Zoledronic Acid (Zometa®, Reclast®) | OncoLink

Author: Karen Arnold-Korzeniowski, BSN RN

Read more about our content writing process

Last Reviewed: August 5, 2021

Pronounced: ZOE-le-DRON-ik AS-id

Classification: bisphosphonate

About: Zoledronic Acid (Zometa®, Reclast®)

Zoledronic acid is a type of medication called a bisphosphonate, which is used to slow the destruction of bone caused by cancer cells. Cancer cells from some tumors (most commonly breast, prostate and lung cancers) can spread to the bone, which is called bone metastasis. Multiple myeloma is a type of cancer affecting plasma cells, which are found in the bone marrow, and thus directly involves bone. In both of these situations, the cancer cells cause breakdown or wearing away of normal bone. In turn, affected bones become more fragile; they may be painful and can even break due to the damage from the cancer cells.  

How to Take Zoledronic Acid

Zoledronic acid is administered intravenously (IV, into a vein). Your dose, and how often you receive it, will be determined by your provider. Your healthcare provider may prescribe you calcium and vitamin D supplements to promote bone health.

You will have lab work done to monitor your electrolytes during treatment. Your creatinine level (indicator of your kidney function) will be monitored closely to determine if the medication is affecting your kidneys. If it is, the dose may be altered or the medication stopped completely.

Possible Side Effects of Zoledronic Acid

There are a number of things you can do to manage the side effects of zoledronic acid. Talk to your care team about these recommendations. They can help you decide what will work best for you. These are some of the most common or important side effects:

Nausea and/or Vomiting

Talk to your doctor or nurse so they can prescribe medications to help you manage nausea and vomiting. In addition, dietary changes may help. Avoid things that may worsen the symptoms, such as heavy or greasy/fatty, spicy or acidic foods (lemons, tomatoes, oranges). Try antacids, (e.g. milk of magnesia, calcium tablets such as Tums), saltines, or ginger ale to lessen symptoms.

Call your doctor or nurse if you are unable to keep fluids down for more than 12 hours or if you feel lightheaded or dizzy at any time.

Low Red Blood Cell Count (Anemia)

Your red blood cells are responsible for carrying oxygen to the tissues in your body. When the red cell count is low, you may feel tired or weak. You should let your oncology care team know if you experience any shortness of breath, difficulty breathing or pain in your chest. If the count gets too low, you may receive a blood transfusion. 

Bone, Joint, and Muscle Pain

Zoledronic acid can cause bone, joint and/or muscle pain that can be severe. This can occur from 1 day to several months after starting the medication. Report these symptoms to your provider, who can advise you on strategies to relieve the pain. Pain in the hip, thigh, and groin can be caused by an atypical femur fracture. Notify your provider immediately of any new pain in this area. 

Fatigue

Fatigue is very common during cancer treatment and is an overwhelming feeling of exhaustion that is not usually relieved by rest. While on cancer treatment, and for a period after, you may need to adjust your schedule to manage fatigue. Plan times to rest during the day and conserve energy for more important activities. Exercise can help combat fatigue; a simple daily walk with a friend can help. Talk to your healthcare team for helpful tips on dealing with this side effect.

Breathing Difficulties

Bronchoconstriction is the constriction of the lung airways caused by muscle tightening. Patients who are sensitive to aspirin may have bronchoconstriction related to zoledronic acid. Notify your provider of any trouble breathing, tightness in the chest or wheezing. 

Less common but important side effects can include:

• Osteonecrosis of the Jaw: Osteonecrosis of the jaw (ONJ) is a rare side effect, however, it is important that you know about it and take steps to protect your dental health. The maxilla (upper jaw bone) and mandible (lower jaw bone) are normally covered by gum tissue. In the case of ONJ, this tissue disappears and the bone is exposed. Typical symptoms associated with ONJ are: pain, swelling or infection of the gums, loosening of the teeth, exposed bone (often at the site of a previous tooth extraction). Some patients may report numbness or tingling in the jaw or a “heavy” feeling jaw. ONJ may have no symptoms for weeks or months and may only be recognized by the presence of exposed bone. ONJ most often occurs soon after a dental procedure, though not always. Stop treatment with zoledronic acid at least 3 weeks prior to any dental procedures.
  • Prior to starting therapy, you should have a complete dental exam, cleaning, and removal of any teeth in poor health.
  • Dentures should be checked for proper fit.
  • Brush your teeth after meals and at bedtime with a soft brush. Floss gently once a day. If your gums bleed, talk with your healthcare team to see if you can continue to floss.
  • Check your teeth and gums in a mirror daily for any sores, swelling, loose teeth, pain or numbness, or other changes and report these to your dentist or oncology team immediately.
• Acute Reaction: The infusion can cause a reaction that occurs within 3 days of the infusion and may cause chills, fever and muscle aches. Prior to taking any medications, check with your healthcare provider as these can also be signs of infection. If you are able to take anti-inflammatory medications, such as ibuprofen (Motrin) and naproxen (Aleve), they may be helpful in treating these side effects. Reactions are most common during or shortly after the first infusion, but not after subsequent doses.
• Kidney problems: This medication can cause kidney problems, including an increased creatinine level, which your oncology care team may monitor for using blood tests. Notify your healthcare provider if you notice decreased urine output, blood in the urine, swelling in the ankles, or loss of appetite.
• Hypocalcemia: This medication can lower your calcium levels. Your healthcare team will monitor your calcium levels with blood tests. If you experience muscle cramps or confusion, contact your healthcare team.

Reproductive Concerns

Exposure of an unborn child to this medication could cause birth defects, so you should not become pregnant or father a child while on this medication. Effective birth control is necessary during treatment. Even if your menstrual cycle stops or you believe you are not producing sperm, you could still be fertile and conceive. You should consult with your healthcare team before breastfeeding while receiving this medication.

Zoledronate – StatPearls – NCBI Bookshelf

Continuing Education Activity

Zoledronate, also known as zoledronic acid, is an example of a class of drugs known as bisphosphonates. It is a bisphosphonate that is administered intravenously. This medication is used to treat many forms of metabolic bone disease. Zoledronate is broadly classified as an antiresorptive medication. Zoledronate is a commonly prescribed agent that is approved and indicated for both benign and malignant bone disorders. This activity outlines the indications, actions, and contraindications for zoledronate. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, monitoring) pertinent for members of a healthcare team to utilize in the treatment of patients on zoledronate.

Objectives:

• Outline the indications for the use of zoledronate.

• Review the mechanism of action of zoledronate.

• Describe adverse reactions associated with zoledronate.

• Summarize the contraindications and monitoring needed for zoledronate.

Access free multiple choice questions on this topic.

Indications

Zoledronate, also known as zoledronic acid, is an intravenous (IV) medication that belongs to a class of drugs known as bisphosphonates. It is an antiresorptive therapy used to treat various bone conditions, including both malignant and benign diseases.[1]

Food and drug administration (FDA) approved indications for this agent include the prevention and treatment of osteoporosis in postmenopausal females, osteoporosis in males, glucocorticoid-induced osteoporosis, Paget disease of bone, hypercalcemia of malignancy, multiple myeloma, and solid tumor bone metastases.[2][3][4][5][6][7][8]

Non-FDA-approved indications include adjuvant therapy in breast cancer, bone loss in postmenopausal patients related to aromatase inhibitor therapy, and bone loss related to androgen deprivation therapy. [9][10]

As zoledronate is administered intravenously, it can be used in patients with an intolerance or contraindication to oral bisphosphonates. It is the treatment of choice for Paget disease of bone and hypercalcemia of malignancy. Using zoledronate as initial therapy in preventing postmenopausal osteoporosis is also appropriate in patients with very high fracture risk.[2][11]

The American Association of Clinical Endocrinologists defined very high fracture risk in the 2020 postmenopausal osteoporosis guideline. A patient is said to be at a very high fracture risk if at least one of the following is present, including

1. Postmenopausal with a history of multiple fractures

2. The presence of a fracture within the preceding 12 months

3. Fracture(s) despite being on appropriate osteoporosis treatment

4. Fracture while on a drug known to cause skeletal harm

5. T-score less than -3.0

6. High fall risk, history of a fall resulting in an injury, or a very high risk of a fracture using a validated fracture risk algorithm[2]

Mechanism of Action

An integral step in new bone formation is the avid binding of inorganic pyrophosphate (PPi) to hydroxyapatite crystals found in bone. Nitrogen-containing bisphosphonates such as zoledronate are PPi analogs with a higher binding affinity. These bisphosphonates, therefore, preferentially bind to bone, especially at sites that are being actively remodeled. The bone-bound bisphosphonates are released during the process of bone breakdown by osteoclasts.

Once released, the bisphosphonate is then absorbed by osteoclasts. Within the osteoclasts, the bisphosphonate binds to and blocks the activity of farnesyl diphosphate synthase (FPPS). FPPS is an essential intracellular enzyme in the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase pathway responsible for producing isoprenoid lipids, cholesterol, and other sterols. Inhibition of this pathway prevents the posttranslational modification of small proteins, including guanosine triphosphate binding proteins, which are needed for the activity and survival of osteoclasts.

Therefore, the administration of zoledronate increases osteoclast apoptosis, thus reducing bone resorption and loss. Osteoblastic activity and bone formation are not impacted by the use of zoledronate. Hence the use of this agent shifts bone metabolic activity in favor of bone formation, reducing bone loss. This ultimately leads to an increase in bone mass and bone density as bone formation exceeds resorption.[12]

Administration

Zoledronate is administered in the following manner:

Dose adjustments may be necessary for patients with renal dysfunction and are as follows:

Adverse Effects

Adverse effects associated with zoledronate include hypocalcemia, secondary hyperparathyroidism, musculoskeletal pain, acute phase response, renal injury, atypical femur fractures, osteonecrosis of the jaw, atrial fibrillation, and ocular inflammation.[17][18]

All bisphosphonates can cause hypocalcemia and secondary hyperparathyroidism; IV formulations such as zoledronate are more prone to cause these adverse effects. Normal serum calcium is largely maintained by a balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. The mechanism behind hypocalcemia and secondary hyperparathyroidism from zoledronate use relates to its actions on the osteoclasts.

Zoledronate halts bone resorption and calcium release by osteoclasts, resulting in hypocalcemia. To conserve calcium, parathyroid hormone (PTH) levels increase and antagonize the actions of zoledronate by acting at the level of the kidneys. The increase in PTH and a decrease in both serum phosphorus and calcium are dose-dependent. In the kidneys, PTH stimulates the production of 1,25-dihydroxy vitamin D, and tubular reabsorption of calcium is increased. Over time bisphosphonate-induced hypocalcemia will typically abate.

However, symptomatic hypocalcemia can occur and would be seen within days of zoledronate administration. Risk factors for symptomatic hypocalcemia include renal failure, vitamin D deficiency, and preexisting hypoparathyroidism. To reduce this risk, supplementation with calcium and vitamin D with the use of zoledronate is recommended. Supplementation should begin at least two weeks before zoledronate administration.[17]

Musculoskeletal pain, including myalgias and arthralgia, has been reported after zoledronate therapy. This adverse effect has been said to occur at varying time points following treatment, ranging from days to years. The mechanism behind this effect is not understood.[17][18]

An acute phase response (APR) with arthralgias, myalgias, pyrexia, chills, and fatigue has been described – this is described as a post-infusion influenza-like illness. This adverse effect is most common following the first infusion, with the frequency and incidence of APR decreasing with subsequent infusions. Symptoms begin approximately 24 to 72 hours following the infusion and resolve within 72 hours.

APR is often self-limiting, though symptomatic treatment with non-steroidal anti-inflammatory drugs or acetaminophen is recommended. Recent data suggest that the coadministration of zoledronate with acetaminophen may reduce the risk of APR in half. The risk of APR may be influenced by the underlying indication for which treatment was initiated.[17][18]

APR is thought to be mediated by high levels of pro-inflammatory cytokines, including interleukin-6 and tumor necrosis factor-alpha. A study looking at patients receiving treatment for aromatase inhibitor-associated osteoporosis noted that APR was around 70%. A large study looking at APR after using zoledronate in women with post-menopausal osteoporosis revealed the incidence to be approximately 40%.[19][20]

The most common form of renal injury following zoledronate administration is acute tubular necrosis (ATN). Risk factors for the development of ATN have been described and include rapid infusions, shorter time intervals between infusions, and higher doses.[18]

Observational studies have demonstrated a risk between long-term zoledronate use and subtrochanteric or atypical femur fractures. These atypical fractures are located between the diaphysis and subtrochanteric region of the femur. These fractures occur with minimal to no trauma and can be bilateral. Symptoms include aching or dull pain in the thigh or groin. Certain comorbid conditions and medications have been associated with a further increase in the risk, including vitamin D deficiency, rheumatoid arthritis, and corticosteroid use. This risk can be decreased with the use of zoledronate holidays.[21][22]

Zoledronate-induced osteonecrosis of the jaw (ONJ) has been extensively described. This relationship seems to be influenced by both the dose and indication for which the medication is prescribed. Treatment of bone metastasis and multiple myeloma with zoledronate 4 mg IV every 3 to 4 weeks carries a higher risk when compared to the treatment of osteoporosis. Other factors, including head/neck radiation, dental disease, and dental procedures with bone manipulation, are also known to increase the risk of the development of ONJ.[17][18]

Atrial fibrillation has also been reported following zoledronate administration. The data regarding this complication is not as robust as other complications, but studies have shown that zoledronate may modestly increase the risk for atrial fibrillation.[23]

Ocular manifestations have been linked to zoledronate therapy. This includes conjunctivitis, scleritis, and uveitis. Overall these reactions appear to be uncommon but warrant prompt evaluation. Thus, patients receiving zoledronate and experiencing changes in vision, eye pain, or eye redness should be evaluated by an ophthalmologist.[17][18]

Contraindications

The contraindications to using zoledronate depend on the nature and type of disease being treated.

Hypocalcemia, acute kidney injury, or creatinine clearance (CrCl) less than or equal to 35 mL/minute are contraindications for use in benign bone disease.[24] In the treatment of hypercalcemia of malignancy, the use of zoledronate should be avoided in patients with serum creatinine greater than 4.5 mg/dL.[25] 

Minimal data exist regarding treating solid tumor bone metastasis patients with a CrCl of less than 30 mL/min. Therefore caution is necessary for this patient group.[26]

A history of allergic reaction to zoledronate is also a contraindication. This contraindication applies to all indications of zoledronate use.

Zoledronate is pregnancy category D and should be avoided during pregnancy, and caution is necessary for women of childbearing age.

Monitoring

The following labs should be checked before each infusion: renal function and clearance, vitamin d, calcium, magnesium, and phosphorus. Electrolyte imbalances and vitamin D deficiency should be corrected before treatment is initiated.[2]

In patients receiving treatment for osteoporosis, periodic monitoring of bone mineral density should be completed to check for treatment response and effectiveness.[2]

In patients receiving treatment for Paget disease of bone, alkaline phosphatase requires periodic monitoring.[5]

In patients receiving treatment for multiple myeloma, periodic monitoring for albuminuria is required. [7]

Toxicity

In the event of toxicity or overdose, there are no reversal agents approved by the FDA for this drug.

Enhancing Healthcare Team Outcomes

Zoledronate is a versatile medication that helps prevent morbidity and mortality in various conditions. It is used in different medical and surgical specialties. As it is an infused therapy, patients often receive this treatment in a healthcare facility. Interprofessional collaboration is vital to providing safe and effective care with this medication.

Counseling patients regarding potential side effects of zoledronate begins with the physician. Pharmacists play an integral role in checking for drug interactions. Nurses infuse this medication and monitor for adverse reactions. This approach requires collaboration from all healthcare team members and can help ensure our patients are given optimal treatment. 

The safety of patients receiving treatment with zoledronate relies on the prescriber’s knowledge of the contraindications, monitoring, and dose adjustments required when using this medication. For this medication, each indication has different parameters for each of these categories. Careful attention to these details is needed for each patient care team member. 

Healthcare costs and the appropriate utilization of healthcare resources are of utmost importance. When making decisions regarding patient care, one must ensure that when selecting a treatment option, all aspects of the patient are considered. Many treatment options for osteoporosis are available, and when zoledronate is selected as therapy, patients receive this medication in a healthcare facility intravenously.

This medication requires more invasive procedures for administration compared to its oral counterparts. Also, as it is administered under direct supervision in a healthcare facility, the total healthcare cost is higher than other options. These factors should not deter prescribers from utilizing this treatment option, but appropriate patient selection is required for this drug to have the most benefit. [Level 5] 

Review Questions

• Access free multiple choice questions on this topic.

• Comment on this article.

References

1.

Reid IR, Green JR, Lyles KW, Reid DM, Trechsel U, Hosking DJ, Black DM, Cummings SR, Russell RGG, Eriksen EF. Zoledronate. Bone. 2020 Aug;137:115390. [PubMed: 32353565]

2.

Camacho PM, Petak SM, Binkley N, Diab DL, Eldeiry LS, Farooki A, Harris ST, Hurley DL, Kelly J, Lewiecki EM, Pessah-Pollack R, McClung M, Wimalawansa SJ, Watts NB. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS/AMERICAN COLLEGE OF ENDOCRINOLOGY CLINICAL PRACTICE GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS-2020 UPDATE. Endocr Pract. 2020 May;26(Suppl 1):1-46. [PubMed: 32427503]

3.

Qaseem A, Forciea MA, McLean RM, Denberg TD, Clinical Guidelines Committee of the American College of Physicians. Barry MJ, Cooke M, Fitterman N, Harris RP, Humphrey LL, Kansagara D, McLean RM, Mir TP, Schünemann HJ. 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. Ann Intern Med. 2017 Jun 06;166(11):818-839. [PubMed: 28492856]

4.

Chotiyarnwong P, McCloskey EV. Pathogenesis of glucocorticoid-induced osteoporosis and options for treatment. Nat Rev Endocrinol. 2020 Aug;16(8):437-447. [PubMed: 32286516]

5.

Kravets I. Paget’s Disease of Bone: Diagnosis and Treatment. Am J Med. 2018 Nov;131(11):1298-1303. [PubMed: 29752905]

6.

Chakhtoura M, El-Hajj Fuleihan G. Treatment of Hypercalcemia of Malignancy. Endocrinol Metab Clin North Am. 2021 Dec;50(4):781-792. [PubMed: 34774248]

7.

Anderson K, Ismaila N, Flynn PJ, Halabi S, Jagannath S, Ogaily MS, Omel J, Raje N, Roodman GD, Yee GC, Kyle RA. Role of Bone-Modifying Agents in Multiple Myeloma: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2018 Mar 10;36(8):812-818. [PubMed: 29341831]

8.

von Moos R, Sternberg C, Body JJ, Bokemeyer C. Reducing the burden of bone metastases: current concepts and treatment options. Support Care Cancer. 2013 Jun;21(6):1773-83. [PubMed: 23468364]

9.

Pineda-Moncusí M, Garcia-Giralt N, Diez-Perez A, Servitja S, Tusquets I, Prieto-Alhambra D, Nogués X. Increased Fracture Risk in Women Treated With Aromatase Inhibitors Versus Tamoxifen: Beneficial Effect of Bisphosphonates. J Bone Miner Res. 2020 Feb;35(2):291-297. [PubMed: 31596961]

10.

Eastham JA. Bone health in men receiving androgen deprivation therapy for prostate cancer. J Urol. 2007 Jan;177(1):17-24. [PubMed: 17161994]

11.

Ganesan K, Goyal A, Roane D. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Sep 5, 2022. Bisphosphonate. [PubMed: 29262103]

12.

Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc. 2008 Sep;83(9):1032-45. [PMC free article: PMC2667901] [PubMed: 18775204]

13.

Van Poznak C, Somerfield MR, Barlow WE, Biermann JS, Bosserman LD, Clemons MJ, Dhesy-Thind SK, Dillmon MS, Eisen A, Frank ES, Jagsi R, Jimenez R, Theriault RL, Vandenberg TA, Yee GC, Moy B. Role of Bone-Modifying Agents in Metastatic Breast Cancer: An American Society of Clinical Oncology-Cancer Care Ontario Focused Guideline Update. J Clin Oncol. 2017 Dec 10;35(35):3978-3986. [PubMed: 29035643]

14.

Saylor PJ, Rumble RB, Tagawa S, Eastham JA, Finelli A, Reddy PS, Kungel TM, Nissenberg MG, Michalski JM. Bone Health and Bone-Targeted Therapies for Prostate Cancer: ASCO Endorsement of a Cancer Care Ontario Guideline. J Clin Oncol. 2020 May 20;38(15):1736-1743. [PubMed: 31990618]

15.

Shapiro CL, Van Poznak C, Lacchetti C, Kirshner J, Eastell R, Gagel R, Smith S, Edwards BJ, Frank E, Lyman GH, Smith MR, Mhaskar R, Henderson T, Neuner J. Management of Osteoporosis in Survivors of Adult Cancers With Nonmetastatic Disease: ASCO Clinical Practice Guideline. J Clin Oncol. 2019 Nov 01;37(31):2916-2946. [PubMed: 31532726]

16.

Eisen A, Somerfield MR, Accordino MK, Blanchette PS, Clemons MJ, Dhesy-Thind S, Dillmon MS, D’Oronzo S, Fletcher GG, Frank ES, Hallmeyer S, Makhoul I, Moy B, Thawer A, Wu JY, Van Poznak CH. Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: ASCO-OH (CCO) Guideline Update. J Clin Oncol. 2022 Mar 01;40(7):787-800. [PubMed: 35041467]

17.

Pazianas M, Abrahamsen B. Safety of bisphosphonates. Bone. 2011 Jul;49(1):103-10. [PubMed: 21236370]

18.

Papapetrou PD. Bisphosphonate-associated adverse events. Hormones (Athens). 2009 Apr-Jun;8(2):96-110. [PubMed: 19570737]

19.

Santini D, Vincenzi B, Caraglia M, Tonini G. A hitherto unreported high incidence of zoledronic acid-induced acute phase reaction in patients with cancer treatment-induced bone loss. Ann Oncol. 2007 Jan;18(1):201-202. [PubMed: 17021272]

20.

Reid IR, Gamble GD, Mesenbrink P, Lakatos P, Black DM. Characterization of and risk factors for the acute-phase response after zoledronic acid. J Clin Endocrinol Metab. 2010 Sep;95(9):4380-7. [PubMed: 20554708]

21.

Rudran B, Super J, Jandoo R, Babu V, Nathan S, Ibrahim E, Wiik AV. Current concepts in the management of bisphosphonate associated atypical femoral fractures. World J Orthop. 2021 Sep 18;12(9):660-671. [PMC free article: PMC8472443] [PubMed: 34631450]

22.

Shane E, Burr D, Abrahamsen B, Adler RA, Brown TD, Cheung AM, Cosman F, Curtis JR, Dell R, Dempster DW, Ebeling PR, Einhorn TA, Genant HK, Geusens P, Klaushofer K, Lane JM, McKiernan F, McKinney R, Ng A, Nieves J, O’Keefe R, Papapoulos S, Howe TS, van der Meulen MC, Weinstein RS, Whyte MP. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2014 Jan;29(1):1-23. [PubMed: 23712442]

23.

Kim DH, Rogers JR, Fulchino LA, Kim CA, Solomon DH, Kim SC. Bisphosphonates and risk of cardiovascular events: a meta-analysis. PLoS One. 2015;10(4):e0122646. [PMC free article: PMC4401508] [PubMed: 25884398]

24.

Lyles KW, Colón-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S., HORIZON Recurrent Fracture Trial. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007 Nov 01;357(18):1799-809. [PMC free article: PMC2324066] [PubMed: 17878149]

25.

Kawada K, Minami H, Okabe K, Watanabe T, Inoue K, Sawamura M, Yagi Y, Sasaki T, Takashima S. A multicenter and open label clinical trial of zoledronic acid 4 mg in patients with hypercalcemia of malignancy. Jpn J Clin Oncol. 2005 Jan;35(1):28-33. [PubMed: 15681601]

26.

Khalafallah AA, Slancar M, Cosolo W, Abdi E, Chern B, Woodfield RJ, Copeman MC. Long-term safety of monthly zoledronic acid therapy beyond 1 year in patients with advanced cancer involving bone (LoTESS): A multicentre prospective phase 4 study. Eur J Cancer Care (Engl). 2018 Mar;27(2):e12638. [PMC free article: PMC5901400] [PubMed: 28134499]

Disclosure: Emma Greear declares no relevant financial relationships with ineligible companies.

Disclosure: Adegbenga Bankole declares no relevant financial relationships with ineligible companies.

Zoledronic acid for osteoporosis and low-energy fractures that complicate its course | Rodionova

1. Russell R.G. Bisphosphonates: the first 40 years. Bone. 2011;49(1):2–19. https://doi.org/10.1016/j.bone.2011.04.022.

2. Rogers M.J., Mönkkönen J., Munoz M.A. Molecular mechanisms of action of bisphosphonates and new insights into their effects outside the skeleton. Bone. 2020;139:115493. https://doi.org/10.1016/j.bone.2020.115493.

3. Pazianas M., van der Geest S., Miller P. Bisphosphonates and bone quality. Bonekey Rep. 2014;3:529. https://doi.org/10.1038/bonekey.2014.24.

4. Cui P., Liu H., Sun J., Amizuka N., Sun Q., Li M. Zoledronate promotes bone formation by blocking osteocyte-osteoblast communication during bone defect healing. Histol Histopathol. 2018;33(1):89–99. https://doi.org/10.14670/HH-11-893.

5. Dhillon S. Zoledronic Acid (Reclast®, Aclasta®): A review in osteoporosis. drugs. 2016;76(17):1683–1697. https://doi.org/10.1007/s40265-016-0662-4.

6. Takimoto R., Suzawa T., Yamada A., Sasa K., Miyamoto Y., Yoshimura K. et al. Zoledronate promotes inflammatory cytokine expression in human CD14-positive monocytes among peripheral mononuclear cells in the presence of γδ T cells. Immunology. 2021;162(3):306–313. https://doi.org/10.1111/imm.13283.

7. Recker R.R., Delmas P.D., Halse J., Reid I.R., Boonen S. , Garcia-Hernandez P.A. et al. Effects of intravenous zoledronic acid once yearly on bone remodeling and bone structure. J Bone Miner Res. 2008;23(1):6–16. https://doi.org/10.1359/jbmr.070906.

8. Black D.M., Delmas P.D., Eastell R., Reid I.R., Boonen S., Cauley J.A. et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356(18):1809–1822. https://doi.org/10.1056/NEJMoa067312.

9. Delmas P.D., Munoz F., Black D.M., Cosman F., Boonen S., Watts N.B. et al. Effects of yearly zoledronic acid 5 mg on bone turnover markers and relation of PINP with fracture reduction in postmenopausal women with osteoporosis. J Bone Miner Res. 2009;24(9):1544–1551. https://doi.org/10.1359/jbmr.090310.

10. Saag K., Lindsay R., Kriegman A., Beamer E., Zhou W. A single zoledronic acid infusion reduces bone resorption markers more rapidly than weekly oral alendronate in postmenopausal women with low bone mineral density. Bone. 2007;40(5):1238–1243. https://doi.org/10.1016/j.bone.2007.01.016.

11. Black D.M., Reid I.R., Boonen S., Bucci-Rechtweg C., Cauley J.A., Cosman F. et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 2012;27(2):243–254. https://doi.org/10.1002/jbmr.1494.

12. Black D.M., Reid I.R., Cauley J.A., Cosman F., Leung P.C., Lakatos P. et al. The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 2015;30(5):934–944. https://doi.org/10.1002/jbmr.2442.

13. Jacques R.M., Boonen S., Cosman F., Reid I.R., Bauer D.C., Black D.M., Eastell R. Relationship of changes in total hip bone mineral density to vertebral and nonvertebral fracture risk in women with postmenopausal osteoporosis treated with once -yearly zoledronic acid 5 mg: the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 2012;27(8):1627–1634. https://doi.org/10.1002/jbmr.1644.

14. Shuai B., Shen L., Yang Y., Ma C., Zhu R., Xu X. Assessment of the impact of zoledronic acid on ovariectomized osteoporosis model using micro-CT scanning. PLOS ONE. 2015;10(7):e0132104. https://doi.org/10.1371/journal.pone.0132104.

15. Burket J.C., Brooks D.J., MacLeay J.M., Baker S.P., Boskey A.L., van der Meulen M.C. Variations in nanomechanical properties and tissue composition within trabeculae from an ovine model of osteoporosis and treatment. Bone. 2013;52(1):326–36. https://doi.org/10.1016/j.bone.2012.10.018.

16. Gamsjaeger S., Buchinger B., Zwettler E., Recker R., Black D., Gasser J.A. et al Bone material properties in actively bone-forming trabeculae in postmenopausal women with osteoporosis after three years of treatment with once-yearly zoledronic acid. J Bone Miner Res. 2011;26(1):12–18. https://doi.org/10.1002/jbmr.180.

17. Gamsjaeger S., Hofstetter B., Zwettler E. , Recker R., Gasser J.A., Eriksen E.F. et al. Effects of 3 years treatment with once-yearly zoledronic acid on the kinetics of bone matrix maturation in osteoporotic patients. Osteoporos Int. 2013;24(1):339–347. https://doi.org/10.1007/s00198-012-2202-8.

18. Nakamura T., Fukunaga M., Nakano T., Kishimoto H., Ito M., Hagino H. et al. Efficacy and safety of once-yearly zoledronic acid in Japanese patients with primary osteoporosis: two-year results from a randomized placebocontrolled double-blind study (ZOledroNate treatment in Efficacy to osteoporosis; ZONE study). Osteoporos Int. 2017;28(1):389–398. https://doi.org/10.1007/s00198-016-3736-y.

19. Wang C. Efficacy and safety of zoledronic acid for treatment of postmenopausal osteoporosis: a meta-analysis of randomized controlled trials. Am J Ther. 2017;24(5):e544–e552. https://doi.org/10.1097/MJT.0000000000000415.

20. Anagnostis P., Stevenson J.C. Bisphosphonate drug holidays – when, why and for how long? Climacteric. 2015;18(Suppl. 2):32–38. https://doi.org/10.3109/13697137.2015.1099092.

21. Anagnostis P., Paschou S.A., Mintziori G., Ceausu I., Depypere H., Lambrinoudaki I. et al. Drug holidays from bisphosphonates and denosumab in postmenopausal osteoporosis: EMAS position statement. Maturitas. 2017;101:23–30. https://doi.org/10.1016/j.maturitas.2017.04.008.

22. Nayak S., Greenspan S.L. Cost-effectiveness of 3 versus 6 years of zoledronic acid treatment before bisphosphonate holiday for women with osteoporosis. Osteoporos Int. 2022;33(1):229–238. https://doi.org/10.1007/s00198-021-06010-5.

23. Ma S., Goh E.L., Jin A., Bhattacharya R., Boughton O.R., Patel B. et al. Longterm effects of bisphosphonate therapy: perforations, microcracks and mechanical properties. sci rep. 2017;7:43399. https://doi.org/10.1038/srep43399.

24. Lloyd A.A., Gludovatz B., Riedel C., Luengo E.A., Saiyed R., Marty E. et al. Atypical fracture with long-term bisphosphonate therapy is associated with altered cortical composition and reduced fracture resistance. Proc Natl Acad Sci U S A. 2017;114(33):8722–8727. https://doi.org/10.1073/pnas.1704460114.

25. Heo Y.M., Park S.E., Cha S.M., Shin H.D., Choi J.K. Diagnostic criteria and treatment of atypical ulnar fractures associated with advanced bisphosphonate therapy: multicenter case analysis. J Hand Surg Am. 2021:S0363–5023(21)00481-0. https://doi.org/10.1016/j.jhsa.2021.08.001.

26. Black D.M., Condra K., Adams A.L, Eastell R. Bisphosphonates and the risk of atypical femur fractures. Bone. 2022;156:116297. https://doi.org/10.1016/j.bone.2021.116297.

27. Black D.M., Abrahamsen B., Bouxsein M.L., Einhorn T., Napoli N. Atypical femur fractures: review of epidemiology, relationship to bisphosphonates, prevention, and clinical management. Endocr Rev. 2019;40(2):333–368. https://doi.org/10.1210/er.2018-00001.

28. Kim H.Y. Review and update of the risk factors and prevention of antiresorptive-related osteonecrosis of the jaw. Endocrinol Metab (Seoul). 2021;36(5):917–927. https://doi.org/10.3803/EnM.2021.1170.

29. Mavi E., Hocaoglu P.T. Effects of a single intravaneous dose of zoledronic acid on bone healing following tooth extraction in ovariectomized rabbits. Saudi Dent J. 2021;33(7):724–730. https://doi.org/10.1016/j.sdentj.2020.03.016.

30. Williams D.W., Lee C., Kim T., Yagita H., Wu H., Park S. et al. Impaired bone resorption and woven bone formation are associated with the development of osteonecrosis of the jaw-like lesions by bisphosphonate and anti-receptor activator of NF-κB ligand antibody in mice. Am J Pathol. 2014;184(11):3084–3093. https://doi.org/10.1016/j.ajpath.2014.07.010.

31. Everts-Graber J., Lehmann D., Burkard J.P., Schaller B., Gahl B., Häuselmann H. et al. Risk of osteonecrosis of the jaw under denosumab compared to bisphosphonates in patients with osteoporosis. J Bone Miner Res. 2022;37(2):340–348. https://doi.org/10.1002/jbmr.4472.

32. Yang G., Singh S., McDonough C.W., Lamba J.K., Hamadeh I. , Holliday L.S. et al. Genome-wide association study identified chromosome 8 locus associated with medication-related osteonecrosis of the jaw. Clin Pharmacol Ther. 2021;110(6):1558–1569. https://doi.org/10.1002/cpt.2397.

33. Yang G., Collins J.M., Rafiee R., Singh S., Langaee T., McDonough C.W. et al. SIRT1 gene SNP rs932658 is associated with drug-related osteonecrosis of the jaw. J Bone Miner Res. 2021;36(2):347–356. https://doi.org/10.1002/jbmr.4185.

34. Curtis J.R., Saag K.G., Arora T., Wright N.C., Yun H., Daigle S. et al. Duration of bisphosphonate drug holidays and associated fracture risk. medical care. 2020;58(5):419–426. https://doi.org/10.1097/MLR.0000000000001294.

35. Nayak S., Greenspan S.L. A systematic review and meta-analysis of the effect of bisphosphonate drug holidays on bone mineral density and osteoporotic fracture risk. Osteoporos Int. 2019;30(4):705–720. https://doi.org/10.1007/s00198-018-4791-3.

36. Naylor K.E., McCloskey E.V. , Jacques R.M., Peel N.F.A., Paggiosi M.A., Gossiel F. et al. Clinical utility of bone turnover markers in monitoring the withdrawal of treatment with oral bisphosphonates in postmenopausal osteoporosis. Osteoporos Int. 2019;30(4):917–922. https://doi.org/10.1007/s00198-018-04823-5.

37. Colón-Emeric C.S., Lee R.H. Bisphosphonate holidays: using cost-effectiveness analysis for the “yes, but” questions. Osteoporos Int. 2021;32(12):2389–2390. https://doi.org/10.1007/s00198-021-06064-5.

38. Hayes K.N., Winter E.M., Cadarette S.M., Burden A.M. Duration of bisphosphonate drug holidays in osteoporosis patients: a narrative review of the evidence and considerations for decision-making. J Clinic Med. 2021;10(5):1140. https://doi.org/10.3390/jcm10051140.

39. Boonen S., Black D.M., Colón-Emeric C.S., Eastell R., Magaziner J.S., Eriksen E.F. et al. Efficacy and safety of a once-yearly intravenous zoledronic acid 5 mg for fracture prevention in elderly postmenopausal women with osteoporosis aged 75 and older. J Am Geriatr Soc. 2010;58(2):292–299. https://doi.org/10.1111/j.1532-5415.2009.02673.x.

40. Eriksen E.F., Lyles K.W., Colón-Emeric C.S., Pieper C.F., Magaziner J.S., Adachi J.D. et al. Antifracture efficacy and reduction of mortality in relation to timing of the first dose of zoledronic acid after hip fracture. J Bone Miner Res. 2009;24(7):1308–1313. https://doi.org/10.1359/jbmr.090209.

41. Fu L.J., Tang T.T., Hao Y.Q., Dai K.R. Long-term effects of alendronate on fracture healing and bone remodeling of femoral shaft in ovariectomized rats. Acta Pharmacol Sin. 2013;34(3):387–392. https://doi.org/10.1038/aps.2012.170.

42. Hauser M., Siegrist M., Keller I., Hofstetter W. Healing of fractures in osteoporotic bones in mice treated with bisphosphonates – A transcriptome analysis. Bone. 2018;112:107–119. https://doi.org/10.1016/j.bone.2018.04.017.

43. He Y., Bao W., Wu X.D., Huang W., Chen H., Li Z. Effects of systemic or local administration of zoledronate on implant osseointegration: a preclinical meta-analysis. Biomed Res Int. 2019;2019:9541485. https://doi.org/10.1155/2019/9541485.

44. Gao Y., Liu X., Gu Y., Song D., Ding M., Liao L. et al. The effect of bisphosphonates on fracture healing time and changes in bone mass density: a meta-analysis. Front Endocrinol (Lausanne). 2021;12:688269. https://doi.org/10.3389/fendo.2021.688269.

45. Reid I.R., Horne A.M., Mihov B., Stewart A., Garratt E., Wong S. et al. Fracture prevention with zoledronate in older women with osteopenia. N Engl J Med. 2018;379(25):2407–2416. https://doi.org/10.1056/NEJMoa1808082.

46. McClung M., Miller P., Recknor C., Mesenbrink P., Bucci-Rechtweg C., Benhamou C.L. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. Obstet Gynecol. 2009;114(5):999–1007. https://doi.org/10.1097/ AOG.0b013e3181bdce0a.

47. Gennari L., Bilezikian J.P. New and developing pharmacotherapy for osteoporosis in men. Expert Opin Pharmacother. 2018;19(3):253–264. https://doi.org/10.1080/14656566.2018.1428559.

48. Orwoll E.S., Miller P.D., Adachi J.D., Brown J., Adler R.A., Kendler D. et al. Efficacy and safety of a once-yearly i.v. Infusion of zoledronic acid 5 mg versus a once-weekly 70-mg oral alendronate in the treatment of male osteoporosis: a randomized, multicenter, double-blind, active-controlled study. J Bone Miner Res. 2010;25(10):2239-2250. https://doi.org/10.1002/jbmr.119.

49. Boonen S., Reginster J.Y., Kaufman J.M., Lippuner K., Zanchetta J., Langdahl B. et al. Fracture risk and zoledronic acid therapy in men with osteoporosis. N Engl J Med. 2012;367(18):1714–1723. https://doi.org/10.1056/NEJMoa1204061.

50. Chiodini I., Merlotti D., Falchetti A., Gennari L. Treatment options for glucocorticoid-induced osteoporosis. Expert Opin Pharmacother. 2020;21(6):721–732. https://doi.org/10.1080/14656566.2020.1721467.

51. Allen C.S., Yeung J.H., Vandermeer B., Homik J. Bisphosphonates for steroidinduced osteoporosis. Cochrane Database Syst Rev. 2016;10(10):CD001347. https://doi.org/10.1002/14651858.CD001347.pub2.

52. Reid D.M., Devogelaer J.P., Saag K., Roux C., Lau C.S., Reginster J.Y. et al. Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, doubleblind, double-dummy, randomized controlled trial. Lancet. 2009;373(9671):1253–1263. https://doi.org/10.1016/S0140-6736(09)60250-6.

53. Raterman H.G., Bultink I.E., Lems W.F. Osteoporosis in patients with rheumatoid arthritis: an update in epidemiology, pathogenesis, and fracture prevention. Expert Opin Pharmacother. 2020;21(14):1725–1737. https://doi.org/10.1080/14656566.2020.1787381.

54. Xie J., Li S., Xiao L., Ouyang G., Zheng L., Gu Y. et al. Zoledronic acid ameliorates the effects of secondary osteoporosis in rheumatoid arthritis patients. J Orthop Surg Res. 2019;14(1):421. https://doi.org/10.1186/s13018-019-1492-3.

55. Jarrett S.J., Conaghan P. G., Sloan V.S., Papanastasiou P., Ortmann C.E., O’Connor P.J. et al. Preliminary evidence for a structural benefit of the new bisphosphonate zoledronic acid in early rheumatoid arthritis. Arthritis Rheum. 2006;54(5):1410–1414. https://doi.org/10.1002/art.21824.

56. Adami S., Giannini S., Bianchi G., Sinigaglia L., Di Munno O., Fiore C.E. et al. Vitamin D status and response to treatment in post-menopausal osteoporosis. Osteoporos Int. 2009;20(2):239–244. https://doi.org/10.1007/s00198-008-0650-y.

57. Rodionova S.S., Elovoi-Vronsky A.A., Bernakevich A.I. Alfacalcidol or cholecalciferol in combination with ibandronic acid in the treatment of postmenopausal systemic osteoporosis. Osteoporosis and osteopathy. 2014;(1):21–24. https://doi.org/10.14341/osteo2014121-24. Rodionova S.S., Elovoy-Vronskiy A.A., Bernakevich A.I. Alfacalcidol or cholecalciferol in combination with ibandronic acid in the treatment of postmenopausal systemic osteoporosis. Osteoporosis and Bone Diseases. 2014;(1):21–24. (In Russ.) https://doi.org/10.14341/osteo2014121-24.

58. Ozasa R., Saito M., Ishimoto T., Matsugaki A., Matsumoto Y., Nakano T. Combination treatment with ibandronate and eldecalcitol prevents osteoporotic bone loss and deterioration of bone quality characterized by nano-arrangement of the collagen /apatite in an ovariectomized aged rat model. Bone. 2022;157:116309. https://doi.org/10.1016/j.bone.2021.116309.

59. Khajuria D.K., Razdan R., Mahapatra D.R. Zoledronic acid in combination with alfacalcidol has additive effects on trabecular microarchitecture and mechanical properties in osteopenic ovariectomized rats. J Orthop Sci. 2014;19(4):646–656. https://doi.org/10.1007/s00776-014-0557-8.

60. Khajuria D.K., Disha C., Razdan R., Mahapatra D.R. Efeito combinado do ácido zoledrônico e do alfacalcidol no tratamento da osteoporose por desuso em ratos. Rev Bras Reumatol. 2015;55(3):240–250. https://doi.org/10.1016/j.rbr.2014.08.007.

61. Anastasilakis A. D., Papapoulos S.E., Polyzos S.A., Appelman-Dijkstra N.M., Makras P. Zoledronate for the prevention of bone loss in women discontinuing denosumab treatment. A prospective 2-year clinical trial. J Bone Miner Res. 2019;34(12):2220–2228. https://doi.org/10.1002/jbmr.3853.

62. Grassi G., Chiodini I., Palmieri S., Cairoli E., Arosio M., Eller-Vainicher C. Bisphosphonates after denosumab withdrawal reduce the vertebral fractures incidence. Eur J Endocrinol. 2021;185(3):387–396. https://doi.org/10.1530/EJE-21-0157.

63. Langdahl B. Treatment of postmenopausal osteoporosis with bone-forming and antiresorptive treatments: combined and sequential approaches. Bone. 2020;139:115516. https://doi.org/10.1016/j.bone.2020.115516.

64. Cosman F., Eriksen E.F., Recknor C., Miller P.D., Guañabens N., Kasperk C. et al. Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1-34)] in postmenopausal osteoporosis. J Bone Miner Res. 2011;26(3):503–511. https://doi. org/10.1002/jbmr.238.

65. You R., Liu J., Ke L., Yu G., Zhang Y., Mori T. Cost-Effectiveness of sequential teriparatide/zoledronic acid compared with zoledronic acid monotherapy for postmenopausal osteoporotic women in china. Front Public Health. 2022;10:794861. https://doi.org/10.3389/fpubh.2022.794861.

66. Yeam C.T., Chia S., Tan H.C.C., Kwan Y.H., Fong W., Seng J.J.B. A systematic review of factors affecting medication adherence among patients with osteoporosis. Osteoporos Int. 2018;29(12):2623–2637. https://doi.org/10.1007/s00198-018-4759-3.

67. Cooper A., ​​Drake J., Brankin E. Treatment persistence with once-monthly ibandronate and patient support vs. once-weekly alendronate: results from the PERSIST study. Int J Clin Pract. 2006;60(8):896–905. https://doi.org/10.1111/j.1742-1241.2006.01059.x.

68. Fobelo Lozano M.J., Sánchez-Fidalgo S. Adherence and preference of intravenous zoledronic acid for osteoporosis versus other bisphosphonates. Eur J Hosp Pharm. 2019;26(1):4–9. https://doi.org/10.1136/ejhpharm-2017-001258.

69. Curtis J.R., Yun H., Matthews R., Saag K.G., Delzell E. Adherence with intravenous zoledronate and intravenous ibandronate in the United States Medicare population. Arthritis Care Res (Hoboken). 2012;64(7):1054–1060. https://doi.org/10.1002/acr.21638.

70. Gray A., Horne A., Gamble G., Mihov B., Reid I.R., Bolland M. Ten years of very infrequent zoledronate therapy in older women: an open-label extension of a randomized trial. J Clin Endocrinol Metab. 2020;105(4):dgaa062. https://doi.org/10.1210/clinem/dgaa062.

71. Mori T., Crandall C.J., Fujii T., Ganz D.A. Cost-effectiveness of zoledronic acid compared with sequential denosumab/alendronate for older osteoporotic women in Japan. Arch Osteoporos. 2021;16(1):113. https://doi.org/10.1007/s11657-021-00956-z.

72. Akehurst R., Brereton N., Ariely R., Lusa T., Groot M., Foss P., Boonen S. The cost effectiveness of zoledronic acid 5 mg for the management of postmenopausal osteoporosis in women with prior fractures : evidence from Finland, Norway and the Netherlands.