo-controlled studies

Of 300 patients, 221 (111 pamidronate, 110 placebo) withdrew prematurely [ ]. The majority of withdrawals (n = 115) were due to disease progression or death due to multiple myeloma. The number of patients who withdrew because of adverse experiences (n = 30) was small in both groups, and no deaths occurred due to the treatment. Adverse gastrointestinal events were reported in patients who received both pamidronate and placebo, but although the rates were not significantly different in the two groups, there were more cases of nausea, dysphagia/dyspepsia, and gastrointestinal ulceration in the pamidronate group.

In a long-term follow-up of two randomized, placebo-controlled trials of pamidronate in women with breast carcinoma and osteolytic bone metastases, adverse events caused premature withdrawal of therapy in 22% of 367 patients taking pamidronate 90 mg/day and 20% of 38 patients taking placebo [ ].

• A 75-year-old woman was withdrawn after developing an allergic reaction in her left eye possibly related to pamidronate.

• Another patient discontinued pamidronate after an episode of symptomatic hypocalcemia.

• Two other serious and unexpected adverse events occurred in patients taking pamidronate.

• A 45-year-old woman who had been taking placebo developed an interstitial pulmonary infiltrate and dyspnea 4 days after taking pamidronate on a compassionate basis after completing the study.

• An 83-year-old woman developed increased weakness, fatigue, and dyspnea 3 weeks after her last dose of pamidronate.

These adverse events were both assessed by the treating physician as being possibly related to pamidronate. Fatigue related to the study drug was reported slightly more often by patients taking pamidronate (40%) than those taking placebo (29%). Fever related to the study drug was reported in 14% of pamidronate patients and in 5% of placebo patients.

The effect of oral pamidronate on bone mineral density and its adverse effect profile has been investigated in a double-blind, placebo-controlled study in 122 patients aged 55–75 years with established vertebral osteoporosis [ ]. The patients took disodium pamidronate 300 mg/day for 4 weeks every 16 weeks (group A), 150 mg/day for 4 weeks every 8 weeks (group B), or placebo (group C). All also took calcium 500 mg/day and vitamin D 400 IU/day. In groups A and B there were significant reductions in serum osteocalcin and urinary deoxypyridinoline and an excess of gastrointestinal adverse effects, particularly in group A. The authors concluded that intermittent pamidronate therapy can prevent bone loss in both the lumbar spine and femoral neck in patients with established vertebral osteoporosis, although the 300 mg dose did not appear suitable for clinical use because of gastrointestinal adverse effects.