Bisphosphonates

Chemistry and Pharmacodynamics

Chemical structure

• Pyrophosphate analogs, which mimic the structure of pyrophosphate
• Common phosphorus-carbon-phosphorus chain
• Long chain: R² side chain determines the drug strength
• Short chain: R¹ side chain determines the pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

Mechanism of action

1. Bisphosphonates bind BIND Hyperbilirubinemia of the Newborn to hydroxyapatite crystals Hydroxyapatite crystals A group of compounds with the general formula m10(PO4)6(OH)2, where m is barium, strontium, or calcium. The compounds are the principal mineral in phosphorite deposits, biological tissue, human bones, and teeth. They are also used as an anticaking agent and polymer catalysts. Calcium Hemostasis and Bone Metabolism in the bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types matrix.
2. Osteoclasts Osteoclasts A large multinuclear cell associated with the bone resorption. An odontoclast, also called cementoclast, is cytomorphologically the same as an osteoclast and is involved in cementum resorption. Bones: Development and Ossification bind BIND Hyperbilirubinemia of the Newborn to and phagocytose bisphosphonate:
   • Nitrogen-containing bisphosphonates inhibit farnesyl pyrophosphate Farnesyl pyrophosphate Cholesterol Metabolism synthetase → promote detachment of the osteoclast from the bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types
   • Simple bisphosphonates are metabolized to metabolites, which prevent ATP use → apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage
3. ↓ Osteoclast-mediated bone resorption Bone resorption Bone loss due to osteoclastic activity. Bones: Remodeling and Healing
4. Indirectly increase bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types formation and bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types mineral density

Pharmacokinetics

Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption

• Absorbed in the GI tract through paracellular Paracellular Renal Potassium Regulation transport
• In general, poorly absorbed in the GI tract

Distribution

• Binds bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types
• Preferentially binds to regions of bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types with a high rate of turnover

Metabolism

• Not metabolized
• Long half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics (may exceed 10 years)

Excretion

• Half excreted unchanged by the kidney
• Half absorbed on the bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types surface

Classification

Bisphosphonates are classified by structure. Bisphosphonate compounds are either nitrogenous or nonnitrogenous. The nitrogenous subtype contains nitrogen Nitrogen An element with the atomic symbol n, atomic number 7, and atomic weight [14. 00643; 14. 00728]. Nitrogen exists as a diatomic gas and makes up about 78% of the earth’s atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. Urea Cycle in the long chain (R²).

• Nitrogenous (more potent osteoclast inhibitors):
  • Pamidronate
  • Alendronate
  • Risedronate
  • Zoledronic acid
• Nonnitrogenous (simple):
  • Etidronate
  • Clodronate
  • Tiludronate

Indications

Bisphosphonates treat a number of conditions associated with bones:

• Postmenopausal osteoporosis Postmenopausal osteoporosis Metabolic disorder associated with fractures of the femoral neck, vertebrae, and distal forearm. It occurs commonly in women within 15-20 years after menopause, and is caused by factors associated with menopause including estrogen deficiency. Osteoporosis:
  • 1st-line therapy
  • Increases bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types mineral density
• Prevention of osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis related to:
  • Glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids
  • Androgen deprivation therapy Androgen Deprivation Therapy Prostate Cancer
• Paget disease of the bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types ( osteitis deformans Osteitis deformans Paget’s disease of bone (PDB), also known historically as osteitis deformans, is a focal disorder of bone metabolism that affects about 2%–9% of people. Commonly affected areas include the skull, spine, pelvis, and long bones of the lower extremity. The 2 main clinical manifestations of Paget’s disease are bone pain and the consequences of bone deformities. Paget Disease of Bone):
  • 1st-line therapy
  • Inhibits initial osteoclast overactivation
• Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types metastases:
  • Reduces the risk of skeletal-related events
  • Zoledronic acid is preferred. 
• Hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia of malignancy Malignancy Hemothorax: reduces bone resorption Bone resorption Bone loss due to osteoclastic activity. Bones: Remodeling and Healing due to parathyroid-related peptide or bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis
• Hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism: improves bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types density
• Osteogenesis imperfecta Osteogenesis imperfecta Osteogenesis imperfecta (OI), or “brittle bone disease,” is a rare genetic connective tissue disorder characterized by severe bone fragility. Although OI is considered a single disease, OI includes over 16 genotypes and clinical phenotypes with differing symptom severity. Osteogenesis Imperfecta (off label)

Adverse Effects and Contraindications

Adverse effects

• Common:
  • Hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia due to decreased calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology from bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types
  • Hypophosphatemia Hypophosphatemia A condition of an abnormally low level of phosphates in the blood. Bartter Syndrome due to decreased phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology from bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types
  • Pill-induced esophagitis Esophagitis Esophagitis is the inflammation or irritation of the esophagus. The major types of esophagitis are medication-induced, infectious, eosinophilic, corrosive, and acid reflux. Patients typically present with odynophagia, dysphagia, and retrosternal chest pain. Esophagitis
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
  • Flatulence
• Rare:
  • Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess
  • Muscle cramps Cramps Ion Channel Myopathy
• Very rare:
  • Dysgeusia Dysgeusia A condition characterized by alterations of the sense of taste which may range from mild to severe, including gross distortions of taste quality. Nitroimidazoles
  • Alopecia Alopecia Alopecia is the loss of hair in areas anywhere on the body where hair normally grows. Alopecia may be defined as scarring or non-scarring, localized or diffuse, congenital or acquired, reversible or permanent, or confined to the scalp or universal; however, alopecia is usually classified using the 1st 3 factors. Alopecia
  • Peripheral edema Peripheral edema Peripheral edema is the swelling of the lower extremities, namely, legs, feet, and ankles. Edema
  • Avascular necrosis Avascular Necrosis Hip Fractures of the femur
  • Osteonecrosis of the jaw Jaw The jaw is made up of the mandible, which comprises the lower jaw, and the maxilla, which comprises the upper jaw. The mandible articulates with the temporal bone via the temporomandibular joint (TMJ). The 4 muscles of mastication produce the movements of the TMJ to ensure the efficient chewing of food. Jaw and Temporomandibular Joint: Anatomy

Warnings

• Severe bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types, muscle, or joint pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
• Use caution in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with renal disease.
• Avoid in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship following bariatric surgery Bariatric surgery Bariatric surgery refers to a group of invasive procedures used to surgically reduce the size of the stomach to produce early satiety, decrease food intake (restrictive type) and/or alter digestion, and artificially induce malabsorption of nutrients (malabsorptive type). The ultimate goal of bariatric surgery is drastic weight loss. Bariatric Surgery due to the risk of ulceration Ulceration Corneal Abrasions, Erosion, and Ulcers and poor absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption.

Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation

• Hypersensitivity reactions
• Hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia
• Esophageal disorders with delayed esophageal emptying:
  • Achalasia Achalasia Achalasia is a primary esophageal motility disorder that develops from the degeneration of the myenteric plexus. This condition results in impaired lower esophageal sphincter relaxation and absence of normal esophageal peristalsis. Patients typically present with dysphagia to solids and liquids along with regurgitation. Achalasia
  • Stricture Stricture Primary Sclerosing Cholangitis
• Inability to stand or sit upright for at least 30 minutes

Drug interactions

• Aminoglycosides Aminoglycosides Aminoglycosides are a class of antibiotics including gentamicin, tobramycin, amikacin, neomycin, plazomicin, and streptomycin. The class binds the 30S ribosomal subunit to inhibit bacterial protein synthesis. Unlike other medications with a similar mechanism of action, aminoglycosides are bactericidal. Aminoglycosides: exacerbate bisphosphonate-induced hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia
• Aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs): increase upper GI side effects of alendronate
• Proton pump Pump ACES and RUSH: Resuscitation Ultrasound Protocols inhibitors: decrease bisphosphonate absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption

Comparison of Bisphosphonate Medications