Bisphosphonates

BISPHOSPHONATES

Bisphosphonates (BPNs) are analogues of pyrophosphate: carbon atom replacing oxygen in the POP skeleton. They inhibit bone resorption and have recently attracted considerable attention because of their ability to prevent osteoporosis in addition to their usefulness in metabolic bone diseases and hypercalcaemia. They are the most effective antiresorptive drugs. Chronologically and according to potency, the BPNs can be grouped into 3 generations (see box). The first generation compounds have simpler side chains, are the least potent and seldom used now. The second and third generation compounds have an amino or nitrogenous ring substitution in the side chain, are more potent, have higher efficacy and additional mode of action.

The mechanism of action of BPNs is not fully understood, but two facets of action have been delineated:

(a) BPNs have strong affinity for calcium phosphate: have selective action in calcified tissue. The two main components of bone are protein matrix and the solid mineral phase (hydroxyapatite). On the surface of resorptive pits the mineral phase is solubilized in the clear acidic zone created at the ruffled border of osteoclasts, followed by resorption of protein matrix in this area by acid hydrolases secreted from osteoclasts. BPNs localise in the acidic zone under the osteoclasts due to their high affinity for Ca2+ ions. When Ca2+ ions are released from the bone surface due to high acidity, the BPNs are also released and are internalized into osteoclasts by endocytosis. This results in:

• Accelerated apoptosis of osteoclasts reducing their number.

• Disruption of cytoskeleton and ruffled border of osteoclasts.

In addition, BPNs appear to affect osteoclast precursors and inhibit their differentiation by suppressing IL6.

(b) It has been shown recently that BPNs, especially the second and third generation potent amino-derivatives like alendronate, zoledronate, have important metabolic effects in the mevalonate pathway for isoprenoid lipid synthesis. They inhibit prenylation of certain GTP-binding proteins involved in cytoskeletal organization, membrane ruffling and vesicle movement. The net result is inactivation of osteoclasts, impaired vesicle fusion and enhanced apoptosis. Interference with mevalonate pathway may also impart antitumor action on bony metastasis.

All oral BPNs are poorly absorbed, and produce gastric irritation, esophagitis as the major side effect. They are contraindicated in gastroesophageal reflux, peptic ulcer and renal impairment.

The BPNs are useful in conditions characterized by enhanced bone turnover.

1. Osteoporosis The second and third generation BPNs (e.g. alendronate, risedronate) are effective in preventing and treating postmenopausal osteoporosis in women as well as age related, idiopathic and steroidinduced osteoporosis in both men and women. Alendronate has been found equally or more effective than HRT or raloxifene in conserving bone mineral density and has reduced the risk of vertebral as well as hip fracture by 47–56%.

Estrogens prevent vertebral but not other fractures. BPNs are more effective than calcitonin and continue to afford protection for at least 5 years of continuous use.

2. Paget’s Disease This disease due to abnormal osteoclast function producing disordered bone remodeling and honeycomblike bone architecture is benefited by BPNs. They arrest osteolytic lesions, reduce bone pain and improve secondary symptoms. Longlasting remissions may be induced. Alendronate, risedronate, pamidronate and zoledronate are used now. They are more convenient, more effective and cheaper than calcitonin. Combined use of BPNs and calcitonin further increases efficacy. Treatment with BPNs should not exceed 6 months; but courses may be repeated after a gap.

3. Hypercalcaemia Of Malignancy Severe hypercalcaemia, a common complication of malignancy, is a medical emergency with altered consciousness. Pamidronate (60–90 mg i.v. over 2–4 hours) or zoledronate (4 mg i.v. over 15 min) are the most effective drugs, but take 24–48 hours to act. They may be supplemented by i.m. calcitonin 6–12 hourly for 2 days for rapid action. Vigorous i.v. hydration along with furosemide to prevent volume over load is started before BPN infusion. It reduces serum calcium within few hours and corrects the attending dehydration. Oral BPNs are not useful.

4. Osteolytic Bone Metastasis Parenteral pamidronate/zoledronate arrests osteolytic lesions and reduces bone pain.

Etidronate 

This is the first BPN to be used clinically, employed in hypercalcaemia and Paget’s disease. However, it also interferes with bone mineralization: continuous therapy produces osteomalacia. Therefore, it has been largely replaced by zoledronate for hypercalcaemia and alendronate/risedronate for Paget’s disease. Etidronate is administered both orally and i.v., but is not preferred now. Adverse effects are gastric irritation, bone pain, headache, metallic taste, pyrexia and hypersensitivity.

Dose: 5–7.5 mg/kg/day; DRONATEOS 200 mg tab, 300 mg inj; DISONATE, ETIFEM 200 mg tab.

Pamidronate

A second generation potent BPN which is administered only by i.v. infusion in a dose of 60–90 mg over 2–4 hours weekly or monthly depending on the condition. It is used in Paget’s disease, hypercalcaemia of malignancy and in bony metastasis. Adverse effects are thrombophlebitis of injected vein, bone pain, fever and leukopenia. A fluelike reaction may occur initially due to cytokine release.

AREDIA 15, 30, 60 mg inj; AREDRONET 30, 90 mg inj.

BONAPAM 30, 60, 90 mg ing.

Alendronate

This potent orally effective second generation amino-BPN is used primarily for prevention and treatment of osteoporosis both in women and men. It is to be taken on empty stomach in the morning with a full glass of water and patient is instructed not to lie down or take food for at least 30 min. These measures are needed to prevent contact with esophageal mucosa which results in esophagitis. Calcium, iron, antacids, mineral water, tea, coffee, fruit juice interfere with alendronate absorption. NSAIDs accentuate gastric irritation caused by alendronate. Other adverse effects are gastric erosion, retrosternal pain, flatulence, headache, bodyache and initial fall in serum Ca2+ level.

Dose: 5–10 mg OD; or 35–70 mg weekly; weekly treatment is as effective, more convenient and better tolerated. OSTEOPHOS, 5, 10, 35, 70 mg tab. DENFOS 5, 10 mg tab, RESTOFOS, DRONAL 10 mg tab.

Oral bioavailability of alendronate is ~1%. Up to 50% of the drug entering the body is sequestrated in bone while the rest is excreted unchanged mainly by the kidney. The terminal elimination t½ of alendronate has been measured as 10.5 years.

Risedronate

It is an oral 3rd generation BPN, more potent than alendronate, but equally efficacious. Oral bioavailability of 1% and other features are also similar to alendronate. It is indicated in the treatment of osteoporosis and Paget’s disease.

Dose: 35 mg/week oral in the morning with a full glass of water.

RESTOFOS, GEMFOS, ACTONEL 35 mg tab.

Zoledronate

This parenteral highly potent 3rd generation BPN is indicated for hypercalcaemia, bony metastasis and Paget’s disease. Osteoclastic activity is markedly suppressed and an additional antitumor effect may be exerted by interference with mevalonate pathway. Proliferation of bony metastasis of prostate/breast cancer and multiple myeloma cells may be arrested. For hypercalcaemia, it is more effective, faster acting than pamidronate and therefore the drug of choice now. Another advantage is that it can be infused over 15 min (because of less venous irritation), whereas pamidronate needs 2–4 hours. Fluelike symptoms due to cytokine release attend the i.v. infusion. Renal toxicity has been encountered.

Dose: 4 mg diluted in 100 ml saline/glucose solution and infused i.v. over 15 min; may be repeated after 7 days and then at 3–4 week intervals.

ZOBONE, ZOLDRIA 4 mg/vial inj.