OSTEOPOROSIS MEDICATIONS









Alendronate | Fosamax® | Fosamax® PLUS D | Binosto®

Dosage forms

Tablet (Fosamax®)
  • 5 mg
  • 10 mg
  • 35 mg
  • 40 mg
  • 70 mg
Tablet (Fosamax® PLUS D)
  • Alendronate : Cholecalciferol
    • 70 mg : 2800 IU
    • 70 mg : 5600 IU
Effervescent tablet (Binosto®)
  • 70 mg

Dosing - Fosamax

Osteoporosis treatment (postmenopausal women)
  • Dosing: 70 mg once weekly or 10 mg once daily
Osteoporosis prevention (postmenopausal women)
  • Dosing: 35 mg once weekly or 5 mg once daily
Osteoporosis treatment (men)
  • Dosing: 70 mg once weekly or 10 mg once daily
Corticosteroid-induced osteoporosis
  • Dosing: 5 mg once daily
  • For postmenopausal women not receiving estrogen, recommended dose is 10 mg once daily
Paget's disease
  • Dosing: 40 mg once daily for 6 months
  • Re-treatment may be considered after a 6 month break in patients who relapse

Dosing - Fosamax PLUS D

Osteoporosis treatment (postmenopausal women)
  • Dosing: 70 mg/5600 IU once weekly
  • 70 mg/5600 IU is the preferred dose. 70 mg/2800 IU dose may also be used.
Osteoporosis treatment (men)
  • Dosing: 70 mg/5600 IU once weekly
  • 70 mg/5600 IU is the preferred dose. 70 mg/2800 IU dose may also be used.

Dosing - Binosto

Osteoporosis treatment (postmenopausal women)
  • Dosing: 70 mg once weekly
Osteoporosis treatment (men)
  • Dosing: 70 mg once weekly

Efficacy


Generic / Price

  • Fosamax® - YES/$
  • Fosamax® PLUS D - NO/$$$$
  • Binosto® - NO/$$$$

Other

Fosamax and Fosamax PLUS D
  • Take Fosamax at least 30 minutes before the first food, beverage, or medication of the day with plain water only
  • Swallow with at least 6 - 8 oz of water
  • Do not lie down for at least 30 minutes and until after the first food of the day
  • If dose is missed, take one dose on morning after remembering. Resume taking on originally scheduled day. Do not take 2 doses in 1 day.
Binosto
  • Take Binosto at least 30 minutes before the first food, beverage, or medication of the day with plain water only
  • Dissolve tablet in 4 oz of room temperature water
  • Wait at least 5 minutes after the effervescence stops and then stir the solution for 10 seconds
  • Do not lie down for at least 30 minutes and until after the first food of the day
  • If dose is missed, take one dose on morning after remembering. Resume taking on originally scheduled day. Do not take 2 doses in 1 day.

Mechanism of action

  • Bisphosphonates enter osteoclasts and inhibit an enzyme called farnesyl pyrophosphate synthase (FPPS)
  • Inhibition of FPPS disrupts the attachment of osteoclasts to the bone surface. This stops absorption and leads to early cell death. [5]

FDA-approved indications

Fosamax
  • Treatment and prevention of osteoporosis in postmenopausal women
  • Treatment to increase bone mass in men with osteoporosis
  • Treatment of glucocorticoid-induced osteoporosis
  • Treatment of Paget's disease of bone
Fosamax PLUS D and Binosto
  • Treatment of osteoporosis in postmenopausal women
  • Treatment to increase bone mass in men with osteoporosis

Side effects

  • In studies, the incidence of side effects with alendronate was no different than placebo

Drug interactions

  • Calcium supplements/antacids - co-administration of alendronate with calcium, antacids, or other medications containing multivalent cations will interfere with the absorption of alendronate. Wait at least 30 minutes after taking alendronate before taking other medications.
  • Aspirin - aspirin may increase the risk of upper gastrointestinal adverse events when taken with alendronate
  • NSAIDs (e.g. ibuprofen, naprosyn) - in trials, concomitant NSAIDs did not increase the risk of upper gastrointestinal adverse events when taken with alendronate. However, the manufacturer recommends using caution with these medications.
  • Drugs that inhibit the absorption of Vitamin D - Olestra, mineral oils, orlistat, and bile acid sequestrants (e.g., cholestyramine, colestipol) may impair the absorption of vitamin D. Additional Vitamin D may be necessary.
  • Drugs that increase the metabolism of Vitamin D - anticonvulsants, cimetidine, and thiazides may increase the metabolism of vitamin D. Additional Vitamin D may be necessary.
  • Bone-imaging agents - bisphosphonates may interfere with the use of bone-imaging agents

Contraindications / Precautions

  • Esophageal abnormalities that delay emptying (e.g. achalasia, stricture) - DO NOT USE
  • Inability to stand or sit upright for at least 30 minutes - DO NOT USE
  • Hypocalcemia - DO NOT USE. Hypocalcemia must be corrected before starting alendronate. In trials, transient decreases in calcium and phosphate were observed in 18% of patients taking alendronate and in 12% taking placebo. The risk appears to be greater in patients with Paget's disease and in patients taking corticosteroids.
  • Upper gastrointestinal (GI) disorders - bisphosphonates may cause local irritation to the upper GI mucosa. Use caution in patients with upper GI disorders such as Barrett's esophagus, dysphagia, esophageal diseases, gastritis, duodenitis, and ulcers. Patients should discontinue their bisphosphonate and notify their provider if upper GI symptoms occur.
  • Osteonecrosis of the jaw (ONJ) - bisphosphonates have been associated with ONJ. ONJ can occur spontaneously, but is generally associated with tooth extraction and/or local infection. Risk factors for ONJ include tooth extraction, dental implants, boney surgery, diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, and ill-fitting dentures. Discontinuing bisphosphonates before dental procedures may decrease the risk of ONJ.
  • Atypical femoral fractures - bisphosphonates have been associated with a slight increase in the risk for atypical subtrochanteric and diaphyseal femoral fractures. Atypical femoral fractures may present as a dull, aching thigh pain that precedes a fracture on X-ray for weeks to months. In one study, the increase in absolute risk of atypical femoral fractures with bisphosphonates was 5 cases per 10,000 patient-years. [PMID 21542743] Another study found that the benefits of bisphosphonates greatly outweigh the potential risk of atypical femoral fractures. For example, in white women, 286 hip fractures were prevented for every 8 atypical femoral fractures over 5 years of bisphosphonate use. The benefit was slightly less for Hispanic women (194 to 11) and Asian women (174 to 38). [PMID 32813950] History of corticosteroid use and shorter height also appear to increase the risk.
  • Severe musculoskeletal pain - in rare cases, severe bone, muscle, and joint pain has been reported in patients taking bisphosphonates. Time to onset of symptoms varied from days to months after starting the drug.
  • Vitamin D deficiency - treat if present to ensure proper mineral metabolism
  • Patients sensitive to sodium (Binosto) - each Binosto tablet contains 603 mg of sodium. Avoid in susceptible patients (e.g. uncontrolled CHF)
  • Glucocorticoid-induced osteoporosis - the risk/benefit of alendronate for treatment of osteoporosis in patients taking daily doses of glucocorticoids less than 7.5 mg of prednisone or equivalent has not been established
  • Liver disease - no dose adjustment necessary
  • Kidney disease
    • CrCl ≥ 35 ml/min: no dose adjustment necessary
    • CrCl < 35 ml/min: DO NOT USE

Ibandronate (Boniva®)

Dosage forms

Tablet (Boniva®)
  • 150 mg
Injection (Boniva®)
  • 3 mg prefilled syringe (1 mg/ml)

Dosing - Tablet

Osteoporosis prevention and treatment in postmenopausal women
  • Dosing: 150 mg once monthly on the same day each month
  • Missed doses:
    • If the next scheduled Boniva day is more than 7 days away, take one Boniva 150 mg tablet in the morning following the date that it is remembered
    • If the next scheduled Boniva day is only 1 to 7 days away, wait until the subsequent month's scheduled Boniva day to take the tablet

Dosing - Injection

Osteoporosis treatment in postmenopausal women
  • Dosing: 3 mg intravenously every 3 months
  • Dose is given over a period of 15 - 30 seconds
  • Missed doses:
    • If the dose is missed, administer as soon as it can be rescheduled. Thereafter, Boniva injection should be scheduled every 3 months from the date of the last injection.

Generic / Price

  • Boniva tablet® - YES/$
  • Boniva® injection - YES/?

Other

Boniva tablet
  • Take at least 60 minutes before the first food or drink (other than water) of the day. Take at least 60 minutes before any medication or supplement.
  • Swallow tablet whole with a full glass of plain water (6 to 8 oz) while standing or sitting in an upright position. Avoid lying down for 60 minutes after taking.
Boniva injection
  • Must be administered intravenously by a healthcare professional
  • Do not use prefilled syringes with particulate matter or discoloration

Mechanism of action

  • Bisphosphonates enter osteoclasts and inhibit an enzyme called farnesyl pyrophosphate synthase (FPPS)
  • Inhibition of FPPS disrupts the attachment of osteoclasts to the bone surface. This stops absorption and leads to early cell death. [5]

FDA-approved indications

Boniva tablet
  • Treatment and prevention of postmenopausal osteoporosis
Boniva injection
  • Treatment of postmenopausal osteoporosis

Side effects


Side effect Ibandronate 2.5 mg/day Placebo
Back pain 14% 12%
Upset stomach 12% 10%
Bronchitis 10% 7%
Pain in extremity 8% 6%
Diarrhea 7% 5%
Pneumonia 6% 4%
UTI 6% 4%
Weakness 4% 2%
Tooth disorder 4% 2%
Other
  • In studies with the injection, injection site reactions occurred in 1.7% of patients


Drug interactions

  • Calcium supplements/antacids - co-administration of ibandronate with calcium, antacids, or other medications containing multivalent cations will interfere with the absorption of ibandronate. Wait at least 60 minutes after taking ibandronate before taking other medications.
  • Aspirin - aspirin may increase the risk of upper gastrointestinal adverse events when taken with bisphosphonates
  • NSAIDs (e.g. ibuprofen, naprosyn) - NSAIDs may increase the risk of upper gastrointestinal adverse events when taken with bisphosphonates
  • Bone-imaging agents - bisphosphonates may interfere with the use of bone-imaging agents

Contraindications / Precautions

  • Esophageal abnormalities that delay emptying (e.g. achalasia, stricture) - DO NOT USE
  • Inability to stand or sit upright for at least 60 minutes - DO NOT USE
  • Hypocalcemia - DO NOT USE. Hypocalcemia must be corrected before starting bisphosphonates. Bisphosphonates may cause a decrease in calcium levels.
  • Upper gastrointestinal (GI) disorders - bisphosphonates may cause local irritation to the upper GI mucosa. Use caution in patients with upper GI disorders such as Barrett's esophagus, dysphagia, esophageal diseases, gastritis, duodenitis, and ulcers. Patients should discontinue their bisphosphonate and notify their provider if upper GI symptoms occur.
  • Osteonecrosis of the jaw (ONJ) - bisphosphonates have been associated with ONJ. ONJ can occur spontaneously, but is generally associated with tooth extraction and/or local infection. Risk factors for ONJ include tooth extraction, dental implants, boney surgery, diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, and ill-fitting dentures. Discontinuing bisphosphonates before dental procedures may decrease the risk of ONJ.
  • Atypical femoral fractures - bisphosphonates have been associated with a slight increase in the risk for atypical subtrochanteric and diaphyseal femoral fractures. Atypical femoral fractures may present as a dull, aching thigh pain that precedes a fracture on X-ray for weeks to months. In one study, the increase in absolute risk of atypical femoral fractures with bisphosphonates was 5 cases per 10,000 patient-years. [PMID 21542743] Another study found that the benefits of bisphosphonates greatly outweigh the potential risk of atypical femoral fractures. For example, in white women, 286 hip fractures were prevented for every 8 atypical femoral fractures over 5 years of bisphosphonate use. The benefit was slightly less for Hispanic women (194 to 11) and Asian women (174 to 38). [PMID 32813950] History of corticosteroid use and shorter height also appear to increase the risk.
  • Severe musculoskeletal pain - in rare cases, severe bone, muscle, and joint pain has been reported in patients taking bisphosphonates. Time to onset of symptoms varied from days to months after starting the drug.
  • Vitamin D deficiency - treat if present to ensure proper mineral metabolism
  • Anaphylactic reactions (injection) - anaphylactic reactions have occurred in patients receiving Boniva injection. Administer under proper supervision.
  • Kidney failure (injection) - renal toxicity including renal failure has been associated with intravenous bisphosphonates. Use caution.
  • Liver disease - no dose adjustment necessary
  • Kidney disease
    • CrCl ≥ 30 ml/min: no dose adjustment necessary
    • CrCl < 30 ml/min: DO NOT USE

Risedronate | Actonel® | Atelvia®

Dosage forms

Tablet (Actonel®)
  • 5 mg
  • 30 mg
  • 35 mg
  • 75 mg
  • 150 mg
Delayed-release tablet (Atelvia®)
  • 35 mg

Dosing - Actonel

Osteoporosis prevention and treatment in postmenopausal women
  • One of the following:
    • 5 mg once daily
    • 35 mg once weekly
    • 75 mg taken on 2 consecutive days for a total of two tablets each month
    • 150 mg once monthly
Osteoporosis treatment in men
  • 35 mg once weekly
Glucocorticoid-induced osteoporosis (treatment and prevention)
  • 5 mg once daily
Paget's disease
  • 30 mg once daily for 2 months
  • Re-treatment may be considered after a 2 month break in patients who relapse
Missed doses
  • 35 mg once weekly
    • Take morning after remembering. Resume taking on originally scheduled day. Do not take 2 tablets on the same day.
  • 75 mg on 2 consecutive days each month
    • If next month's doses are > 7 days away, take missing dose(s) and resume originally scheduled dosing. Do not take more than 2 tablets within 7 days.
    • If next month's doses are within 7 days away, wait until next month's scheduled doses and resume original schedule
  • 150 mg dose
    • If next month's dose is > 7 days away, take missing dose and resume originally scheduled dosing. Do not take more than 1 tablet within 7 days.
    • If next month's dose is within 7 days away, wait until next month's scheduled dose and resume original schedule

Dosing - Atelvia

Osteoporosis treatment in postmenopausal women
  • Dosing: 35 mg once weekly
  • Missed doses: Take morning after remembering. Resume taking on originally scheduled day. Do not take 2 tablets on the same day.

Efficacy


Generic / Price

  • Actonel® (5 mg tablets #30) - YES/$$
  • Actonel® (30 mg tablets #30) - YES/$$$$
  • Actonel® (150 mg tablets #1) - YES/$$
  • Actonel® (35 mg tablets #4) - YES/$
  • Actonel® (75 mg tablets) - ?
  • Atelvia® (4 tablets) - YES/$$

Other

Actonel
  • Take at least 30 minutes before the first food or drink (other than water) of the day. Take at least 30 minutes before any medication or supplement.
  • Swallow tablet whole with a full glass of plain water (6 to 8 oz) while standing or sitting in an upright position. Avoid lying down for 30 minutes after taking.
Atelvia
  • Take immediately following breakfast. Do not take under fasting conditions because of increased risk of abdominal pain.
  • Swallow tablet whole with at least 4 oz of plain water while standing or sitting in an upright position. Avoid lying down for 30 minutes after taking.

Mechanism of action

  • Bisphosphonates enter osteoclasts and inhibit an enzyme called farnesyl pyrophosphate synthase (FPPS)
  • Inhibition of FPPS disrupts the attachment of osteoclasts to the bone surface. This stops absorption and leads to early cell death. [5]

FDA-approved indications

Actonel
  • Treatment and prevention of postmenopausal osteoporosis
  • Treatment of osteoporosis in men
  • Treatment and prevention of glucocorticoid-induced osteoporosis
  • Paget's disease
Atelvia
  • Treatment of postmenopausal osteoporosis

Side effects

  • In clinical trials with Actonel 5 mg/day, only abdominal pain occurred at an incidence ≥ 2% more than placebo (12.2% vs 9.9%)

Drug interactions

  • Calcium supplements/antacids - co-administration of risedronate with calcium, antacids, or other medications containing multivalent cations will interfere with the absorption of risedronate. Wait at least 30 minutes after taking risedronate before taking other medications.
  • H2 blockers and PPIs (Atelvia) - acid-reducing drugs like H2 blockers (e.g. famotidine) and PPIs (e.g. omeprazole) may increase exposure to Atelvia. Atelvia should not be taken with these drugs.
  • Aspirin - aspirin may increase the risk of upper gastrointestinal adverse events when taken with bisphosphonates. In risedronate trials, adverse upper GI events among patients taking aspirin were no different between risedronate users and placebo.
  • NSAIDs (e.g. ibuprofen, naprosyn) - NSAIDs may increase the risk of upper gastrointestinal adverse events when taken with bisphosphonates. In risedronate trials, adverse upper GI events among patients taking NSAIDs were no different between risedronate users and placebo.
  • Bone-imaging agents - bisphosphonates may interfere with the use of bone-imaging agents

Contraindications / Precautions

  • Esophageal abnormalities that delay emptying (e.g. achalasia, stricture) - DO NOT USE
  • Inability to stand or sit upright for at least 30 minutes - DO NOT USE
  • Hypocalcemia - DO NOT USE. Hypocalcemia must be corrected before starting bisphosphonates. Bisphosphonates may cause a decrease in calcium levels.
  • Upper gastrointestinal (GI) disorders - bisphosphonates may cause local irritation to the upper GI mucosa. Use caution in patients with upper GI disorders such as Barrett's esophagus, dysphagia, esophageal diseases, gastritis, duodenitis, and ulcers. Patients should discontinue their bisphosphonate and notify their provider if upper GI symptoms occur.
  • Osteonecrosis of the jaw (ONJ) - bisphosphonates have been associated with ONJ. ONJ can occur spontaneously, but is generally associated with tooth extraction and/or local infection. Risk factors for ONJ include tooth extraction, dental implants, boney surgery, diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, and ill-fitting dentures. Discontinuing bisphosphonates before dental procedures may decrease the risk of ONJ.
  • Atypical femoral fractures - bisphosphonates have been associated with a slight increase in the risk for atypical subtrochanteric and diaphyseal femoral fractures. Atypical femoral fractures may present as a dull, aching thigh pain that precedes a fracture on X-ray for weeks to months. In one study, the increase in absolute risk of atypical femoral fractures with bisphosphonates was 5 cases per 10,000 patient-years. [PMID 21542743] Another study found that the benefits of bisphosphonates greatly outweigh the potential risk of atypical femoral fractures. For example, in white women, 286 hip fractures were prevented for every 8 atypical femoral fractures over 5 years of bisphosphonate use. The benefit was slightly less for Hispanic women (194 to 11) and Asian women (174 to 38). [PMID 32813950] History of corticosteroid use and shorter height also appear to increase the risk.
  • Severe musculoskeletal pain - in rare cases, severe bone, muscle, and joint pain has been reported in patients taking bisphosphonates. Time to onset of symptoms varied from days to months after starting the drug.
  • Vitamin D deficiency - treat if present to ensure proper mineral metabolism
  • Liver disease - no dose adjustment necessary
  • Kidney disease
    • CrCl ≥ 30 ml/min: no dose adjustment necessary
    • CrCl < 30 ml/min: DO NOT USE

Zoledronic acid (Reclast®)

Dosage forms

Injection
  • 5 mg/100 ml

Dosing

Osteoporosis treatment in postmenopausal women
  • 5 mg via intravenous infusion once yearly
Osteoporosis prevention in postmenopausal women
  • 5 mg intravenous infusion once every 2 years
Osteoporosis treatment in men
  • 5 mg intravenous infusion once yearly
Glucocorticoid-induced osteoporosis (treatment and prevention)
  • 5 mg intravenous infusion once yearly
Paget's disease
  • 5 mg intravenous infusion
  • Consider retreatment in patients who relapse

Efficacy


Generic / Price

  • Reclast® - NO/$$$$

Other

  • Patients must be appropriately hydrated before infusion
  • Infuse over no less than 15 minutes at a constant rate
  • Flush line with 10 ml of normal saline after infusion
  • Administering acetaminophen after infusion may decrease incidence of acute-phase reactions
  • Store at room temperature

Mechanism of action

  • Bisphosphonates enter osteoclasts and inhibit an enzyme called farnesyl pyrophosphate synthase (FPPS)
  • Inhibition of FPPS disrupts the attachment of osteoclasts to the bone surface. This stops absorption and leads to early cell death. [5]

FDA-approved indications

  • Treatment and prevention of postmenopausal osteoporosis
  • Treatment of osteoporosis in men
  • Treatment and prevention of glucocorticoid-induced osteoporosis
  • Paget's disease

Side effects



Side effect Zoledronic acid Placebo
Joint pain 23.8% 20.4%
Fever 17.9% 4.6%
Headache 12.4% 8.1%
Muscle pain 11.7% 3.7%
Influenza-like illness 8.8% 2.7%
Nausea 8.5% 5.2%
Bone pain 5.8% 2.3%
Chills 5.4% 1%
Weakness 5.3% 2.9%
Pain 3.3% 1.3%


Drug interactions

  • Aminoglycosides - aminoglycosides may potentiate the decrease in calcium levels seen with bisphosphonates. Use caution.
  • Loop diuretics - loop diuretics may potentiate the decrease in calcium levels seen with bisphosphonates. Use caution.
  • Nephrotoxic drugs - use caution when administering zoledronic acid with other potentially nephrotoxic drugs
  • Renally-excreted drugs - zoledronic acid may impair renal function. Use caution when given with drugs that are primarily renally excreted.
  • Bone-imaging agents - bisphosphonates may interfere with the use of bone-imaging agents

Contraindications / Precautions

  • Hypocalcemia - DO NOT USE. Hypocalcemia must be corrected before starting bisphosphonates. Bisphosphonates may cause a decrease in calcium levels.
  • Acute renal impairment - DO NOT USE. Zoledronic acid may worsen kidney function.
  • Dehydration - DO NOT USE until proper hydration has been established
  • Renal impairment - use caution in patients with renal impairment. Acute renal toxicity including renal failure have been reported in patients receiving zoledronic acid. Risk may be higher with advanced age, concomitant nephrotoxic medications, concomitant diuretic therapy, and/or severe dehydration.
  • Osteonecrosis of the jaw (ONJ) - bisphosphonates have been associated with ONJ. ONJ can occur spontaneously, but is generally associated with tooth extraction and/or local infection. Risk factors for ONJ include tooth extraction, dental implants, boney surgery, diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, and ill-fitting dentures. Discontinuing bisphosphonates before dental procedures may decrease the risk of ONJ.
  • Osteonecrosis of other bones - case reports of osteonecrosis in other bones including the femur, hip, knee, ankle, wrist, and humerus have been reported in patients receiving zoledronic acid.
  • Atypical femoral fractures - bisphosphonates have been associated with a slight increase in the risk for atypical subtrochanteric and diaphyseal femoral fractures. Atypical femoral fractures may present as a dull, aching thigh pain that precedes a fracture on X-ray for weeks to months. In one study, the increase in absolute risk of atypical femoral fractures with bisphosphonates was 5 cases per 10,000 patient-years. [PMID 21542743] Another study found that the benefits of bisphosphonates greatly outweigh the potential risk of atypical femoral fractures. For example, in white women, 286 hip fractures were prevented for every 8 atypical femoral fractures over 5 years of bisphosphonate use. The benefit was slightly less for Hispanic women (194 to 11) and Asian women (174 to 38). [PMID 32813950] History of corticosteroid use and shorter height also appear to increase the risk.
  • Severe musculoskeletal pain - in rare cases, severe bone, muscle, and joint pain has been reported in patients taking bisphosphonates. Time to onset of symptoms varied from days to months after starting the drug.
  • Asthma - there have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates
  • Vitamin D deficiency - treat if present to ensure proper mineral metabolism
  • Liver disease - no dose adjustment necessary
  • Kidney disease
    • CrCl ≥ 35 ml/min: no dose adjustment necessary
    • CrCl < 35 ml/min: DO NOT USE



Calcitonin | Miacalcin® | Fortical®

Dosage forms

Nasal spray (Miacalcin®)
  • 200 IU/spray
  • Comes in 3.7 ml bottle that delivers 30 doses
Nasal spray (Fortical®)
  • 200 IU/spray
  • Comes in 3.7 ml bottle that delivers 30 doses
Injection (Miacalcin®)
  • 200 IU/ml
  • Comes in 2 ml vial

Dosing - Miacalcin

Nasal spray
  • Osteoporosis treatment in postmenopausal women
    • Dosing: 1 spray (200 IU) once daily
    • Alternate nostrils daily
Injection
  • Osteoporosis treatment in postmenopausal women
    • Dosing: 100 IU (0.5 ml) given subcutaneously or intramuscularly once daily
  • Paget's disease
    • Dosing: 100 IU (0.5 ml) given subcutaneously or intramuscularly once daily
  • Hypercalcemia
    • Starting: 4 IU/kg every 12 hours by subcutaneous or intramuscular injection
    • If response is not adequate after 1 - 2 days, may increase to 8 IU/kg every 12 hours. If response is still not adequate after 2 more days, may increase to 8 IU/kg every 6 hours

Dosing - Fortical

Osteoporosis treatment in postmenopausal women
  • Dosing: 1 spray (200 IU) once daily
  • Alternate nostrils daily

Generic / Price

  • Miacalcin® nasal spray (1 bottle) - YES/$
  • Fortical® nasal spray (1 bottle) - NO/$$
  • Miacalcin® vial - NO/$$$$

Other

Miacalcin nasal spray
  • Store unopened bottle in refrigerator
  • Once opened, store at room temperature for up to 35 days
  • Allow bottle to reach room temperature before using
  • Before first use, prime until full spray is emitted. Do not prime again.
Fortical nasal spray
  • Store unopened bottle in refrigerator
  • Once opened, store at room temperature
  • Allow bottle to reach room temperature before using
  • Before first use, prime bottle at least 5 times until a full spray is emitted. Do not prime again.
Miacalcin injection
  • Store vial in refrigerator
  • Solution should be clear and colorless
  • If volume of injection exceeds 2 ml, intramuscular injection is preferred

Mechanism of action

  • Calcitonin is an endogenous hormone that inhibits osteoclastic bone resorption

FDA-approved indications

Miacalcin and Fortical
  • Treatment of postmenopausal osteoporosis in women who are > 5 years postmenopause
Miacalcin injection
  • Treatment of postmenopausal osteoporosis in women who are > 5 years postmenopause
  • Paget's disease
  • Hypercalcemic emergencies

Side effects



Side effect Calcitonin nasal spray Placebo
Runny nose 12% 7%
Back pain 5% 2%
Other (injection)
  • Injection site reactions - 10%


Drug interactions

  • Lithium - calcitonin may increase renal excretion of lithium. Monitor lithium levels with concomitant therapy.

Contraindications / Precautions

  • Hypersensitivity reactions - hypersensitivity reactions including anaphylaxis, bronchospasm, and swelling of the tongue and throat have been reported
  • Hypocalcemia - calcitonin may lower calcium levels. Severe hypocalcemia has been reported in some patients receiving calcitonin. Hypocalcemia should be corrected before treatment with calcitonin.
  • Adverse nasal reactions - nasal mucosal alterations may occur with prolonged use. Periodic nasal exam is recommended.
  • Malignancy - a meta-analysis of 21 randomized placebo-controlled trials found a higher incidence of malignancy in calcitonin-users when compared to placebo-users (4.1% vs 2.9%). A definitive causal relationship has not been established.
  • Calcitonin antibodies - antibodies to calcitonin may develop in some users. In a 2-year nasal spray study, 69% of patients treated with Miacalcin developed calcitonin antibodies compared to 3% of placebo-treated patients. It is unknown if antibody formation affects efficacy.
  • Vitamin D deficiency - treat if present to ensure proper mineral metabolism
  • Urine sediment - coarse granular casts and casts containing renal tubular epithelial cells have been reported in young healthy patients who were given injectable calcitonin and prescribed bed rest. Urine sediment abnormalities have not been reported in ambulatory patients.
  • Liver disease - has not been studied. Manufacturer makes no dosage recommendation.
  • Kidney disease - has not been studied. Manufacturer makes no dosage recommendation.



Denosumab (Prolia®)

Dosage forms

Injection
  • 60 mg/1 ml prefilled syringe
  • 60 mg/1 ml single-use vial

Dosing

Osteoporosis and bone loss treatment
  • Dosing: 60 mg subcutaneously once every 6 months
  • Administer in the upper arm, the upper thigh, or the abdomen
  • All patients should receive calcium 1000 mg daily and at least 400 IU of vitamin D daily
  • If a dose is missed, administer as soon as available. Schedule next dose 6 months from date of last injection.

Efficacy


Generic / Price

- NO/$$$$

Other

  • Store syringes and vials in a refrigerator
  • May allow syringes and vials to warm to room temperature before injecting
  • Syringes and vials are good for 14 days at room temperature. Do not expose to temperatures > 77°F.
  • Do not shake syringes or vials vigorously
  • Prolia is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles

Mechanism of action

  • Osteoclasts are cells that are responsible for bone resorption (see bone remodeling)
  • RANKL is a protein that is essential for the formation, function, and survival of osteoclasts
  • Denosumab is a human IgG antibody that binds to RANKL. Denosumab inactivates RANKL thus preventing it from activating osteoclasts.

FDA-approved indications

  • Treatment of postmenopausal osteoporosis in women who are at high risk for fracture
  • Treatment of osteoporosis in men
  • Treatment of bone loss in women receiving adjuvant aromatase inhibitor therapy for breast cancer

Side effects


Side effect Prolia
(N=3886)
Placebo
(N=3876)
Back pain 34.7% 34.6%
Pain in extremity 11.7% 11.1%
Musculoskeletal pain 7.6% 7.5%
High cholesterol 7.2% 6.1%
Cystitis 5.9% 5.8%
Vertigo 5.0% 4.8%
Upper respiratory tract infection 4.9% 4.3%
Edema peripheral 4.9% 4.0%
Sciatica 4.6% 3.8%
Pneumonia 3.9% 3.9%
Bone pain 3.7% 3.0%
Abdominal pain upper 3.3% 2.9%
Anemia 3.3% 2.8%
Insomnia 3.2% 3.1%
Myalgia 2.9% 2.4%
Angina pectoris 2.6% 2.2%
Rash 2.5% 2.0%
Asthenia 2.3% 1.9%
Pharyngitis 2.3% 2.0%
Flatulence 2.2% 1.4%
Pruritus 2.2% 2.1%
Gastroesophageal reflux disease 2.1% 1.7%
Spinal osteoarthritis 2.1% 1.7%
Atrial fibrillation 2.0% 2.0%
Herpes zoster 2.0% 1.9%


Drug interactions

  • None known

Contraindications / Precautions

  • Pregnancy - DO NOT USE. May cause fetal harm.
  • Hypersensitivity reactions - hypersensitivity reactions including anaphylaxis, shortness of breath, swelling, and urticaria have been reported
  • Hypocalcemia - denosumab may lower calcium levels. The peak effect occurs 10 days after dosing. In one study, the average change in calcium levels 10 days after dosing was -5.5% in patients with CrCl < 30 ml/min, and -3.1% in patients with CrCl ≥ 30 ml/min. Patients at high risk for hypocalcemia (e.g. hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine, kidney disease) should have their calcium and phosphorous levels checked within 14 days after an injection.
  • Osteonecrosis of the jaw (ONJ) - denosumab has been associated with ONJ. ONJ can occur spontaneously, but is generally associated with tooth extraction and/or local infection. Risk factors for ONJ include tooth extraction, dental implants, boney surgery, diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, and ill-fitting dentures. A routine oral exam should be performed before administering denosumab. The risk of ONJ may increase with duration of exposure to denosumab.
  • Atypical femoral fractures - denosumab has been associated with a slight increase in risk for atypical subtrochanteric and diaphyseal femoral fractures. Concomitant corticosteroids may increase the risk. A prodromal phase of dull, aching thigh pain may precede the fracture for weeks to months.
  • Multiple vertebral fractures following discontinuation - prolia suppresses bone turnover and when discontinued, bone turnover increases above pretreatment levels for up to 24 months after the last dose. Because of this, fracture risk is increased after discontinuing therapy. In trials, 6% of women who discontinued denosumab developed new vertebral fractures, and 3% of women developed multiple vertebral fractures. The average time to onset of multiple vertebral fractures was 17 months (range 7 - 43 months) after the last injection. BMD returns to pretreatment values within 18 months after the last dose of denosumab. Consider starting another antiresorptive therapy upon discontinuation of denosumab.
  • Serious infections - RANKL receptors are present on the surface of activated T and B lymphocytes and in lymph nodes. Denosumab may affect the function of these cells and increase the risk of infection. In trials, the incidence of nonfatal serious infections was 4% in the denosumab group and 3.3% in the placebo group. Use caution in patients with immunodeficiencies.
  • Skin reactions - skin reactions including dermatitis, eczema, and rashes have been reported in denosumab users. In trials, 10.8% of patients in the denosumab group reported skin reactions compared to 8.2% in the placebo group.
  • Severe musculoskeletal pain - in rare cases, severe bone, muscle, and joint pain has been reported in patients taking denosumab. Time to onset of symptoms varied from days to months after starting the drug.
  • Denosumab antibodies - in trials lasting 5 years, less than 1% of patients developed antibodies to denosumab. Antibody production did not affect efficacy.
  • Kidney disease - no dose adjustment necessary. Patients with CrCl < 30 ml/min are at greater risk for hypocalcemia. Monitor closely.
  • Liver disease - has not been studied



Romosozumab (Evenity®)

Dosage forms

Single-use prefilled syringe
  • 105 mg
  • Comes in a carton with 2 pens

Dosing

Osteoporosis in postmenopausal women at high risk for fracture
  • Dosing: 210 mg subcutaneously once monthly
  • Dose requires 2 single-use prefilled syringes administered one after another
  • Should be administered by a healthcare provider
  • Give in the abdomen, thigh or upper arm
  • Patients should be adequately supplemented with calcium and vitamin D during therapy
  • Efficacy wanes after 12 months, so treatment duration should be limited to 12 months
  • If dose is missed, administer as soon as it can be rescheduled. Thereafter, scheduled every month from the date of the last dose.

Efficacy


Generic / Price

- NO/$$$$

Other

  • Store syringes in refrigerator
  • If removed from the refrigerator, can be kept at room temperature up to 77°F (25°C) in the original carton and must be used within 30 days
  • Do not expose to temperature above 77°F (25°C)

Mechanism of action

  • Romosozumab-aqqg is a humanized monoclonal antibody (IgG2) that binds to and inhibits sclerostin, a regulatory factor in bone metabolism
  • Romosozumab-aqqg increases bone formation and, to a lesser extent, decreases bone resorption. Animal studies showed that romosozumab-aqqg stimulates new bone formation on trabecular and cortical bone surfaces by stimulating osteoblastic activity resulting in increases in trabecular and cortical bone mass and improvements in bone structure and strength

FDA-approved indications

  • Treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy
  • The anabolic effect of Evenity wanes after 12 monthly doses of therapy. Therefore, the duration of Evenity use should be limited to 12 monthly doses. If osteoporosis therapy remains warranted, continued therapy with an anti-resorptive agent should be considered.

Side effects


Side effect Evenity
(N=3581)
Placebo
(N=3576)
Arthralgia 13.1% 12.1%
Headache 6.6% 5.8%
Injection site reactions
(e.g. pain, erythema)
4.9% 2.8%
Muscle spasm 4.6% 3.9%
Peripheral edema 2.4% 1.9%
Asthenia 2.3% 2.2%
Neck pain 2.2% 1.5%
Insomnia 2.0% 1.9%
Paresthesia 2.0% 1.7%


Drug interactions

  • None known

Contraindications / Precautions

  • Hypocalcemia - Evenity may lower calcium levels. In trials, calcium levels < 8.3 mg/dl were reported in 0.2% of Evenity-treated women. Nadir calcium levels occurred by 1 month after initiating therapy. Patients with severe renal impairment (CrCl < 30 ml/min) or on dialysis are at greater risk and should have levels monitored. Hypocalcemia should be corrected before initiating therapy. Patients should be adequately supplemented with calcium and vitamin D during therapy.
  • Major adverse cardiac events - Evenity may increase the risk of myocardial infarction, stroke, and cardiovascular death. In a 12-month trial that compared Evenity to alendronate, myocardial infarction occurred in 0.8% of Evenity-treated women compared to 0.2% of alendronate-treated women, stroke occurred in 0.6% of Evenity-treated women compared to 0.3% of alendronate-treated women, and cardiovascular death occurred in 0.8% of Evenity-treated women compared to 0.6% of alendronate-treated women. Evenity should not be initiated in patients who have had a myocardial infarction or stroke within the preceding year. Consider whether the benefits outweigh the risks in patients with other cardiovascular risk factors. If a patient experiences a myocardial infarction or stroke during therapy, Evenity should be discontinued.
  • Hypersensitivity reactions - hypersensitivity reactions including angioedema, erythema multiforme, dermatitis, rash, and urticaria have occurred in patients being treated with Evenity. In trials, these reactions were reported in ≤ 1.1% of Evenity-treated women.
  • Osteonecrosis of the jaw (ONJ) - ONJ has occurred in patients treated with Evenity. ONJ can occur spontaneously, but is generally associated with tooth extraction and/or local infection with delayed healing. Concomitant drugs associated with ONJ (chemotherapy, bisphosphonates, denosumab, angiogenesis inhibitors, and corticosteroids) may also increase the risk as can cancer, radiotherapy, poor oral hygiene, pre-existing dental disease or infection, anemia, and coagulopathy. A routine oral exam should be performed before administering Evenity. For patients requiring invasive dental procedures, the risk/benefit ratio of Evenity should be considered.
  • Atypical femoral fractures - atypical low-energy or low trauma fractures of the femoral shaft have occurred in patients treated with Evenity. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated. Patients should be advised to report new or unusual thigh, hip, or groin pain when taking Evenity. Fractures may be bilateral so both femurs should be evaluated.
  • Immunogenicity - in trials, Evenity has been shown to induce anti-Evenity antibodies in up to 18.1% of subjects. Of the subjects who developed antibodies, 4.7% had neutralizing antibodies. Antibodies to Evenity were generally not associated with changes in efficacy or safety.
  • Kidney disease - no dose adjustment necessary. Patients with CrCl < 30 ml/min or on dialysis are at greater risk for hypocalcemia. Monitor closely and ensure adequate supplementation.
  • Liver disease - has not been studied



Abaloparatide (Tymlos™)

Dosage forms

Prefilled pen
  • Contains 30 doses of 80 mcg

Dosing

Osteoporosis treatment in postmenopausal women at high risk for fracture
  • Dosing: 80 mcg subcutaneously once daily
  • Cumulative use beyond a 2-year period has not been studied. Use beyond 2 years is not recommended.
  • Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate

Generic / Price

- NO/$$$$ (30 doses)

Other

  • Administer in periumbilical region of the abdomen
  • Rotate the site of the injection every day and administer at approximately the same time every day
  • Store in refrigerator before first use. After first use, may be kept at room temperature for up to 30 days.
  • Abaloparatide is a clear and colorless solution. Do not use if solid particles appear or if the solution is cloudy or colored.

Mechanism of action

  • Abaloparatide is a synthetic version of human parathyroid hormone (PTH). Abaloparatide is a PTHrP(1-34) analog which acts as an agonist at the PTH1 receptor (PTH1R).
  • PTH regulates bone metabolism, and its actions are highly dependent upon the pattern of its exposure to bone. Intermittent, low-dose exposure to PTH stimulates bone development while long-term, sustained exposure stimulates bone resorption. The mechanism behind these differing effects is not completely understood.
  • The pattern of PTH exposure produced by abaloparatide stimulates bone formation

FDA-approved indications

  • Treatment of postmenopausal women with osteoporosis at high risk for fracture defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral fractures and nonvertebral fractures

Side effects



Side effect Abaloparatide Placebo
Hypercalciuria 11% 9%
Dizziness 10% 6%
Nausea 8% 3%
Headache 8% 6%
Palpitations 5% 0.4%
Fatigue 3% 2%
Upper abdominal pain 3% 2%
Vertigo 2% 2%
Other
  • Injection site reactions - redness (58%), edema (10%), pain (9%)


Drug interactions

  • None known

Contraindications / Precautions

  • Bone cancer and bone metastases - DO NOT USE
  • Metabolic bone disease (e.g. Paget's disease) - DO NOT USE
  • Hypercalcemia - DO NOT USE. Abaloparatide may raise calcium levels and worsen hypercalcemia. In trials, 3% of abaloparatide-treated patients experienced hypercalcemia at 4 hours after dosing.
  • Hypercalcemic disorders - DO NOT USE in hypercalcemic disorders like primary hyperparathyroidism.
  • Osteosarcoma - in male and female rats, abaloparatide caused a dose-dependent increase in the incidence of osteosarcoma in male and female rats after subcutaneous administration at exposures 4 to 28 times the human exposure. Abaloparatide is not recommended in patients at increased risk of osteosarcoma including those with Paget's disease of bone or unexplained elevations of alkaline phosphatase, open epiphyses, bone metastases or skeletal malignancies, hereditary disorders predisposing to osteosarcoma, or prior external beam or implant radiation therapy involving the skeleton.
  • Orthostatic hypotension - in trials, orthostatic hypotension occurred after the first dose in 4% of abaloparatide-treated patients and 3% of placebo-treated patients. At later time points, the incidence was the same. Symptoms typically occur within 4 hours of injection. When initiating therapy, patients should be aware of the risk and take necessary precautions.
  • Kidney stones (hypercalciuria) - abaloparatide may increase renal calcium excretion. Use caution in patients with a history of calcium stones. In trials, kidney stones were reported in 2.1% of abaloparatide-treated patients and 1.7% of placebo-treated patients.
  • Tachycardia - in trials, 2% of abaloparatide-treated patients and 1% of placebo-treated patients experienced tachycardia after injection. Symptoms typically occurred within 15 minutes of injection and resolved in 6 hours.
  • Increase in serum uric acid (gout) - abaloparatide may increase serum uric acid levels. Among patients who had normal baseline uric acid levels, elevated uric acid levels were reported in 25% of abaloparatide-treated patients and 6% of placebo-treated patients. Use caution in susceptible patients (e.g. gout).
  • Anti-abaloparatide antibodies - in trials, anti-abaloparatide antibodies developed in 49% of patients who received therapy for 18 months. Of these patients, 68% developed neutralizing antibodies and 2.3% developed cross-reactivity to PTHrP. Antibody formation did not appear to affect efficacy outcomes or increase hypersensitivity reactions.
  • Liver disease - has not been studied
  • Kidney disease - no dosage adjustment is required for patients with mild, moderate, or severe renal impairment. Patients with severe renal impairment may have increased abaloparatide exposure that may increase the risk of adverse reactions.

Teriparatide (Forteo®)

Dosage forms

Prefilled pen
  • Each pen contains 28 doses of 20 mcg

Dosing

Osteoporosis treatment in men and women
  • Dosing: 20 mcg subcutaneously once daily
  • The safety of teriparatide has not been evaluated beyond a 2-year period. Use beyond 2 years is not recommended.
Glucocorticoid-induced osteoporosis
  • Dosing: 20 mcg subcutaneously once daily
  • The safety of teriparatide has not been evaluated beyond a 2-year period. Use beyond 2 years is not recommended.

Efficacy


Generic / Price

- NO/$$$$ (28 doses)

Other

  • Keep pen refrigerated at all times
  • During the use period, time out of the refrigerator should be minimized. The dose may be delivered immediately following removal from the refrigerator.
  • Administer in thigh or abdominal wall
  • Teriparatide is a clear and colorless solution. Do not use if cloudy, colored, or particulate matter is present.

Mechanism of action

  • Teriparatide is a synthetic version of human parathyroid hormone (PTH). Teriparatide has an identical sequence to the 34 N-terminal amino acids (the biologically active region) of the 84-amino acid human parathyroid hormone.
  • PTH regulates bone metabolism, and its actions are highly dependent upon the pattern of its exposure to bone. Intermittent, low-dose exposure to PTH stimulates bone development while long-term, sustained exposure stimulates bone resorption. The mechanism behind these differing effects is not completely understood.
  • The pattern of PTH exposure produced by teriparatide stimulates bone formation

FDA-approved indications

  • Treatment of postmenopausal women with osteoporosis at high risk for fracture
  • Increase of bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture
  • Treatment of men and women with glucocorticoid-induced osteoporosis at high risk for fracture

Side effects


Side effect Teriparatide Placebo
Joint pain 10.1% 8.4%
Weakness 8.7% 6.8%
Nausea 8.5% 6.7%
Dizziness 8% 5.4%
Upset stomach 5.2% 4.1%
Depression 4.1% 2.7%
Vertigo 3.8% 2.7%
Shortness of breath 3.6% 2.6%
Leg cramps 2.6% 1.3%
Syncope 2.6% 1.4%


Drug interactions

  • Digoxin - teriparatide may increase calcium levels. High calcium levels may increase the risk of digitalis toxicity. Use caution in patients taking digoxin.
  • Hydrochlorothiazide (HCTZ) - HCTZ may cause calcium retention in some patients. In studies, HCTZ 25 mg did not affect the serum calcium response to teriparatide 40 mcg. Effects of higher HCTZ doses are unknown.
  • Furosemide - loop diuretics like furosemide cause renal calcium excretion. Administration of teriparatide with furosemide resulted in small increases in the serum calcium (2%) and 24-hour urine calcium (37%) responses to teriparatide that did not appear to be clinically important.

Contraindications / Precautions

  • Bone cancer and bone metastases - DO NOT USE
  • Metabolic bone disease (e.g. Paget's disease) - DO NOT USE
  • Hypercalcemia - DO NOT USE. Teriparatide may raise calcium levels and worsen hypercalcemia. In trials, the maximum effect of teriparatide on calcium levels was seen 4 - 6 hours post-dose. At 16 hours post-dose, levels were not different from baseline.
  • Hypercalcemic disorders - DO NOT USE in hypercalcemic disorders like primary hyperparathyroidism
  • Calciphylaxis - calciphylaxis is an uncommon condition where calcium accumulates in the small blood vessels of fat and skin tissue. It can lead to blood clots and painful skin ulcers. Rare cases of calciphylaxis have been reported in patients receiving teriparatide. Risk factors for the development of calciphylaxis include underlying autoimmune disease, kidney failure, and concomitant warfarin or systemic corticosteroid use.
  • Osteosarcoma - in male and female rats, teriparatide caused an increased incidence of osteosarcoma. The effect was seen with exposures 3 - 60 times those seen in humans. Osteosarcoma has been reported in patients treated with teriparatide in the postmarketing setting; however, an increased risk of osteosarcoma has not been observed in observational studies in humans. There are limited data assessing the risk of osteosarcoma beyond 2 years of teriparatide use. Teriparatide should not be given to patients at increased risk of osteosarcoma. Risk factors for osteosarcoma include open epiphyses (pediatric and young adult patients); metabolic bone diseases other than osteoporosis (e.g. Paget's disease); bone metastases or a history of skeletal malignancies; hereditary disorders predisposing to osteosarcoma; prior external beam or implant radiation therapy involving the skeleton.
  • Kidney stones (hypercalciuria) - teriparatide may increase renal calcium excretion. Use caution in patients with a history of calcium stones. In trials, the incidence of kidney stones was similar between teriparatide-treated patients and placebo-treated patients.
  • Orthostatic hypotension - in trials, transient episodes of orthostatic hypotension occurred in about 5% of patients during the first several doses. Typically, an event began within 4 hours of dosing and spontaneously resolved within a few minutes to a few hours. When starting teriparatide, patients should take proper precautions in case symptoms of hypotension occur.
  • Hypersensitivity reactions - hypersensitivity reactions including angioedema and anaphylaxis have been reported
  • Teriparatide antibodies - in trials, teriparatide antibodies developed in 3% of women. Antibody formation was not associated with a decrease in efficacy or an increase in adverse reactions.
  • Increase in uric acid - teriparatide may increase serum uric acid levels. Use caution in susceptible patients (e.g. gout).
  • Liver disease - has not been studied
  • Kidney disease
    • CrCl ≥ 30 ml/min: in single dose studies, no pharmacokinetic differences were observed
    • CrCl < 30 ml/min: exposure is increased. Use caution.



Raloxifene (Evista®)

Dosage forms

Tablet
  • 60 mg

Dosing

Osteoporosis treatment and prevention in postmenopausal women
  • Dosing: 60 mg once daily
  • May take without regard to food
Reduction in the risk of breast cancer
  • Dosing: 60 mg once daily
  • See breast cancer prevention for information on determining who to treat
  • May take without regard to food

Generic / Price

- YES/$ (30 tablets)

Mechanism of action

Overview
  • Raloxifene is an estrogen agonist/antagonist, also referred to as a selective estrogen receptor modulator (SERM)
  • SERMs stimulate estrogen receptors in some tissues and block them in other tissues. See SERM activity table for more.
  • Stimulating estrogen receptors in bone leads to an increase in bone mineral density
  • Blocking estrogen receptors in breast tissue decreases the risk of breast cancer
Raloxifene has the following actions:
  • Bone
    • Osteoclast formation - neutral
    • Bone formation - agonist
    • Bone resorption - antagonist
  • Endometrium - neutral to partial agonist
  • Vagina - neutral
  • Breast - antagonist [9]

FDA-approved indications

  • Treatment and prevention of osteoporosis in postmenopausal women
  • Reduction in the risk of invasive breast cancer in postmenopausal women with osteoporosis
  • Reduction in the risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer

Side effects



Side effect Raloxifene Placebo
Joint pain 15.5% 14%
Flu syndrome 13.5% 11.4%
Hot flashes 9.7% 6.4%
Leg cramps 7% 3.7%
Uterine disorder 3.3% 2.3%


Drug interactions

  • Cholestyramine - DO NOT COMBINE. Raloxifene absorption is reduced.
  • Warfarin - raloxifene may decrease the effectiveness of warfarin. Monitor PT/INR.
  • Highly protein-bound drugs - raloxifene is > 95% protein bound. It may theoretically interact with other highly protein-bound drugs (e.g. gemfibrozil, diazepam, diazoxide, lidocaine). In vitro, raloxifene did not interact with the binding of phenytoin, tamoxifen, or warfarin.
  • Estrogen - the safety of concomitant exogenous estrogens with raloxifene has not been evaluated and is not recommended

Contraindications / Precautions

  • Childbearing potential - DO NOT USE in women who are pregnant or may become pregnant
  • Venous thromboembolism (VTE) - DO NOT USE. Raloxifene increases the risk of VTE and should not be used in women with a history of VTE. In the RUTH trial (median follow-up 5.6 years), there was an absolute increase in risk of VTE in the raloxifene group of 1.2 cases per 1000 woman-years when compared to the placebo group. [8]
  • Surgery and immobilization because of the increased risk of VTE, raloxifene should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g. surgery). Raloxifene should be resumed only when the patient is fully ambulatory.
  • Death due to stroke - in the RUTH trial (median follow-up 5.6 years), there was an increased risk of death due to stroke in the raloxifene group when compared to the placebo group (absolute risk increase, 0.7 cases per 1000 woman-years; hazard ratio 1.49; 95% CI, 1.00-2.24; p=0.0499). There was no statistically significant difference between the groups in the incidence of stroke. Risk/benefit should be considered when prescribing to women at increased risk of stroke. [8]
  • Premenopausal women - raloxifene has not been studied in premenopausal women and should not be used in these women
  • Effects on endometrium - raloxifene may cause a slight increase in endometrial thickness. In trials, placebo-treated women had a 0.27 mm mean decrease from baseline in endometrial thickness over 3 years, whereas the raloxifene-treated women had a 0.06 mm mean increase.
  • Endometrial polyps - in trials, histologically benign endometrial polyps were reported in 17 of 1999 placebo-treated women, 37 of 1948 Evista-treated women, and in 31 of 2010 women treated with raloxifene 120 mg/day.
  • Elevated triglycerides - estrogens and estrogen-like compounds may raise triglyceride levels. Monitor triglycerides in susceptible patients.
  • History of breast cancer - raloxifene has not been studied in women with a history of breast cancer
  • Unexplained uterine bleeding - unexplained uterine bleeding should be investigated as clinically indicated. In studies, raloxifene-treated and placebo-treated patients had similar incidences of endometrial proliferation.
  • Liver disease - clearance is decreased. Use caution.
  • Kidney disease
    • CrCl ≥ 60 ml/min: no dose adjustment necessary
    • CrCl < 60 ml/min: clearance is decreased. Use caution.







VERO Study - Teriparatide vs Risedronate in Postmenopausal Women with Severe OP, Lancet (2018) [PubMed abstract]
  • The trial enrolled 680 postmenopausal women with at least two moderate or one severe vertebral fracture and a BMD T-score ≤ –1·50
Main inclusion criteria
  • Female ≥ 45 years old
  • Postmenopausal
  • BMD less than –1.50 at the femoral neck, total hip, or lumbar spine
  • Radiographic evidence of at least two moderate (a reduction in vertebral body height of 26 – 40%) or one severe (more than 40% reduction) prevalent vertebral fragility fracture
Main exclusion criteria
  • Skeletal disease other than OP
  • Malignant tumor within 5 years
  • CrCl < 30 ml/min
Baseline characteristics
  • Average age 72 years
  • Average lumbar T-score: -2.28
  • More than 1 fracture - 65%
  • Previous bisphosphonate use - 58% with a median use of 3.6 years
Randomized treatment groups
  • Group 1 (680 patients): Teriparatide 20 mcg once daily
  • Group 2 (680 patients): Risedronate 35 mg once weekly
  • Patients received daily supplements of 500 – 1000 mg of elemental calcium and roughly 400 – 800 IU of vitamin D3 or D2
Primary outcome: Percentage of patients with at least one new vertebral fracture during the 24-month study period. Spine X-rays were done when clinically indicated and at 12 and 24 months in all patients.
Results

Duration: 24 months
Outcome Teriparatide Risedronate Comparisons
Primary outcome 5.4% 12% RR 0.44, 95%CI [0.29–0.68], p<0.0001
Nonvertebral fragility fractures 4% 6.1% RR 0.66, 95%CI [0.39–1.10], p=0.10

Findings: Among postmenopausal women with severe osteoporosis, the risk of new vertebral and clinical fractures is significantly lower in patients receiving teriparatide than in those receiving risedronate.

Zoledronic Acid vs Placebo for Fracture Prevention in Osteopenia, NEJM (2018) [PubMed abstract]
  • The study enrolled 2000 postmenopausal women with a T score of −1.0 to −2.5 at either the total hip or the femoral neck on either side
Main inclusion criteria
  • Female
  • Age > 65 years
  • > 5 years postmenopausal
  • Total hip T-score at either hip between -1.0 and -2.5
Main exclusion criteria
  • BMD of lumbar spine less than -3.0
  • CrCl < 30 ml/min
  • Other bone-active drug within 1 year
  • HRT within previous year
Baseline characteristics
  • Average age 71 years
  • Median 10-year risk of osteoporotic fracture - 12%
  • Median 10-year risk of hip fracture - 2.4%
  • Average BMD T-score: Lumbar spine -0.89 | Total hip -1.25 | Femoral neck -1.63 | Total body -0.80
Randomized treatment groups
  • Group 1 (1000 patients): Zoledronic acid 5 mg every 18 months for 4 doses
  • Group 2 (1000 patients): Placebo infusion
  • Dietary calcium intake of 1 g per day was advised
  • Women who were not already taking vitamin D supplements were given a single oral dose of cholecalciferol (2.5 mg [100,000 IU]) at least 1 week before their first infusion and subsequently received cholecalciferol at a dose of 1.25 mg per month for the duration of the trial
Primary outcome: Time to first occurrence of a fragility fracture defined as any nonvertebral fractures (excluding fractures of the toes, metatarsal bones, fingers, metacarpal bones, skull, facial bones, and mandible) and vertebral fractures as confirmed by radiographic evidence
Results

Duration: 6 years
Outcome Zoledronic acid Placebo Comparisons
Primary outcome (fractures/1000 woman-year) 22.1 38.5 HR 0.63, 95%CI [0.50 - 0.79] p<0.001
Vertebral fractures (fractures/1000 woman-year) 4.2 10.9 HR 0.45, 95%CI [0.27 - 0.73] p=0.002
Nonvertebral fractures (fractures/1000 woman-year) 18.2 30.2 HR 0.66, 95%CI [0.51 - 0.85] p=0.001
Cancer (cases/1000 woman-year) 14.7 21.5 HR 0.67, 95%CI [0.50 - 0.89]

Findings: The risk of nonvertebral or vertebral fragility fractures was significantly lower in women with osteopenia who received zoledronate than in women who received placebo.
StraightHealthcare analysis
  • This study found zoledronic acid to be effective at preventing fractures in women with osteopenia. Other bisphosphonates have had mixed results in osteopenia studies.
  • Current guidelines recommend treatment of women with osteopenia who have a 10-year risk of ≥ 3% for a hip fracture or ≥ 20% for major osteoporosis-related fracture. This study found a benefit in women with a lower median risk (baseline study median risk: hip fracture - 2.4%, osteoporosis-related fracture - 12%).



  • References PMID 25423325, PMID 25210448, PMID 10874566
SERM ACTIVITY TABLE
SERM Endometrium Vagina Breast Bone formation Hypothalamus
Bazedoxifene (Duavee®) Neutral to
Antagonist
No data Neutral to
Antagonist
Agonist ?
Clomiphene (Clomid®) Antagonist ? ? Agonist Antagonist
Ospemifene (Osphena®) Neutral to
Partial agonist
Agonist Antagonist Agonist ?
Raloxifene (Evista®) Neutral to
Partial agonist
Neutral Antagonist Agonist ?
Tamoxifen (Nolvadex®) Neutral to
Agonist
Agonist Antagonist Agonist ?



Pricing legend
  • $ = 0 - $50
  • $$ = $51 - $100
  • $$$ = $101 - $150
  • $$$$ = > $151
  • Pricing based on one month of therapy at standard dosing in an adult
  • Pricing based on information from GoodRX.com®
  • Pricing may vary by region and availability