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Bisphosphonates: Oral (Alendronate, Clodronate, Etidronate, Risedronate)
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Pharmacology
Bisphosphonates (previously called diphosphonates) were first synthesized in the 19th century and used as antiscaling and anticorrosive agents in industrial cleaning powders. In the 1960s, their bone-seeking properties sparked interest in their potential clinical usefulness. This monograph focuses on the use of oral bisphosphonates.
Bisphosphonates are stable analogues of pyrophosphate. After binding to bone surfaces, they slow the formation of hydroxyapatite crystals and delay their aggregation into large clusters. They also interfere with the resorptive action and promote apoptosis (programmed cell death) of osteoclasts, resulting in decreased depth and rate of formation of new bone remodeling units. Lifelong accumulation of remodeling deficits begins shortly after bone growth stops and is thought to be the underlying mechanism of age-related bone loss. By inhibiting this process, bisphosphonates increase bone mass and decrease susceptibility to fracture. An additional proposed mechanism of action is inhibition of osteocyte and osteoblast apoptosis, thereby increasing the life span of osteocytes and decreasing bone fragility.
The bisphosphonates have been classified as 1 st, 2 nd or 3 rd generation agents, based on the type of side chain on the carbon atom, their relative antiresorptive potencies and when they were developed. Of the oral agents available in Canada, etidronate and clodronate, with short alkyl or halide side chains, are considered 1 st generation. Alendronate, with its amino terminal group, is considered a 2 nd generation agent and is sometimes referred to as an aminobisphosphonate. Risedronate, the most recent arrival on the Canadian market, possesses a cyclic side chain and is a 3 rd generation bisphosphonate. With each new generation has come a 10- to 100-fold increase in antiresorptive potency.
The antiresorptive properties of bisphosphonates have widespread clinical applications. In the treatment of Paget's disease of bone, bisphosphonate therapy results in reduction of elevated alkaline phosphatase levels and relief of bone pain. Bisphosphonates have been shown to maintain and increase bone mass and decrease the incidence of vertebral and non-vertebral fractures in the prevention and treatment of primary and secondary osteoporosis. They are also used in the management of hypercalcemia of malignancy, metastatic and osteolytic bone disease and in bone-imaging.
Pharmacokinetics: Bisphosphonates are poorly absorbed from the gastrointestinal tract. Typically, absorption ranges from 0.7% to 3% of an oral dose and is significantly reduced in the presence of calcium, other divalent cations or food or beverages other than plain water. Bisphosphonates are not metabolized. After binding to bone surfaces and exerting their effects on osteoclasts, they are retained in the bone for months or years and are slowly released with the process of bone turnover. The portion of absorbed drug that is not bound to bone is excreted by the kidney unchanged.
Bisphosphonates (previously called diphosphonates) were first synthesized in the 19th century and used as antiscaling and anticorrosive agents in industrial cleaning powders. In the 1960s, their bone-seeking properties sparked interest in their potential clinical usefulness. This monograph focuses on the use of oral bisphosphonates.
Bisphosphonates are stable analogues of pyrophosphate. After binding to bone surfaces, they slow the formation of hydroxyapatite crystals and delay their aggregation into large clusters. They also interfere with the resorptive action and promote apoptosis (programmed cell death) of osteoclasts, resulting in decreased depth and rate of formation of new bone remodeling units. Lifelong accumulation of remodeling deficits begins shortly after bone growth stops and is thought to be the underlying mechanism of age-related bone loss. By inhibiting this process, bisphosphonates increase bone mass and decrease susceptibility to fracture. An additional proposed mechanism of action is inhibition of osteocyte and osteoblast apoptosis, thereby increasing the life span of osteocytes and decreasing bone fragility.
The bisphosphonates have been classified as 1 st, 2 nd or 3 rd generation agents, based on the type of side chain on the carbon atom, their relative antiresorptive potencies and when they were developed. Of the oral agents available in Canada, etidronate and clodronate, with short alkyl or halide side chains, are considered 1 st generation. Alendronate, with its amino terminal group, is considered a 2 nd generation agent and is sometimes referred to as an aminobisphosphonate. Risedronate, the most recent arrival on the Canadian market, possesses a cyclic side chain and is a 3 rd generation bisphosphonate. With each new generation has come a 10- to 100-fold increase in antiresorptive potency.
The antiresorptive properties of bisphosphonates have widespread clinical applications. In the treatment of Paget's disease of bone, bisphosphonate therapy results in reduction of elevated alkaline phosphatase levels and relief of bone pain. Bisphosphonates have been shown to maintain and increase bone mass and decrease the incidence of vertebral and non-vertebral fractures in the prevention and treatment of primary and secondary osteoporosis. They are also used in the management of hypercalcemia of malignancy, metastatic and osteolytic bone disease and in bone-imaging.
Pharmacokinetics: Bisphosphonates are poorly absorbed from the gastrointestinal tract. Typically, absorption ranges from 0.7% to 3% of an oral dose and is significantly reduced in the presence of calcium, other divalent cations or food or beverages other than plain water. Bisphosphonates are not metabolized. After binding to bone surfaces and exerting their effects on osteoclasts, they are retained in the bone for months or years and are slowly released with the process of bone turnover. The portion of absorbed drug that is not bound to bone is excreted by the kidney unchanged.
Indications
Bisphosphonates (previously Called Diphosphonates) Were First Synthesized In The 19th Century And Used As Antiscaling And Anticorrosive Agents In Industrial Cleaning Powders. In The 1960s, Their Bone-seeking Properties Sparked Interest In Their Potential Clinical Usefulness. This Monograph Focuses On The Use Of Oral Bisphosphonates.
Bisphosphonates Are Stable Analogues Of Pyrophosphate. After Binding To Bone Surfaces, They Slow The Formation Of Hydroxyapatite Crystals And Delay Their Aggregation Into Large Clusters. They Also Interfere With The Resorptive Action And Promote Apoptosis (programmed Cell Death) Of Osteoclasts, Resulting In Decreased Depth And Rate Of Formation Of New Bone Remodeling Units. Lifelong Accumulation Of Remodeling Deficits Begins Shortly After Bone Growth Stops And Is Thought To Be The Underlying Mechanism Of Age-related Bone Loss. By Inhibiting This Process, Bisphosphonates Increase Bone Mass And Decrease Susceptibility To Fracture. An Additional Proposed Mechanism Of Action Is Inhibition Of Osteocyte And Osteoblast Apoptosis, Thereby Increasing The Life Span Of Osteocytes And Decreasing Bone Fragility.
The Bisphosphonates Have Been Classified As 1 St, 2 Nd Or 3 Rd Generation Agents, Based On The Type Of Side Chain On The Carbon Atom, Their Relative Antiresorptive Potencies And When They Were Developed. Of The Oral Agents Available In Canada, Etidronate And Clodronate, With Short Alkyl Or Halide Side Chains, Are Considered 1 St Generation. Alendronate, With Its Amino Terminal Group, Is Considered A 2 Nd Generation Agent And Is Sometimes Referred To As An Aminobisphosphonate. Risedronate, The Most Recent Arrival On The Canadian Market, Possesses A Cyclic Side Chain And Is A 3 Rd Generation Bisphosphonate. With Each New Generation Has Come A 10- To 100-fold Increase In Antiresorptive Potency.
The Antiresorptive Properties Of Bisphosphonates Have Widespread Clinical Applications. In The Treatment Of Paget's Disease Of Bone, Bisphosphonate Therapy Results In Reduction Of Elevated Alkaline Phosphatase Levels And Relief Of Bone Pain. Bisphosphonates Have Been Shown To Maintain And Increase Bone Mass And Decrease The Incidence Of Vertebral And Non-vertebral Fractures In The Prevention And Treatment Of Primary And Secondary Osteoporosis. They Are Also Used In The Management Of Hypercalcemia Of Malignancy, Metastatic And Osteolytic Bone Disease And In Bone-imaging.
Pharmacokinetics: Bisphosphonates Are Poorly Absorbed From The Gastrointestinal Tract. Typically, Absorption Ranges From 0.7% To 3% Of An Oral Dose And Is Significantly Reduced In The Presence Of Calcium, Other Divalent Cations Or Food Or Beverages Other Than Plain Water. Bisphosphonates Are Not Metabolized. After Binding To Bone Surfaces And Exerting Their Effects On Osteoclasts, They Are Retained In The Bone For Months Or Years And Are Slowly Released With The Process Of Bone Turnover. The Portion Of Absorbed Drug That Is Not Bound To Bone Is Excreted By The Kidney Unchanged.
Bisphosphonates (previously Called Diphosphonates) Were First Synthesized In The 19th Century And Used As Antiscaling And Anticorrosive Agents In Industrial Cleaning Powders. In The 1960s, Their Bone-seeking Properties Sparked Interest In Their Potential Clinical Usefulness. This Monograph Focuses On The Use Of Oral Bisphosphonates.
Bisphosphonates Are Stable Analogues Of Pyrophosphate. After Binding To Bone Surfaces, They Slow The Formation Of Hydroxyapatite Crystals And Delay Their Aggregation Into Large Clusters. They Also Interfere With The Resorptive Action And Promote Apoptosis (programmed Cell Death) Of Osteoclasts, Resulting In Decreased Depth And Rate Of Formation Of New Bone Remodeling Units. Lifelong Accumulation Of Remodeling Deficits Begins Shortly After Bone Growth Stops And Is Thought To Be The Underlying Mechanism Of Age-related Bone Loss. By Inhibiting This Process, Bisphosphonates Increase Bone Mass And Decrease Susceptibility To Fracture. An Additional Proposed Mechanism Of Action Is Inhibition Of Osteocyte And Osteoblast Apoptosis, Thereby Increasing The Life Span Of Osteocytes And Decreasing Bone Fragility.
The Bisphosphonates Have Been Classified As 1 St, 2 Nd Or 3 Rd Generation Agents, Based On The Type Of Side Chain On The Carbon Atom, Their Relative Antiresorptive Potencies And When They Were Developed. Of The Oral Agents Available In Canada, Etidronate And Clodronate, With Short Alkyl Or Halide Side Chains, Are Considered 1 St Generation. Alendronate, With Its Amino Terminal Group, Is Considered A 2 Nd Generation Agent And Is Sometimes Referred To As An Aminobisphosphonate. Risedronate, The Most Recent Arrival On The Canadian Market, Possesses A Cyclic Side Chain And Is A 3 Rd Generation Bisphosphonate. With Each New Generation Has Come A 10- To 100-fold Increase In Antiresorptive Potency.
The Antiresorptive Properties Of Bisphosphonates Have Widespread Clinical Applications. In The Treatment Of Paget's Disease Of Bone, Bisphosphonate Therapy Results In Reduction Of Elevated Alkaline Phosphatase Levels And Relief Of Bone Pain. Bisphosphonates Have Been Shown To Maintain And Increase Bone Mass And Decrease The Incidence Of Vertebral And Non-vertebral Fractures In The Prevention And Treatment Of Primary And Secondary Osteoporosis. They Are Also Used In The Management Of Hypercalcemia Of Malignancy, Metastatic And Osteolytic Bone Disease And In Bone-imaging.
Pharmacokinetics: Bisphosphonates Are Poorly Absorbed From The Gastrointestinal Tract. Typically, Absorption Ranges From 0.7% To 3% Of An Oral Dose And Is Significantly Reduced In The Presence Of Calcium, Other Divalent Cations Or Food Or Beverages Other Than Plain Water. Bisphosphonates Are Not Metabolized. After Binding To Bone Surfaces And Exerting Their Effects On Osteoclasts, They Are Retained In The Bone For Months Or Years And Are Slowly Released With The Process Of Bone Turnover. The Portion Of Absorbed Drug That Is Not Bound To Bone Is Excreted By The Kidney Unchanged.
Contraindications
All bisphosphonates are contraindicated in patients with hypersensitivity to any bisphosphonate. Alendronate is contraindicated in patients with abnormalities of the esophagus that delay emptying, such as stricture or achalasia, in patients who cannot stand or sit upright for at least 30 minutes and in patients with creatinine clearance <0.58mL/s. Clodronate is contraindicated in patients with serum creatinine >440µmol/L or severe inflammation of the gastrointestinal tract. Etidronate is contraindicated in patients with clinically overt osteomalacia, until appropriate treatment has been initiated for it. Risedronate is contraindicated in patients with hypocalcemia.
All bisphosphonates are contraindicated in patients with hypersensitivity to any bisphosphonate. Alendronate is contraindicated in patients with abnormalities of the esophagus that delay emptying, such as stricture or achalasia, in patients who cannot stand or sit upright for at least 30 minutes and in patients with creatinine clearance <0.58mL/s. Clodronate is contraindicated in patients with serum creatinine >440µmol/L or severe inflammation of the gastrointestinal tract. Etidronate is contraindicated in patients with clinically overt osteomalacia, until appropriate treatment has been initiated for it. Risedronate is contraindicated in patients with hypocalcemia.
Safety Information / Warning
Bisphosphonates may cause upper gastrointestinal disorders such as dysphagia, esophagitis, esophageal ulcer and gastric ulcer. Esophageal injury has been more commonly associated with aminobisphosphonates such as alendronate. There appears to be a higher risk of esophageal injury if the patient does not remain upright following the dose. It is recommended that patients take bisphosphonates on an empty stomach with a full glass of water and remain in an upright position for at least 30 minutes after a dose.
Because bisphosphonates are excreted renally, caution and appropriate monitoring are advised for patients with renal failure.
In the treatment of Paget's disease with etidronate, it can take months to realize the maximum benefit of therapy. Caution is advised regarding treatment beyond the recommended duration of therapy, because of the potential for impaired mineralization of new bone. A drug-free interval is recommended between courses of treatment for Paget's disease.
Bisphosphonates may cause upper gastrointestinal disorders such as dysphagia, esophagitis, esophageal ulcer and gastric ulcer. Esophageal injury has been more commonly associated with aminobisphosphonates such as alendronate. There appears to be a higher risk of esophageal injury if the patient does not remain upright following the dose. It is recommended that patients take bisphosphonates on an empty stomach with a full glass of water and remain in an upright position for at least 30 minutes after a dose.
Because bisphosphonates are excreted renally, caution and appropriate monitoring are advised for patients with renal failure.
In the treatment of Paget's disease with etidronate, it can take months to realize the maximum benefit of therapy. Caution is advised regarding treatment beyond the recommended duration of therapy, because of the potential for impaired mineralization of new bone. A drug-free interval is recommended between courses of treatment for Paget's disease.
Precautions
Gastrointestinal: To minimize the risk of upper gastrointestinal irritation or injury, bisphosphonates should be taken on an empty stomach with a full glass of plain water. They should not be taken with food, calcium, other medications, or any beverage other than water. Patients should remain in an upright position (sitting or standing) for 30 minutes after a dose. Manufacturers' recommendations vary for the different agents with respect to the time of day and how long before a meal they should be taken (see Dosage).
Dosing instructions should be clearly explained and reinforced. Patients should be advised to stop taking the bisphosphonate and consult their physician if symptoms of esophageal injury develop, such as such as difficulty swallowing, retrosternal pain or new or worsening heartburn.
Caution is advised for patients with a history of gastrointestinal disorders, especially delayed esophageal transit time. Alendronate is contraindicated in patients with delayed esophageal emptying.
Bone Metabolism: Hypocalcemia and other disturbances of bone and mineral metabolism should be effectively treated prior to bisphosphonate therapy. Because mild decreases in serum calcium and phosphorus have been observed with some bisphosphonates, maintaining adequate intake of calcium and vitamin D is recommended. Calcium interferes with the absorption of the bisphosphonate and should be taken at a different time. In the case of cyclic etidronate therapy, calcium and vitamin D supplements are not recommended during the 14-day etidronate phase (see Dosage, TableII). For information on recommended intake of calcium and vitaminD, see the Calcium Salts: Oral and VitaminD general monographs in the White pages and Osteoporosis and the Older Adult in the Clin-Info section.
Dose and time dependent impairment of new bone mineralization can occur with continuous etidronate dosing regimens. This can lead to accumulation of unmineralized osteoid with bone pain and fractures, similar to the clinical manifestations of osteomalacia. Extended periods of continuous use should be approached cautiously.
Pregnancy: No published data are available on the use of oral bisphosphonates in pregnancy. One case report described the use of intravenous pamidronate in pregnancy with no serious adverse outcomes to the fetus.
Lactation: It is not known whether bisphosphonates are excreted in breast milk.
Drug Interactions : Because bisphosphonates are highly bound to bone, are not metabolized, not highly protein bound and do not induce or inhibit micorosomal enzyme systems, they do not possess an obvious potential for interacting with other drugs. Their absorption can, however, be greatly decreased in the presence of food, calcium and other cations or beverages other than plain water.
Drug-Laboratory Test Interactions : Bisphosphonates could potentially interfere with the binding of bone imaging diagnostic agents to bone.
Gastrointestinal: To minimize the risk of upper gastrointestinal irritation or injury, bisphosphonates should be taken on an empty stomach with a full glass of plain water. They should not be taken with food, calcium, other medications, or any beverage other than water. Patients should remain in an upright position (sitting or standing) for 30 minutes after a dose. Manufacturers' recommendations vary for the different agents with respect to the time of day and how long before a meal they should be taken (see Dosage).
Dosing instructions should be clearly explained and reinforced. Patients should be advised to stop taking the bisphosphonate and consult their physician if symptoms of esophageal injury develop, such as such as difficulty swallowing, retrosternal pain or new or worsening heartburn.
Caution is advised for patients with a history of gastrointestinal disorders, especially delayed esophageal transit time. Alendronate is contraindicated in patients with delayed esophageal emptying.
Bone Metabolism: Hypocalcemia and other disturbances of bone and mineral metabolism should be effectively treated prior to bisphosphonate therapy. Because mild decreases in serum calcium and phosphorus have been observed with some bisphosphonates, maintaining adequate intake of calcium and vitamin D is recommended. Calcium interferes with the absorption of the bisphosphonate and should be taken at a different time. In the case of cyclic etidronate therapy, calcium and vitamin D supplements are not recommended during the 14-day etidronate phase (see Dosage, TableII). For information on recommended intake of calcium and vitaminD, see the Calcium Salts: Oral and VitaminD general monographs in the White pages and Osteoporosis and the Older Adult in the Clin-Info section.
Dose and time dependent impairment of new bone mineralization can occur with continuous etidronate dosing regimens. This can lead to accumulation of unmineralized osteoid with bone pain and fractures, similar to the clinical manifestations of osteomalacia. Extended periods of continuous use should be approached cautiously.
Pregnancy: No published data are available on the use of oral bisphosphonates in pregnancy. One case report described the use of intravenous pamidronate in pregnancy with no serious adverse outcomes to the fetus.
Lactation: It is not known whether bisphosphonates are excreted in breast milk.
Drug Interactions : Because bisphosphonates are highly bound to bone, are not metabolized, not highly protein bound and do not induce or inhibit micorosomal enzyme systems, they do not possess an obvious potential for interacting with other drugs. Their absorption can, however, be greatly decreased in the presence of food, calcium and other cations or beverages other than plain water.
Drug-Laboratory Test Interactions : Bisphosphonates could potentially interfere with the binding of bone imaging diagnostic agents to bone.
Side Effects / Adverse Effects
Oral bisphosphonates are generally well tolerated, especially when taken properly by appropriately selected patients. Gastrointestinal effects such as dyspepsia and nausea are the most frequently reported side effects. Esophageal injury is thought to be more common with the use of aminobisphosphonates such as alendronate (see Warnings, Precautions). Nausea and diarrhea occur in a significant percentage of patients treated with etidronate in doses greater than 5mg/kg/day, but are less common at doses used for osteoporosis.
Rarely, the following adverse effects have been reported with the use of bisphosphonates, although a causal relationship has not always been established: acute-phase reactions involving fever and lymphopenia, leukemia, iritis, skin reactions and arthralgias.
Oral bisphosphonates are generally well tolerated, especially when taken properly by appropriately selected patients. Gastrointestinal effects such as dyspepsia and nausea are the most frequently reported side effects. Esophageal injury is thought to be more common with the use of aminobisphosphonates such as alendronate (see Warnings, Precautions). Nausea and diarrhea occur in a significant percentage of patients treated with etidronate in doses greater than 5mg/kg/day, but are less common at doses used for osteoporosis.
Rarely, the following adverse effects have been reported with the use of bisphosphonates, although a causal relationship has not always been established: acute-phase reactions involving fever and lymphopenia, leukemia, iritis, skin reactions and arthralgias.
Overdose
Symptoms: Clinical experience with oral bisphosphonate overdose is extremely limited. Expected signs and symptoms might include gastrointestinal upset, esophageal symptoms, diarrhea and hypocalcemia.
Treatment: Suggested measures for management of bisphosphonate overdose include giving milk or antacids orally to bind unabsorbed drug, correcting electrolyte imbalances such as hypocalcemia, keeping the patient upright and monitoring of renal function. It has been suggested that vomiting should not be induced because of the possible risk of esophageal irritation.
Symptoms: Clinical experience with oral bisphosphonate overdose is extremely limited. Expected signs and symptoms might include gastrointestinal upset, esophageal symptoms, diarrhea and hypocalcemia.
Treatment: Suggested measures for management of bisphosphonate overdose include giving milk or antacids orally to bind unabsorbed drug, correcting electrolyte imbalances such as hypocalcemia, keeping the patient upright and monitoring of renal function. It has been suggested that vomiting should not be induced because of the possible risk of esophageal irritation.
Recommended Dosage
Tablets and capsules should be swallowed whole, not sucked or chewed. Adequate intake of calcium and vitaminD should be maintained during bisphosphonate therapy.
Tablets and capsules should be swallowed whole, not sucked or chewed. Adequate intake of calcium and vitaminD should be maintained during bisphosphonate therapy.
Supplied / Packaging
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Brand Name
Bisphosphonates: Oral
Bisphosphonates: Oral
Generic Name
Alendronate, Clodronate, Etidronate, Risedronate
Alendronate, Clodronate, Etidronate, Risedronate
General Indications
Bone Metabolism Regulator
Bone Metabolism Regulator
