(tye LOO droe nate)
- Tiludronate Disodium
- Bisphosphonate Derivative
Inhibition of normal and abnormal bone resorption. Inhibits osteoclasts through at least two mechanisms: disruption of the cytoskeletal ring structure, possibly by inhibition of protein-tyrosine-phosphatase, thus leading to the detachment of osteoclasts from the bone surface area and the inhibition of the osteoclast proton pump.
Widely to bone and soft tissue
Little, if any
Urine (~60%, as tiludronic acid within 13 days)
Onset of Action
Delayed, may require several weeks
Time to Peak
Plasma: Within 2 hours
Healthy volunteers: Single dose: 50 hours; CrCl 11-18 mL/minute: 205 hours; Pagetic patients: Repeated dosing: 150 hours
~90%, primarily to albumin
Special Populations: Elderly
Plasma concentrations of tiludronic acid were higher in elderly pagetic patients; however, this difference was not clinically significant.
Use: Labeled Indications
Treatment of Paget's disease of the bone (osteitis deformans) in patients who have a level of serum alkaline phosphatase (SAP) at least twice the upper limit of normal, or who are symptomatic, or who are at risk for future complications of their disease
Hypersensitivity to tiludronate, bisphosphonates, or any component of the formulation; inability to stand or sit upright for at least 30 minutes
Note: Skelid has been discontinued in the US for more than 1 year.
Paget's disease: Oral: 400 mg (2 tablets of tiludronic acid) daily for a period of 3 months
Refer to adult dosing.
Dosing: Renal Impairment
No dosage adjustment provided in manufacturer’s labeling. However, tiludronate is excreted renally. It is not recommended for use in patients with severe renal impairment (CrCl <30 mL/minute) and is not removed by dialysis.
Dosing: Hepatic Impairment
No dosage adjustment necessary.
Administer as a single oral dose, take with 6-8 oz of plain water. Should not be taken with beverages containing minerals (eg, mineral water), food, or with other medications (may reduce absorption). Do not take within 2 hours of food. Take calcium or mineral supplements at least 2 hours before or after tiludronate. Take aluminum- or magnesium-containing antacids at least 2 hours after taking tiludronate. Patients should be instructed to stay upright (not to lie down) for at least 30 minutes and until after first food of the day (to reduce esophageal irritation).
Do not take within 2 hours of food. Ensure adequate intake of vitamin D and calcium supplements during treatment.
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Do not remove tablets from foil strips until they are to be used.
Aminoglycosides: May enhance the hypocalcemic effect of Bisphosphonate Derivatives. Monitor therapy
Antacids: May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of antacids containing polyvalent cations within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Exceptions: Magaldrate; Sodium Bicarbonate. Consider therapy modification
Aspirin: May decrease the serum concentration of Tiludronate. Monitor therapy
Calcium Salts: May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of oral calcium supplements within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Consider therapy modification
Deferasirox: Bisphosphonate Derivatives may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy
Indomethacin: May increase the serum concentration of Tiludronate. Consider therapy modification
Iron Salts: May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of oral iron supplements within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Exceptions: Ferric Carboxymaltose; Ferric Gluconate; Ferric Hydroxide Polymaltose Complex; Ferric Pyrophosphate Citrate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Consider therapy modification
Magnesium Salts: May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of oral magnesium salts within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Consider therapy modification
Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Bisphosphonate Derivatives. Specifically, polyvalent cation-containing multivitamins may decrease the absorption of orally-administered bisphosphonate derivatives. Management: Avoid administration of polyvalent cation-containing multivitamins within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Consider therapy modification
Multivitamins/Minerals (with AE, No Iron): May decrease the serum concentration of Bisphosphonate Derivatives. Specifically, polyvalent cation-containing multivitamins may decrease the absorption of orally-administered bisphosphonate derivatives. Management: Avoid administration of polyvalent cation-containing multivitamins within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Consider therapy modification
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. Monitor therapy
Proton Pump Inhibitors: May diminish the therapeutic effect of Bisphosphonate Derivatives. Monitor therapy
Systemic Angiogenesis Inhibitors: May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Monitor therapy
Bisphosphonates may interfere with diagnostic imaging agents such as technetium-99m-diphosphonate in bone scans.
1% to 10%:
Cardiovascular: Chest pain (3%), edema (3%), peripheral edema (3%), flushing, hypertension, syncope
Central nervous system: Anxiety, fatigue, insomnia, nervousness, somnolence, vertigo
Dermatologic: Rash (3%), skin disorder (3%), pruritus
Endocrine & metabolic: Hyperparathyroidism (3%)
Gastrointestinal: Nausea (9%), diarrhea (9%), dyspepsia (5%), vomiting (4%), flatulence (3%), abdominal pain, anorexia, constipation, gastritis, xerostomia
Genitourinary: Urinary tract infection
Neuromuscular & skeletal: Paresthesia (4%), arthrosis (3%), fractures, muscle spasm, weakness
Ocular: Cataract (3%), conjunctivitis (3%), glaucoma (3%)
Respiratory: Rhinitis (5%), sinusitis (5%), pharyngitis (3%), bronchitis
Miscellaneous: Accidental injury (4%), infection (3%), diaphoresis
<1% (Limited to important or life-threatening): Musculoskeletal pain (sometimes severe and/or incapacitating), osteonecrosis (primarily of the jaw), Stevens-Johnson syndrome
Concerns related to adverse effects:
• Bone/joint/muscle pain: Infrequently, 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 same drug or another bisphosphonate; avoid use in patients with a history of these symptoms in association with bisphosphonate therapy.
• Gastrointestinal mucosa irritation: May cause irritation to upper gastrointestinal 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.
• Osteonecrosis of the jaw (ONJ): According to a position paper by the American Association of Maxillofacial Surgeons (AAOMS), medication-related osteonecrosis of the jaw (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. 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]).
• Renal impairment: Use with caution in patients with mild-to-moderate renal impairment (not recommended in patients with a CrCl <30 mL/minute).
Alkaline phosphatase; pain; serum calcium and 25(OH)D
Pregnancy Risk Factor
Adverse events were observed in some animal reproduction studies. It is not known if bisphosphonates cross the placenta, but fetal exposure is expected (Djokanovic, 2008; Stathopoulos, 2011). Bisphosphonates are incorporated into the bone matrix and gradually released over time. The amount available in the systemic circulation varies by dose and duration of therapy. Theoretically, there may be a risk of fetal harm when pregnancy follows the completion of therapy; however, available data have not shown that exposure to bisphosphonates during pregnancy significantly increases the risk of adverse fetal events (Djokanovic, 2008; Levy, 2009; Stathopoulos, 2011). Until additional data is available, most sources recommend discontinuing bisphosphonate therapy in women of reproductive potential as early as possible prior to a planned pregnancy; use in premenopausal women should be reserved for special circumstances when rapid bone loss is occurring (Bhalla, 2010; Pereira, 2012; Stathopoulos, 2011). Because hypocalcemia has been described following in utero bisphosphonate exposure, exposed infants should be monitored for hypocalcemia after birth (Djokanovic, 2008; Stathopoulos, 2011).
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience rhinitis, nausea, vomiting, or diarrhea. Have patient report immediately to prescriber black, tarry, or bloody stools; angina; dysphagia; painful swallowing; pharyngitis; heartburn; vomiting blood; severe abdominal pain; severe bone pain; severe joint pain; severe muscle pain; groin, hip, or thigh pain; burning or numbness feeling; swelling of hands or feet; vision changes; or jaw pain or edema (HCAHPS).
• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.