Alendronate

Pharmacologic Category

Bisphosphonate Derivative

Dosing: Adult

Note: In order for alendronate to be sufficiently absorbed, it needs to be administered in the morning ≥30 minutes before the first food, beverage (except plain water), or other medications. Patients with swallowing difficulties, esophageal motility disorders, or the inability to stand or sit upright for ≥30 minutes should not receive oral bisphosphate therapy. Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate. Calcium and other supplements/medications containing polyvalent cations (eg, aluminum, iron, magnesium, zinc) can cause bisphosphonates to be insufficiently absorbed; accordingly, wait ≥30 to 60 minutes after taking alendronate to take calcium or other medications and supplements that interfere with the absorption of alendronate (Gertz 1999; Rosen 2019).

Androgen deprivation therapy-associated osteoporosis, prevention (alternative agent) (off-label use): Note: For use in men with prostate cancer without bone metastases treated long term with androgen deprivation therapy who are at elevated risk of osteoporotic fractures. Due to uncertain efficacy relative to preferred agents, some experts recommend against the use of alendronate for this indication unless preferred agents are unavailable or inappropriate (Smith 2019).

Oral: 70 mg once weekly (Bruder 2006; Greenspan 2007; Klotz 2013).

Osteoporosis, prevention of fractures (males and postmenopausal females): Note: Prior to use, evaluate and treat any potential causes of secondary osteoporosis (eg, hypogonadism in males) (ES [Watts 2012]).

High fracture risk patients include those with a history of fragility fracture, as well as males ≥50 years of age and postmenopausal females with a T-score ≤−2.5, or a T-score between −1 and −2.5 at high fracture risk according to an assessment (Finkelstein 2019; NOF [Cosman 2014]):

Treatment: Oral: 70 mg once weekly or 10 mg once daily.

Patients with T-scores between −1 and −2.5 and not at high fracture risk according to an assessment but who desire pharmacologic therapy for prevention of bone loss and/or fracture (Lewiecki 2019):

Prevention: Oral: 35 mg once weekly or 5 mg once daily.

Duration of therapy: The optimal duration of therapy has not been established. If fracture risk remains high (eg, fragility fracture before or during therapy) after the initial 5 years, consider extending therapy for up to 10 years or switching to alternative therapy (AACE/ACE [Camacho 2016]; Adler 2016; ES [Eastell 2019]; Watts 2010). Alternatively, if bone mineral density (BMD) is stable, there have been no previous fragility fractures, and short-term fracture risk is low, consider discontinuation (ie, drug holiday) after the initial 5 years. The optimal length of a drug holiday has not been established, although it is usually for a period of up to 5 years for oral bisphosphonates (ES [Eastell 2019]). The decision to resume therapy following a drug holiday is based on multiple factors, including decline in BMD, duration of discontinuation, and risk factors for fracture (ES [Eastell 2019]; Rosen 2019).

Osteoporosis, glucocorticoid-induced: Note: Recommended for use in males ≥50 years of age and postmenopausal females with low BMD (T-scores between −1 and −2.5 in either group) and expected to receive systemic glucocorticoid therapy for at least 3 months at a prednisone dose of ≥7.5 mg/day (or its equivalent); or in any patient whose baseline risk of fracture is high and is receiving a glucocorticoid at any dose or duration. In younger males and premenopausal females, patient selection must be individualized (Rosen 2019). Avoid use in females who are pregnant, who plan on becoming pregnant, or who are not using effective birth control (ACR [Buckley 2017]).

Prevention (off-label use) or treatment: Oral: 70 mg once weekly (Stoch 2009; Yeap 2008) or 10 mg once daily (de Nijs 2006; Tee 2012).

Paget disease, treatment (alternative agent): Note: For symptomatic patients with active disease and select patients with asymptomatic disease (eg, abnormal biochemical marker, prior to planned surgery at an active pagetic site) (Charles 2019; ES [Singer 2014]).

Initial: Oral: 40 mg once daily for 6 months (ES [Singer 2014]; manufacturer's labeling).

Re-treatment: A second course (ie, 40 mg orally once daily for 6 months) may be considered following a 6-month posttreatment evaluation period in patients whose serum alkaline phosphatase normalized during initial treatment but then subsequently rose above normal after discontinuation or if serum alkaline phosphatase failed to normalize during the initial course (Charles 2019; manufacturer's labeling).

Missed doses (once weekly): If a once-weekly dose is missed, administer the next morning after remembered; then return to the original scheduled day of the week on the once-weekly schedule; however, do not administer 2 doses on the same day.

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment: Adult

CrCl ≥35 mL/minute: No dosage adjustment necessary.

CrCl <35 mL/minute: Use not recommended.

Dosing: Hepatic Impairment: Adult

No dosage adjustment necessary.

Dosing: Pediatric

Note: Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate.

Osteogenesis imperfecta: Limited data available, dosing regimens and efficacy results variable (Akcay 2008; Pizones 2005; Seikaly 2005; Ward 2011): Children ≥2 years and Adolescents:

≤30 kg: Oral: 5 mg once daily

30 to <40 kg: 5 or 10 mg once daily

≥40 kg: Oral: 10 mg once daily

Dosing based on several prospective and retrospective trials; most smaller studies reported increased bone mineral density (BMD), decreased frequency of fractures, alleviation of chronic pain, and in some patients increased mobility (Akcay 2008; Pizones 2005; Seikaly2005; Unal 2005; Vyskocil 2005). The largest trial, a multicenter, randomized, placebo-controlled trial (n=109 in treatment group, n=83 completed 2-year follow-up) reported significant increases in lumbar spine BMD; however, other efficacy markers including long-bone fracture rate and pediatric disability score were no different than placebo (Ward 2011).

Osteopenia associated with cystic fibrosis (CF): Limited data available: Children ≥5 years and Adolescents: Oral:

≤25 kg: 5 mg once daily

>25 kg: 10 mg once daily

Dosing based on a randomized, placebo-controlled trial of CF patients (n=128, treatment group: n=65) with low apparent BMD age and inadequate response to calcium and calcifediol treatment; results showed a significant increase in BMD (16.3% vs 3.1% from baseline); evaluation of effect on fracture rate not possible due to sample size and duration (trial duration: 2 years); alendronate appeared to be well-tolerated with no notable difference in adverse effects reported (Bianchi 2013)

Osteopenia, nonambulatory patients (eg, cerebral palsy, muscular dystrophy): Limited data available, efficacy results variable: Note: Due to added complexity of administration requirements (eg, remaining in an upright position for an extended time) weekly dosing is preferred in these patients.

Fixed dosing (Apkon 2008; Houston 2014; Sholas 2005): Children ≥6 years and Adolescents: Oral: Usual reported dose: 35 mg once weekly. Dosing based on experience in 42 patients (age range: 6 to 16 years) from two case series and a retrospective trial. In the retrospective cohort study (n=29 mean age: 12 years), treatment showed a non-statistically significant trend in Z-score stabilization (Houston 2014). A case series of 10 patients (age range: 6 to 16 years) reported fewer fractures after treatment started compared to the prior year; alendronate was reported as being well tolerated; one patient discontinued therapy for hematemesis (also receiving high-dose ibuprofen therapy) (Sholas 2005).

Weight-directed dosing: Children ≥3 years and Adolescents: Oral: 1 mg/kg/dose once weekly (Paksu 2012); if using a solid dosage form, consider dose rounding to the nearest 10 mg (up or down as appropriate) (Lethaby 2007). Dosing based on a prospective trial of 26 patients (age range: 3 to 17 years); results showed after one year of treatment, increased BMD and decreased alkaline phosphatase.

Osteopenia/Osteoporosis, rheumatology patients (eg, JIA, SLE, dermatomyositis): Limited data available: Children ≥4 years and Adolescents:

≤20 kg: Oral: 5 mg once daily

>20 kg to 30 kg: Oral: 5 or 10 mg once daily

>30 kg: Oral: 10 mg once daily

Dosing based on a prospective trial (multicenter and single center) (Bianchi 2000; Cimaz 2002; Unal 2006); results from trials showed bone mineral density (BMD) was significantly increased (to normal values in some patients) after alendronate therapy; in some cases, bone turnover markers were reduced without a reduction of inflammatory activity (underlying rheumatologic disease process)

Dosing: Renal Impairment: Pediatric

There are no pediatric-specific recommendations provided in the manufacturer's labeling; based on experience in adult patients, use is not recommended in patients with a CrCl of <35 mL/minute.

Dosing: Hepatic Impairment: Pediatric

There are no pediatric-specific recommendations provided in the manufacturer's labeling; based on experience in adult patients, no adjustment required.

Calculations

• Creatinine Clearance by Cockcroft-Gault
• Creatinine Clearance by Cockcroft-Gault (SI units)
• Creatinine Clearance by Cockcroft-Gault with IBW
• Creatinine Clearance by Cockcroft-Gault with IBW (SI units)
• Creatinine Clearance by Jelliffe
• Creatinine Clearance by Sanaka
• Glomerular Filtration Rate by Abbreviated MDRD
• Glomerular Filtration Rate by Abbreviated MDRD (SI units)
• Glomerular Filtration Rate by MDRD
• Glomerular Filtration Rate by MDRD (IDMS-Traceable SCr)
• Glomerular Filtration Rate by MDRD (SI units)
• Glomerular Filtration Rate Estimate in African Americans by AASK Equation

Use: Labeled Indications

Osteoporosis:

Binosto: Treatment of osteoporosis in postmenopausal females and to increase bone mass in males with osteoporosis

Fosamax: Treatment and prevention of osteoporosis in postmenopausal females; treatment to increase bone mass in males with osteoporosis; treatment of glucocorticoid-induced osteoporosis in males and females with low bone mineral density who are receiving a prednisone dosage of ≥7.5 mg/day (or equivalent)

Paget disease: Fosamax: Treatment of Paget disease of the bone in patients (males and females) who are symptomatic, at risk for future complications, or with alkaline phosphatase ≥2 times the upper limit of normal

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

Androgen deprivation therapy-associated osteoporosis, preventionLevel of Evidence [A]

Data from a randomized, double-blind, placebo-controlled, crossover study support the use of once-weekly alendronate (in conjunction with calcium and vitamin D supplementation) for the prevention of bone loss associated with androgen deprivation therapy (ADT) in nonmetastatic prostate cancer Ref. Data from a multicenter, randomized, double-blind, placebo-controlled study also support the use of weekly alendronate (in conjunction with calcium and vitamin D supplementation) for prevention of ADT-associated bone loss Ref. Access Full Off-Label Monograph

Osteoporosis, glucocorticoid-induced preventionLevel of Evidence [A, G]

Data from a randomized, placebo-controlled clinical study support the use of alendronate in the prevention of glucocorticoid-induced osteoporosis Ref.

Based on the 2017 American College of Rheumatology (ACR) guideline for the prevention and treatment of glucocorticoid-induced osteoporosis, bisphosphonates (including alendronate) are effective and recommended for prevention of glucocorticoid-induced osteoporosis in women (either not of childbearing potential or who do not plan to become pregnant) and men with moderate to high fracture risk and who are initiating long-term glucocorticoid treatment.

Level of Evidence Definitions

Level of Evidence Scale

Class and Related Monographs

Bisphosphonates

Clinical Practice Guidelines

Oncology:

ASCO, "Management of Osteoporosis in Survivors of Adult Cancers with Nonmetastatic Disease," September 2019

National Comprehensive Cancer Network® (NCCN), Clinical Practice Guidelines in Oncology, Prostate Cancer

Osteoporosis:

American Association of Clinical Endocrinologists and American College of Endocrinology, “Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis,” 2016

American College of Physicians, “Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update from the American College of Physicians,” 2017

American College of Rheumatology, "Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis," 2017

Endocrine Society, “Osteoporosis in Men: An Endocrine Society Clinical Practice Guideline,” 2012

Endocrine Society, “Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Clinical Practice Guideline,” 2019

National Osteoporosis Foundation, Clinician’s Guide to Prevention and Treatment of Osteoporosis, 2014

Paget Disease:

The Endocrine Society, “Paget's Disease of Bone,” 2014

Paget’s Association, “Diagnosis and Management of Paget’s Disease of Bone in Adults: A Clinical Guideline,” February 2019

Administration: Oral

Administer first thing in the morning and ≥30 minutes before the first food, beverage (except plain water), or other medication(s) of the day. Do not take with mineral water or with other beverages. Patients should be instructed to stay upright (not to lie down) for ≥30 minutes and until after first food of the day (to reduce esophageal irritation).

Oral solution: Administer oral solution, followed with ≥2 oz of plain water.

Tablet (Fosamax): Must be taken with 6 to 8 oz of plain water. The tablet should be swallowed whole; do not chew or suck.

Tablet, effervescent (Binosto): Dissolve one tablet in 4 oz of room temperature plain water only; once effervescence stops, wait ≥5 minutes and stir the solution for ~10 seconds and then drink.

Administration: Pediatric

Oral: Administer first thing in the morning and ≥30 minutes before the first food, beverage (except plain water), or other medication of the day. Do not take with mineral water or with other beverages. Remain upright (do not lie down) for at least 30 minutes and until after first food of the day (to reduce esophageal irritation).

Oral solution: Follow administration of oral solution with at least 2 oz of plain water.

Tablet (Fosamax): Must be taken with 6 to 8 oz of plain water. The tablet should be swallowed whole; do not chew or suck on the tablet.

Tablet, effervescent (Binosto): Dissolve one tablet in 4 oz of room temperature plain water only; once effervescence stops, wait ≥5 minutes and stir the solution for ~10 seconds and then drink

Missed doses (once weekly): If a once-weekly dose is missed, it should be given the next morning after remembered; then return to the original scheduled day of the week on the once-weekly schedule; however, do not give 2 doses on the same day.

Dietary Considerations

Ensure adequate calcium and vitamin D intake; if dietary intake is inadequate, dietary supplementation is recommended. Males and females should consume:

Calcium: 1,000 mg/day (men: 50 to 70 years) or 1,200 mg/day (females ≥51 years and males ≥71 years) (IOM 2011; NOF [Cosman 2014]).

Vitamin D: 800 to 1,000 int. units/day (males and females ≥50 years) (NOF [Cosman 2014]). Recommended Dietary Allowance (RDA): 600 int. units daily (males and females ≤70 years) or 800 int. units/day (males and females ≥71 years) (IOM 2011).

Storage/Stability

Oral solution: Store at 25°C (77°F), excursions permitted to 15°C to 30°C (59°F to 86°F). Do not freeze.

Tablet (Fosamax): Store at room temperature of 15°C to 30°C (59°F to 86°F). Keep in well-closed container.

Tablet, effervescent (Binosto): Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture. Store in original blister package until use.

Preparation for Administration: Adult

Tablet, effervescent (Binosto): Dissolve effervescent tablet in 120 mL of room temperature plain water (not mineral water or flavored water); wait ≥5 minutes after effervescence stops, then stir for 10 seconds and administer.

Preparation for Administration: Pediatric

Tablet, effervescent (Binosto): Dissolve effervescent tablet in 120 mL of room temperature plain water (not mineral water or flavored water); wait ≥5 minutes after effervescence stops, then stir for 10 seconds and administer

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to prevent or treat soft, brittle bones (osteoporosis).

• It is used to treat Pagets disease.

• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Headache

• Nausea

• Vomiting

• Abdominal pain

• Constipation

• Diarrhea

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Low calcium like muscle cramps or spasms, numbness and tingling, or seizures

• Black, tarry, or bloody stools

• Chest pain

• Coughing up blood

• Heartburn

• Trouble swallowing

• Pain when swallowing

• Sore throat

• Vomiting blood

• Severe bone pain

• Severe joint pain

• Severe muscle pain

• Groin, hip, or thigh pain

• Mouth sores

• Jaw pain or swelling

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

International issues:

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Binosto: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/BinostoMedGuide.pdf

Fosamax: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020560s068,021575s024lbl.pdf#page=24

Contraindications

Hypersensitivity to alendronate or any component of the formulation; hypocalcemia; abnormalities of the esophagus (eg, stricture, achalasia) which delay esophageal emptying; inability to stand or sit upright for at least 30 minutes; increased risk of aspiration (effervescent tablets; oral solution)

Canadian labeling: Additional contraindications (not in the US labeling): Renal insufficiency with CrCl <35 mL/minute

Documentation of allergenic cross-reactivity for bisphosphonates is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Warnings/Precautions

Concerns related to adverse effects:

• Bone fractures: Atypical femur fractures (AFF) have been reported in patients receiving bisphosphonates. The fractures include subtrochanteric femur (bone just below the hip joint) and diaphyseal femur (long segment of the thigh bone). Some patients experience prodromal pain weeks or months before the fracture occurs. It is unclear if bisphosphonate therapy is the cause for these fractures; AFFs have also been reported in patients not taking bisphosphonates, and in patients receiving glucocorticoids. Patients receiving long-term (>3 to 5 years) bisphosphonate therapy may be at an increased risk (Adler 2016; NOF [Cosman 2014]); however, benefits of therapy (when used for osteoporosis) generally outweigh absolute risk of AFF within the first 5 years of treatment, especially in patients with high fracture risk (Adler 2016; ES [Eastell 2019]). Patients presenting with thigh or groin pain with a history of receiving bisphosphonates should be evaluated for femur fracture. Consider interrupting bisphosphonate therapy in patients who develop a femoral shaft fracture; assess for fracture in the contralateral limb.

• Bone/joint/muscle pain: Severe (and occasionally debilitating) bone, joint, and/or muscle pain have been reported during bisphosphonate treatment. The onset of pain ranged from a single day to several months. Consider discontinuing therapy in patients who experience severe symptoms; symptoms usually resolve upon discontinuation. Some patients experienced recurrence when rechallenged with the same drug or another bisphosphonate; avoid use in patients with a history of these symptoms in association with bisphosphonate therapy.

• GI mucosa irritation: May cause irritation to upper GI mucosa. Esophagitis, dysphagia, esophageal ulcers, esophageal erosions, and esophageal stricture (rare) have been reported with oral bisphosphonates; risk increases in patients unable to comply with dosing instructions. Use with caution in patients with dysphagia, esophageal disease, gastritis, duodenitis, or ulcers (may worsen underlying condition). Discontinue use if new or worsening symptoms develop.

• Hypocalcemia: Hypocalcemia has been reported with the use of bisphosphonates. Prior to therapy initiation, hypocalcemia must be corrected; ensure adequate calcium and vitamin D intake.

• Ocular effects: Conjunctivitis, uveitis, episcleritis, and scleritis have been reported with alendronate; patients presenting with signs of ocular inflammation may require further ophthalmologic evaluation.

• Osteonecrosis of the jaw: Osteonecrosis of the jaw (ONJ), also referred to as medication-related osteonecrosis of the jaw (MRONJ), has been reported in patients receiving bisphosphonates. Known risk factors for MRONJ include invasive dental procedures (eg, tooth extraction, dental implants, boney surgery), cancer diagnosis, concomitant therapy (eg, chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, ill-fitting dentures, and comorbid disorders (anemia, coagulopathy, infection, preexisting dental or periodontal disease). Risk may increase with increased duration of bisphosphonate use. According to a position paper by the American Association of Maxillofacial Surgeons (AAOMS), MRONJ has been associated with bisphosphonate and other antiresorptive agents (denosumab), and antiangiogenic agents (eg, bevacizumab, sunitinib) used for the treatment of osteoporosis or malignancy; risk of MRONJ is significantly higher in cancer patients receiving antiresorptive therapy compared to patients receiving osteoporosis treatment (regardless of medication used or dosing schedule). MRONJ risk is also increased with intravenous antiresorptive use compared to the minimal risk associated with oral bisphosphonate use, although risk appears to increase with oral bisphosphonates when duration of therapy exceeds 4 years (AAOMS [Ruggiero 2014]). The manufacturer's labeling states that in patients requiring invasive dental procedures, discontinuing bisphosphonates may reduce the risk of ONJ and clinical judgment should guide the decision. However, the AAOMS suggests there is currently no evidence that interrupting oral bisphosphonate therapy alters the risk of ONJ following tooth extraction, and that in patients receiving oral bisphosphonates for <4 years who have no clinical risk factors, no alternations or delay in any procedure common to oral/maxillofacial surgeons, periodontists, and other dental providers is necessary (special considerations apply to patients receiving dental implants). Conversely, in patients receiving oral bisphosphonates for >4 years or in patients receiving oral bisphosphonates for <4 years who have also taken corticosteroids or antiangiogenic medications concomitantly, the AAOMS recommends considering a 2-month, drug-free period prior to invasive dental procedures (recommendation based on a theoretical benefit). Patients developing ONJ during therapy should receive care by an oral surgeon (AAOMS [Ruggiero 2014]). According to the manufacturer, discontinuation of the bisphosphonate therapy should be considered (based on risk/benefit evaluation) in patients who develop ONJ.

Disease-related concerns:

• Bariatric surgery: Altered absorption and ulceration risk: Avoid oral bisphosphates after bariatric surgery; inadequate oral absorption and potential anastomotic ulceration may occur. If therapy is indicated, IV administered bisphosphonates are recommended.

• Osteoporosis in survivors of adult cancers (nonmetastatic disease): Survivors of adult cancers with nonmetastatic disease who have osteoporosis (T score of -2.5 or lower in femoral neck, total hip, or lumbar spine) or who are at increased risk of osteoporotic fractures, should be offered bone modifying agents (utilizing the osteoporosis-indicated dose) to reduce the risk of fracture. For patients without hormonal responsive cancers, when clinically appropriate, estrogens may be administered along with other bone modifying agents (ASCO [Shapiro 2019]). The choice of bone modifying agent (eg, oral or IV bisphosphonates or subQ denosumab) should be based on several factors (eg, patient preference, potential adverse effects, quality of life considerations, availability, adherence, cost). Adequate calcium and vitamin D intake, exercise (using a combination of exercise types), as well as lifestyle modifications (if indicated), should also be encouraged.

• Renal impairment: Use with caution in patients with renal impairment (not recommended for use in patients with CrCl <35 mL/minute).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Effervescent tablet: Each effervescent tablet contains 650 mg of sodium (NaCl 1,650 mg). Use with caution in patients following a sodium-restricted diet.

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

The elderly are frequently treated long-term for osteoporosis. Elderly patients should be advised to report any lower extremity, jaw (osteonecrosis), or muscle pain that cannot be explained or lasts longer than 2 weeks. Additionally, elderly often receive concomitant diuretic therapy and therefore their electrolyte status (eg, calcium, phosphate) should be periodically evaluated.

Due to the reports of atypical femur fractures and osteonecrosis of the jaw, recommendations for duration of bisphosphonate use in osteoporosis have been modified. Based on available data, consider discontinuing bisphosphonates after 5 years of use in low-risk patients, since the risk of nonvertebral fracture is the same as those patients taking bisphosphonates for 10 years. Those patients with high risk (fracture history) may be continued for a longer period, taking into consideration the risks versus benefits associated with continued therapy.

Warnings: Additional Pediatric Considerations

The potential adverse effects of bisphosphonate therapy on the immature bones of growing children are concerning and data to fully describe are insufficient. Animal data has shown alendronate (high-dose) inhibits longitudinal bone growth (Rauch 2004); pediatric patients with osteogenesis imperfecta (OI) treated with pamidronate for 4 years showed increased height z scores (Zeitlin 2003); pediatric growth effects with other bisphosphonates is lacking. Possible decreased bone remodeling affecting growth or fracture healing may occur with bisphosphonate therapy; a case-report in an adolescent treated with high-dose pamidronate described abnormal long-bone modeling (Rauch 2004); a large, placebo-controlled OI trial (n=109, age range: 4 to 19 years) reported that alendronate did not interfere with fracture healing (Ward 2011). Rapid and in some cases significant weight gain has been reported with pamidronate therapy in pediatric patients which may negatively affect rehabilitation in patients with OI (Zeitlin 2003). Monitor patients closely.

Reproductive Considerations

Bisphosphonates are incorporated into the bone matrix and gradually released over time. Because exposure prior to pregnancy may theoretically increase the risk of fetal harm, most sources recommend discontinuing bisphosphonate therapy in females of reproductive potential as early as possible prior to a planned pregnancy. Use in premenopausal females should be reserved for special circumstances when rapid bone loss is occurring; a bisphosphonate with the shortest half-life should then be used (Bhalla 2010; Pereira 2012; Stathopoulos 2011).

Oral bisphosphonates can be considered for the prevention of glucocorticoid-induced osteoporosis in premenopausal females with moderate to high risk of fracture who do not plan to become pregnant during the treatment period and who are using effective birth control (or are not sexually active); intravenous therapy should be reserved for high risk patients only (Buckley [ACR 2017]).

Pregnancy Considerations

It is not known if bisphosphonates cross the placenta, but based on their lower molecular weight, fetal exposure is expected (Djokanovic 2008; Stathopoulos 2011).

Information related to the use of alendronate in pregnancy is available from case reports and small retrospective studies (Gerin 2016; Green 2014; Levy 2009; Ornoy 2006; Sokal 2019; Stathopoulos 2011).

Bisphosphonates are incorporated into the bone matrix and gradually released over time. The amount available in the systemic circulation varies by drug, dose, and duration of therapy. Theoretically, there may be a risk of fetal harm when pregnancy follows the completion of therapy (hypocalcemia, low birth weight, and decreased gestation have been observed in some case reports); however, available data have not shown that exposure to bisphosphonates during pregnancy significantly increases the risk of adverse fetal events (Djokanovic 2008; Green 2014; Levy 2009; Sokal 2019; Stathopoulos 2011). Exposed infants should be monitored for hypocalcemia after birth (Djokanovic 2008; Stathopoulos 2011).

Breast-Feeding Considerations

It is not known if alendronate is present in breast milk.

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.

Briggs' Drugs in Pregnancy & Lactation

• Alendronate

Adverse Reactions

Note: Incidence of adverse effects (mostly GI) increases significantly in patients treated for Paget disease at 40 mg/day.

>10%: Endocrine & metabolic: Decreased serum calcium (18%; transient, mild)

1% to 10%:

Central nervous system: Headache (3%)

Endocrine & metabolic: Decreased serum phosphate (10%; transient, mild)

Gastrointestinal: Abdominal pain (2% to 7%), acid regurgitation (1% to 5%), flatulence (≤4%), gastroesophageal reflux disease (3%), constipation (≤3%), diarrhea (≤3%), dyspepsia (1% to 3%), nausea (1% to 3%), esophageal ulcer (2%), dysphagia (1%), melena (1%), abdominal distension (≤1%), gastric ulcer (≤1%; may be severe with complications), gastritis (≤1%)

Neuromuscular & skeletal: Musculoskeletal pain (≤6%; includes bone pain, joint pain, and muscle pain), muscle cramps (≤1%)

<1%, postmarketing, and/or case reports: Alopecia, conjunctivitis, dizziness, duodenal ulcer (may be severe with complications), dysgeusia, episcleritis, erythema, erosive esophagitis, esophageal perforation, esophageal stenosis, esophageal ulcer, esophagitis, exacerbation of asthma, femur fracture (low-energy fractures, including subtrochanteric and diaphyseal), fever, hypersensitivity reaction (includes angioedema and urticaria), hypocalcemia (symptomatic), joint swelling, malaise, oropharyngeal ulcer; osteonecrosis of the jaw, peripheral edema, pruritus, scleritis, skin rash (occasionally with photosensitivity), Stevens-Johnson syndrome, toxic epidermal necrolysis, uveitis, vertigo, weakness

* See Cautions in AHFS Essentials for additional information.

Allergy and Idiosyncratic Reactions

• Bisphosphonate Allergy

Metabolism/Transport Effects

None known.

Drug Interactions Open Interactions

Aminoglycosides: May enhance the hypocalcemic effect of Bisphosphonate Derivatives. Risk C: Monitor therapy

Angiogenesis Inhibitors (Systemic): May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Risk C: Monitor therapy

Aspirin: May enhance the adverse/toxic effect of Alendronate. Specifically, the incidence of upper gastrointestinal adverse events may be increased Risk C: Monitor therapy

Deferasirox: Bisphosphonate Derivatives may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Both an increased risk of gastrointestinal ulceration and an increased risk of nephrotoxicity are of concern. Risk C: Monitor therapy

Parathyroid Hormone: Alendronate may diminish the therapeutic effect of Parathyroid Hormone. More specifically, Alendronate may interfere with normalization of blood calcium concentrations. Risk X: Avoid combination

Polyvalent Cation Containing Products: May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of oral medications containing polyvalent cations within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Risk D: Consider therapy modification

Proton Pump Inhibitors: May diminish the therapeutic effect of Bisphosphonate Derivatives. Risk C: Monitor therapy

Food Interactions

All food and beverages interfere with absorption. Coadministration with dairy products may decrease alendronate absorption. Beverages (especially orange juice, coffee, and mineral water) and food may reduce the absorption of alendronate as much as 60%. Management: Alendronate must be taken first thing in the morning and ≥30 minutes before the first food, beverage (except plain water), or other medication of the day.

Test Interactions

Bisphosphonates may interfere with diagnostic imaging agents such as technetium-99m-diphosphonate in bone scans.

Monitoring Parameters

Osteoporosis: Serial bone mineral density (BMD) should be evaluated at baseline and every 1 to 3 years on treatment (usually at ~2 years following initiation of therapy, then more or less frequently depending on patient-specific factors and stability of BMD) (AACE/ACE [Camacho 2016]; ES [Eastell 2019]; NOF [Cosman 2014]); evaluate BMD every 2 to 4 years during a drug holiday (ES [Eastell 2019]); in patients with combined alendronate and glucocorticoid treatment, evaluate BMD at initiation of glucocorticoid therapy and after 6 to 12 months, then every 2 to 3 years if patient continues to have significant osteoporosis risk factors (ACR [Buckley 2017]); annual measurements of height and weight, assessment of chronic back pain; serum calcium and 25(OH)D; may consider monitoring biochemical markers of bone turnover (eg, fasting serum CTX or urinary NTX) at baseline, 3 months, and 6 months, to assess treatment response, adherence to therapy, and/or possible malabsorption (ES [Eastell 2019]).

Paget disease: Serum total alkaline phosphatase at 6 to 12 weeks for initial response to treatment (when bone turnover will have shown a substantial decline) and potentially at 6 months (maximal suppression of high bone turnover); following treatment completion, monitor at ~6- to 12-month intervals (ES [Singer 2014]); monitoring more specific biochemical markers of bone turnover (eg, serum P1NP, NTX, serum beta-CTx) is generally only warranted in patients with Paget disease who have abnormal liver or biliary tract function or when early assessment of response to treatment is needed (eg, spinal compression, very active disease) (ES [Singer 2014]); pain (posttreatment pain may not strictly correlate with increased biochemical markers [Ralston 2019]); serum calcium and 25(OH)D

Reference Range

Calcium (total): Adults: 9.0 to 11.0 mg/dL (2.05 to 2.54 mmol/L), may slightly decrease with aging

Phosphorus: 2.5 to 4.5 mg/dL (0.81 to 1.45 mmol/L)

Vitamin D: There is no clear consensus on a reference range for total serum 25(OH)D concentrations or the validity of this level as it relates clinically to bone health. In addition, there is significant variability in the reporting of serum 25(OH)D levels as a result of different assay types in use; however, the following ranges have been suggested:

Adults (IOM 2011): Sufficient levels in practically all persons: ≥20 ng/mL (50 nmol/L); concern for risk of toxicity: >50 ng/mL (125 nmol/L)

Osteoporosis patients: Recommended level to reach and maintain may vary by guideline/organization: ≥20 ng/mL (50 nmol/L) is considered adequate according to some experts (ES [Eastell 2019]); others suggest a goal of ~30 ng/mL (75 nmol/L) (NOF [Cosman 2014]).

Advanced Practitioners Physical Assessment/Monitoring

Obtain serum calcium and 25(OH)D. Evaluate bone mineral density every 1 to 2 years after initiation. In patients also receiving glucocorticoid therapy evaluate BMD at initiation of glucocorticoid, 6 to 12 months after, and then every 2 to 3 years. Assess height and weight annually. Assess for chronic back pain. Consider obtaining biochemical markers of bone turnover. Obtain alkaline phosphatase every 6 to 12 weeks in patients with Paget disease. Education patient on proper administration technique as well as proper diet.

Nursing Physical Assessment/Monitoring

Check ordered labs and report abnormalities. Teach patient proper administration technique. Instruct patient in lifestyle and dietary changes that may optimize bone strength. Monitor for and educate patient to report any back pain. Educate patient about need for good oral hygiene and regular dental exams.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Oral:

Generic: 70 mg/75 mL (75 mL)

Tablet, Oral:

Fosamax: 70 mg

Generic: 5 mg, 10 mg, 35 mg, 40 mg [DSC], 70 mg

Tablet Effervescent, Oral:

Binosto: 70 mg

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Fosamax: 70 mg

Generic: 5 mg, 10 mg, 40 mg, 70 mg

Anatomic Therapeutic Chemical (ATC) Classification

• M05BA04

Generic Available (US)

May be product dependent

Pricing: US

Solution (Alendronate Sodium Oral)

70 mg/75 mL (per mL): $0.76

Tablet, effervescent (Binosto Oral)

70 mg (per each): $90.00

Tablets (Alendronate Sodium Oral)

5 mg (per each): $2.93

10 mg (per each): $2.93

35 mg (per each): $20.48 - $52.83

70 mg (per each): $20.41 - $59.08

Tablets (Fosamax Oral)

70 mg (per each): $38.35

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

A bisphosphonate which inhibits bone resorption via actions on osteoclasts or on osteoclast precursors; decreases the rate of bone resorption, leading to an indirect increase in bone mineral density. In Paget disease, characterized by disordered resorption and formation of bone, inhibition of resorption leads to an indirect decrease in bone formation; but the newly-formed bone has a more normal architecture.

Pharmacodynamics/Kinetics

Distribution: 28 L (exclusive of bone)

Protein binding: ~78%

Metabolism: None

Bioavailability: Fasting:

Children ≥4 years and Adolescents: Mean range: 0.41% to 0.56% (Nakhla 2011; Ward 2005)

Adults: 0.6%; reduced up to 60% with coffee or orange juice

Half-life elimination: Exceeds 10 years

Excretion: Urine; feces (as unabsorbed drug)

Pharmacodynamics/Kinetics: Additional Considerations

Renal function impairment: Elimination may be reduced.

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Dental Health Professional Considerations

A review of 2,408 published cases of bisphosphonate-associated osteonecrosis of the jaw bone (BP-associated ONJ) was done by Filleul 2010. BP therapy was associated with 89% of the cases to treat malignancies and 11% of the cases to treat nonmalignant conditions. Information on the specific bisphosphonate used was available for 1,694 of the patients. Intravenous therapy (primarily zoledronic acid) was received by 88% of the patients and 12% received oral treatment (primarily alendronate). Of all the cases of BP-associated ONJ, 67% were preceded by tooth extraction and for 26% of patients, there was no predisposing factor identified.

A 2010 retrospective case review reported the prevalence of BP-associated ONJ in patients using alendronate-type drugs was one out of 952 patients or ~0.1% (Lo 2010). Of the 8,572 respondents, nine cases of ONJ were identified; five had developed ONJ spontaneously and four developed ONJ after tooth extraction. When extrapolated to patient-years of bisphosphonate exposure, this prevalence rate of 0.1% equates to a frequency of 28 cases per 100,000 person-years of oral bisphosphonate treatment. An Australian group (Mavrokokki 2007), identified the frequency of BP-associated ONJ in osteoporotic patients, mainly taking weekly oral alendronate, was 1 in 8,470 to 1 in 2,260 (0.01% to 0.04%) patients. If extractions were carried out, the calculated frequency was 1 in 1,130 to 1 in 296 (0.09% to 0.34%) patients. The median time to onset of ONJ in alendronate patients was 24 months.

According to the 2011 report by the American Dental Association (ADA), the incidence of BP-associated ONJ remains low and the benefits of using oral bisphosphonates significantly outweighs the risk of developing BP-associated ONJ for treatment and prevention of osteoporosis and cancer treatment (Hellstein 2011). The full 47-page report can be accessed at http://www.ada.org/~/media/ADA/Member%20Center/FIles/topics_ARONJ_report.ashx.

The ADA review of 2011 stated the incidence of oral BP-associated ONJ was one case for every 1,000 individuals exposed to oral bisphosphonates (0.1%) (Hellstein 2011).

The most comprehensive review to date on osteonecrosis of the jaw bone (ONJ) has been published in the Journal of Bone and Mineral Research (Khan 2015), and written by an International Task Force of authors, totaling 34, from academe; industry; clinical medical and dental practice; oral and maxillofacial surgery; bone and mineral research; epidemiology; medical and dental oncology; orthopedic surgery; osteoporosis research; muscle and bone research; endocrinology and diagnostic sciences. The work provides a systematic review of the literature and international consensus on the classification, incidence, pathophysiology, diagnosis, and management of ONJ in both oncology and osteoporosis patient populations. This review of the literature from January 2003 to April 2014, with 299 references, offers recommendations for management of ONJ based on multidisciplinary international consensus.

Prevalence and incidence of ONJ in osteoporosis patients from the Task Force report:

Prevalence – the percent of osteoporotic population affected with ONJ

After reviewing all literature reports on this subject, the Task Force concluded that the prevalence of ONJ in patients prescribed oral BPs for the treatment of osteoporosis ranges from 0% to 0.04% with the majority being below 0.001%. However, the Task Force does cite the study of (Lo et al) that evaluated the Kaiser Permanente database and found the prevalence of ONJ in those receiving BPs for more than 2 years to range from 0.05% to 0.21% and appeared to be related to duration of exposure. As mentioned above, the American Dental Association has previously reported that the prevalence of ONJ in osteoporosis patients using oral BPs to be 1 out of 1,000 or 0.1% (Hellstein 2011).

Incidence - the rate at which ONJ occurs or the number of times it happens

From currently available data, the incidence of ONJ in the osteoporosis patient population appears to be low ranging from 0.15% to less than 0.001% person-years drug exposure. In terms of the osteoporosis patient population taking oral BPs, the incidence ranges from 1.04 to 69 per 100,000 patient years of drug exposure.

Effects on Dental Treatment

Osteonecrosis of the jaw (ONJ), generally associated with local infection and/or tooth extraction and often with delayed healing, has been reported in patients taking bisphosphonates. Symptoms included nonhealing extraction socket or an exposed jawbone. Most reported cases of bisphosphonate-associated osteonecrosis have been in cancer patients treated with intravenous bisphosphonates. However, some have occurred in patients with postmenopausal osteoporosis taking oral bisphosphonates. The risk of developing ONJ in patients taking oral bisphosphonates remains low with an estimated prevalence of 0.1% (one out of every 1000 cases of patients exposed to oral bisphosphonates). The benefits of using the oral bisphosphonates to prevent osteoporosis significantly outweighs the small risk of developing bisphosphonate-associated ONJ. Also, at the present time, there are no validated diagnostic techniques to determine which patients are at increased risk of developing ONJ. ONJ in patients taking these drugs can occur spontaneously. In addition, the risk of ONJ increases with specific procedures that increase bone trauma, particularly tooth extractions. Other factors that increase risk of ONJ in patients taking these drugs are age (>65 years of age), periodontitis, use of bisphosphonates for >2 years, smoking, wearing dentures, and diabetes. Patients who develop ONJ while on bisphosphonate therapy should receive care by an oral surgeon. See Dental Health Professional Considerations.

Effects on Bleeding

No information available to require special precautions

Related Information

• Oral Medications That Should Not Be Crushed or Altered

Index Terms

Alendronate Sodium; Alendronic Acid Monosodium Salt Trihydrate; MK-217

FDA Approval Date

September 29, 1995

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Brand Names: International

Adronat (AU, IT, PT); Adronik (RO); Aldren 70 (PH, TH); Aldron (HR); Aldrox (CL); Alenato (AR); Alend (KR); Alendomax (JO); Alendra (PH, UA); Alendrate (NZ); Alendrex (NZ); Alendro (AU, LK, SA); Alendro Once Weekly (KW); Alendrobell (AU); Alendronate (TH); Alendros (KR); Alendroxl (PH); Alenfos (KR); Alenfosa (VN); Allentop (HK); Alnate (LK); Alovell (PH, VN); Arendal (PE); Armol (CR, DO, GT, HN, NI, PA, SV); Bifosa (IN); Binosto (MY, SG); Bisbon (KR); Bonafide (LK); Bonaid (KR); Bonalene (EG); Bonalon (JP); Bonapex (EG); Bonmax (JO); BonMax (TH); Calidron (JO); Densate (AU); Drate (LK); Endronax (BR); Fonat (AU); Forosa (PH); Fosalan (IL); Fosamax (AE, AR, AT, AU, BB, BE, BG, BH, BM, BR, BS, BZ, CH, CL, CN, CY, CZ, DE, DK, EC, EE, EG, ES, FI, FR, GB, GR, GY, HK, HR, IE, IT, JM, JO, KR, KW, LB, LK, LU, MT, MX, NL, NO, NZ, PE, PK, PL, PR, PT, QA, RO, RU, SA, SE, SG, SI, SK, SR, TR, TT, TW, VE, VN); Fosamax Once Weekly (AE, BH, HK, LB, SA); Fosmin (EC, PE); Fostepor (IE); Fostolin (IE); Fosval (PY); Gendarin (SE); Gubang (CN); Kalosten (CR, DO, GT, HN, NI, PA, SV); Lendomax (AE); Londromax (UA); Malend (KR); Marvil (LB, PE, UY); MaxiBone (IL); MaxiBone 70 (IL); Maxlen (TH); Nichospor (ID); Oseomax (CR, DO, GT, HN, NI, PA, SV); Oseotenk (AR); Osficar (CO); Ostemax (UA); Osteo-Plus (PH); Osteocor (PH); Osteodron (PH); Osteofar (ID); Osteofos (HK, IN, UA); Osteol (PY); Osteomel (IE); Osteopor (UY); Osteosan (CL); Osteovan (CR); Osteve (QA); Ostex (CO); Osto (LK); Porosal (VE); Prevost (VN); Reventa (PH); Romax (IE); Tevanate (BG, TW); Valora (HR); Zeroclast (CR, DO, GT, HN, NI, PA, SV)

Last Updated 5/2/20