Bisphosphonates

Aka: Bisphosphonates, Alendronate, Fosamax, Etidronate, Didronel, Tiludronate, Skelid, Risedronate, Actonel, Pamidronate, Aredia, Ibandronate, Boniva, Binosto

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II. Indications

  1. Osteoporosis
  2. Metabolic bone disease (e.g. Paget's Disease of Bone)

III. Contraindications

  1. Delayed Gastric Emptying

IV. Efficacy

  1. Decreases rate of bone resorption
  2. Reduces risk of Vertebral Fracture: 8.8%
  3. Reduces risk of non-Vertebral Fracture (5.6%)
  4. Reference
    1. Black (1996) 348:1535-41 [PubMed]

V. Efficacy: Number Needed to Treat (NNT) per agent

  1. Prevention of Hip Fracture over 3 years (NNT)
    1. Risedronate (Actonel): 77
    2. Alendronate (Fosamax): 91
    3. Zoledronic Acid (Reclast): 91
    4. Compare to Vitamin D 800 IU daily: 45
    5. Compare to Hormone Replacement Therapy: 385
  2. Prevention of Vertebral Fracture over 3 years (NNT)
    1. Zoledronic Acid (Reclast): 13
    2. Risedronate (Actonel): 15
    3. Ibandronate (Boniva): 20
    4. Alendronate (Fosamax): 37
    5. Compare to Calcitonin (Miacalcin) or Teriparatide (Forteo): 10-11

VI. Precautions: Drug Holiday

  1. Adverse effect risk increases with cummulative use
  2. Stopping bisphosphonate (start of drug holiday)
    1. Consider stopping oral Bisphosphonates after 5 years, or Reclast after 3 years
    2. Consider stopping especially if no history of osteoporotic Fracture
  3. Restarting bisphosphonate
    1. Biomarkers (Serum Ctx and Alkaline Phosphatase)
      1. Not typically helpful in making decision to restart bisphosphonate
      2. Markers often return conflicting results
    2. Primary prevention (Osteopenia and risk)
      1. Restart after fixed interval 3 year period or
      2. Restart at 1-5 years based on patient factors or Bone Mineral Density
    3. Osteoporosis (e.g. Fracture history)
      1. Restart after fixed interval or
      2. Restart after 2-4% Bone Mineral Density reduction
  4. References
    1. Kennel (2012) Mayo POIM Conference, Rochester

VII. Adverse effects

  1. Osteonecrosis of the jaw
    1. Marx (2005) J Oral Maxillofac Surg 63:1567–1575 [PubMed]
  2. Bone, joint or muscle pain
    1. Consider stopping medication if persists
  3. Significant Gastrointestinal risks
    1. Esophageal erosions or Esophageal ulcers
      1. Appears to occur more with Alendronate
    2. Take with over 8 ounces water
    3. Stay upright for at least 30 minutes after dose
    4. Take at least 60 minutes before breakfast
  4. Atypical Subtrochanteric Fractures (rare)

VIII. Pharmacokinetics: Absorption inhibited if taken with food

  1. Wait 1-2 hours before eating

IX. Preparations: Osteoporosis and Metabolic Bone Disease

  1. See Adverse effects for Patient Instructions
  2. Alendronate (Fosamax, Fosamax plus D or Binosto)
    1. Background
      1. Fosamax is generic and low cost (less than $10/month) in United States
      2. Binosto is Alendronate effervescent tab (marketed in 2013)
        1. Less gastrointestinal side effects (unproven) and costs over $140/month
        2. Hodges (2012) Int J Pharm 432:57-62 [PubMed]
    2. Osteoporosis
      1. Indicated for the prevention and treatment of Osteoporosis (hip, Vertebral, non-Vertebral)
      2. Prophylaxis: 5 mg orally daily or 35 mg orally Weekly
      3. Treatment: 10 mg orally daily or 70 mg orally Weekly
    3. Paget's Disease
      1. Dose: 40 mg orally daily for 6 months
  3. Risedronate (Actonel)
    1. Indicated for the prevention and treatment of Osteoporosis (hip, Vertebral, non-Vertebral)
    2. Osteoporosis: 5 mg orally daily or 35 mg orally weekly or 75 mg monthly
    3. Paget's Disease: 30 mg orally daily for 2 months
  4. Ibandronate (Boniva)
    1. Indicated for the prevention and treatment of Osteoporosis (Vertebral only) and Paget's Disease
    2. Oral: 2.5 mg daily or 150 mg monthly
    3. IV: 3 mg every 3 months (treatment only)
    4. Monthly: 150 mg orally (same cost as for daily)
    5. Chestnut (2004) J Bone Miner Res 19:1241-9 [PubMed]
  5. Zoledronic Acid (Reclast)
    1. Indicated for the prevention and treatment of Osteoporosis (hip, Vertebral, non-Vertebral) and Paget's Disease
    2. IV: 5 mg yearly infused over 15 minutes (every 2 years for prevention)
    3. Contraindicated in Hypocalcemia and GFR <35 ml/min
    4. Adverse effects: Acute phase reaction with fever, myalgias, Headache
    5. Black (2007) N Engl J Med 356(18): 1809-22 [PubMed]

X. Preparations: Metabolic bone disease

  1. Etidronate (Didronel)
    1. Paget's Disease: 5-10 mg/kg orally daily for 6 months
    2. Hypercalcemia: 7.5 mg/kg in 250 cc NS IV daily for 3 days
      1. Given slowly over >2 hours
  2. Tiludronate (Skelid)
    1. S-Containing agent
    2. No effect on Fracture risk
    3. Indicated for Paget's Disease of Bone
    4. Dose: 40 mg PO qd
  3. Pamidronate (Aredia)
    1. Dose: 40-80 mg IV slowly over >2 hours every 4 months
    2. Indications
      1. Paget's Disease of Bone
      2. Hypercalcemia of Malignancy
      3. Osteolytic bone lesions (e.g. Multiple Myeloma)

XI. References

  1. Greenspan (2000) Am Fam Physician 61(9):2371-6 [PubMed]

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Cost: Medications

Alendronate SOD (on 6/18/2017 at Walmart.com)
Alendronate SOD 35mg #4 tablets for $9.00 $2.25 each
Alendronate SOD 35mg #12 tablets for $24.00 $2.00 each
Alendronate SOD 70mg #4 tablets for $9.00 $2.25 each
Alendronate SOD 70mg #12 tablets for $24.00 $2.00 each
alendronate (on 3/22/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
ALENDRONATE SODIUM 10 MG TAB Generic $0.16 each
ALENDRONATE SODIUM 35 MG TAB Generic $0.54 each
ALENDRONATE SODIUM 5 MG TABLET Generic $0.15 each
ALENDRONATE SODIUM 70 MG TAB Generic $0.35 each
fosamax (on 6/8/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
FOSAMAX 70 MG TABLET Generic $0.35 each
FOSAMAX PLUS D 70 MG-2,800 UNITS $41.84 each
risedronate (on 5/17/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
RISEDRONATE SOD DR 35 MG TAB Generic $34.18 each
RISEDRONATE SODIUM 150 MG TAB Generic $78.38 each
RISEDRONATE SODIUM 35 MG TAB Generic $11.54 each
RISEDRONATE SODIUM 35 MG TABLET Generic $11.54 each
actonel (on 1/1/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
ACTONEL 150 MG TABLET Generic $78.38 each
ACTONEL 35 MG TABLET Generic $11.54 each
ACTONEL 5 MG TABLET $10.16 each
ibandronate (on 5/17/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
IBANDRONATE SODIUM 150 MG TAB Generic $12.08 each
boniva (on 1/1/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
BONIVA 150 MG TABLET Generic $12.08 each
BONIVA 3 MG/3 ML SYRINGE $171.01 per ml
FPNotebook does not benefit financially from showing this medication data or their pharmacy links. This information is provided only to help medical providers and their patients see relative costs. Insurance plans negotiate lower medication prices with suppliers. Prices shown here are out of pocket, non-negotiated rates. See Needy Meds for financial assistance information.

Ontology: pamidronate (C0043603)

Definition (NCI_NCI-GLOSS) A drug that is used to treat hypercalcemia (too much calcium in the blood) and cancer that has spread to the bones. It belongs to the family of drugs called bisphosphonates.
Definition (NCI) An amino- bisphosphonate with anti-resorptive and anti-hypercalcemic activities. Pamidronic acid binds to and adsorbs onto hydroxyapatite crystals in the bone matrix, thereby preventing osteoclast resorption. This agent also binds to and inhibits farnesyl pyrophosphate synthase, an enzyme that plays an important role in the mevalonate pathway. This inhibits the formation of isoprenoid metabolites that are substrates for protein prenylation. This prevents farnesylation and geranylgeranylation of proteins essential for osteoclast function, leading to the induction of apoptosis of osteoclasts. By preventing osteoclast-mediated bone resorption, pamidronic acid decreases bone turnover rate, stabilizes the bone matrix and reduces hypercalcemia.
Definition (PDQ) A synthetic bisphosphonate agent. Although its mechanism of action is not completely understood, pamidronate appears to adsorb to calcium phosphate crystals in bone, blocking their dissolution by inhibiting osteoclast-mediated bone resorption. This agent does not inhibit bone mineralization and formation. Check for "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=39149&idtype=1" active clinical trials or "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=39149&idtype=1&closed=1" closed clinical trials using this agent. ("http://nciterms.nci.nih.gov:80/NCIBrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&code=C1345" NCI Thesaurus)
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C019248
SnomedCT 420481001, 96288007
English (3-amino-1-hydroxypropylidene)-1,1-biphosphonate, (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate, amino-1-hydroxypropane-1,1-diphosphonate, aminohydroxypropylidene diphosphonate, aminopropanehydroxydiphosphonate, APD, amidronate, Pamidronic Acid, 1-hydroxy-3-aminopropane-1,1-diphosphonic acid, pamidronate [Chemical/Ingredient], apd, apds, AHPrBP, PAMIDRONIC ACID, Pamidronate, Pamidronate (substance), PAMIDRONATE, pamidronate
Spanish ácido pamidrónico, ácido pamidrónico (producto), ácido pamidrónico (sustancia), pamidronato (sustancia), pamidronato
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Etidronate (C0086268)

Definition (CSP) ethane-1-hydroxy-1,1-diphosphonate; a diphosphonate compound that affects calcium metabolism and inhibits the resorption and deposition of hydroxyapatite crystals in bone.
Concepts Organophosphorus Compound (T115) , Pharmacologic Substance (T121)
MSH D012968
SnomedCT 49791005, 96284009, 372908005
English 1 Hydroxyethane 1,1 Diphosphonate, 1 Hydroxyethylidene 1,1 Bisphosphonate, 1-Hydroxyethane-1,1-Diphosphonate, 1-Hydroxyethylidene-1,1-Bisphosphonate, EHDP, Ethanehydroxydiphosphonate, Ethanehydroxyphosphate, Etidronate, HEDP, Hydroxyethanediphosphonate, 1,1-hydroxyethylenediphosphonate, etidronate, Etidronate (product), Etidronate [Chemical/Ingredient], ehdp, 1,1 hydroxyethylenediphosphonate, Etidronate (substance), Etidronate -RETIRED-, ETIDRONATE
Czech EHDP, etidronát, ethanhydroxydifosfonát
Portuguese Etidronato, EHDP, Etanoidroxidifosfonato
Spanish Etidronato, etidronato (producto), etidronato-RETIRADO- (concepto no activo), etidronato-RETIRADO-, etidronato (sustancia), etidronato, EHDP, Etanohidroxidifosfonato
German Etidronat, EHDP, Ethanhydroxydiphosphonat
French Étidronate
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Alendronate (C0102118)

Definition (CHV) a drug used to prevent or treat osteoporosis
Definition (CSP) bone resorption inhibitor.
Definition (MSH) A nonhormonal medication for the treatment of postmenopausal osteoporosis in women. This drug builds healthy bone, restoring some of the bone loss as a result of osteoporosis.
Concepts Pharmacologic Substance (T121) , Organophosphorus Compound (T115)
MSH D019386
SnomedCT 96290008
LNC LP171384-3
English alendronate, Alendronate, Aminohydroxybutane Bisphosphonate, Bisphosphonate, Aminohydroxybutane, AHBUTBP, (4-Amino-1-hydroxybutylidene)bisphosphonic Acid, Alendronate [Chemical/Ingredient], 4 Amino 1 Hydroxybutylidene 1,1 Biphosphonate, 4-Amino-1-Hydroxybutylidene 1,1-Biphosphonate, Alendronate (substance), ALENDRONATE
Swedish Alendronat
Czech alendronát
Finnish Alendronaatti
Russian ALENDRONAT, АЛЕНДРОНАТ
Japanese アレンドロン酸, アレンドロナート, アレンドロネート
Polish Alendronian
Spanish alendronato (sustancia), alendronato, Alendronato
French Alendronate
German Alendronat
Italian Alendronato
Portuguese Alendronato
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Aredia (C0104018)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C019248
English Novartis brand of pamidronate disodium salt, Aredia, aredia
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Tiludronate (C0145942)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C058651
SnomedCT 422263009, 96286006
English (chloro-4-phenyl)thiomethylene biphosphonate, (chloro-4-phenyl)thiomethylene bisphosphonate, TILUDRONATE, Tiludronate, Tiludronate (substance), tiludronate
Japanese チルドロン酸
Spanish tiludronato (sustancia), tiludronato
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Risedronate (C0246719)

Definition (PDQ) A synthetic pyridinyl bisphosphonate agent. Risedronate binds to hydroxyapatite crystals in bone and inhibits osteoclast-dependent bone resorption Check for "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=256445&idtype=1" active clinical trials or "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=256445&idtype=1&closed=1" closed clinical trials using this agent. ("http://nciterms.nci.nih.gov:80/NCIBrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&code=C1528" NCI Thesaurus)
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C073008
SnomedCT 96289004, 387582001
LNC LP171635-8
English 2-(3-pyridinyl)-1-hydroxyethylidenebisphosphonate, RISEDRONATE, Risedronate (product), RISEDRONATE SODIUM ANHYDROUS, Risedronate, Risedronate (substance), RISE, risedronate, 2-(3-pyridinyl)-1-hydroxyethylidene-bisphosphonate
Spanish risedronato (producto), risedronato (sustancia), risedronato
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Fosamax (C0376569)

Concepts Pharmacologic Substance (T121) , Organophosphorus Compound (T115)
MSH D019386
French Fosamax
English fosamax, Fosamax
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Ibandronate (C0379199)

Definition (PDQ) A synthetic nitrogen-containing bisphosphonate. Ibandronate inhibits farnesyl pyrophosphate synthase, resulting in a reduction in geranylgeranyl GTPase signaling proteins and apoptosis of osteoclasts. This agent increases bone mineral density, decreases bone remodeling, inhibits osteoclast-mediated bone resorption, and reduces metastases-related and corticosteroid-related bone pain. Check for "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=365963&idtype=1" active clinical trials or "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=365963&idtype=1&closed=1" closed clinical trials using this agent. ("http://nciterms.nci.nih.gov:80/NCIBrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&code=C1670" NCI Thesaurus)
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C073007
SnomedCT 96287002
English 1-hydroxy-3-(methylpentylamino)propylidenebisphosphonate, (1-hydroxy-3-(methylpentylamino)propylidene)bisphosphonate, Ibandronate (substance), Ibandronate, ibandronate, IBANDRONATE
Spanish ibandronato (sustancia), ibandronato
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Didronel (C0591373)

Concepts Pharmacologic Substance (T121) , Organophosphorus Compound (T115)
MSH D012968
English didronel, Didronel
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Skelid (C0592793)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C058651
English Skelid
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Actonel brand of risedronate sodium (C0718248)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C073008
English actonel, Actonel brand of risedronate sodium, Actonel, Aventis brand of risedronic acid, monosodium salt, Procter & Gamble Pharmaceuticals brand of risedronic acid, monosodium salt, Procter & Gamble brand of risedronic acid, monosodium salt
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Boniva (C1541222)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C073007
English Boniva
Derived from the NIH UMLS (Unified Medical Language System)

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