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Bisphosphonates are a class of medications approved by the Food and Drug Administration (FDA) to reduce the risk of bone fracture secondary to osteoporosis (very low bone density) in postmenopausal women.[1],[2] Some of these drugs also are approved to reduce fracture risk in men with osteoporosis and in men or women with Paget’s disease, which involves localized bone deformation and bone loss.[3] Three oral forms of bisphosphonates are approved for use in the U.S.: alendronate (BINOSTO,...
Bisphosphonates are a class of medications approved by the Food and Drug Administration (FDA) to reduce the risk of bone fracture secondary to osteoporosis (very low bone density) in postmenopausal women.[1],[2] Some of these drugs also are approved to reduce fracture risk in men with osteoporosis and in men or women with Paget’s disease, which involves localized bone deformation and bone loss.[3] Three oral forms of bisphosphonates are approved for use in the U.S.: alendronate (BINOSTO, FOSAMAX), ibandronate (BONIVA) and risedronate (ACTONEL, ATELVIA).
Bisphosphonates (sometimes referred to as “antiresorptive agents”) inhibit the activity of bone cells that break down and reabsorb bone. The breakdown and creation of bone are linked, and as a result, these drugs decrease overall bone loss by inhibiting bone breakdown.
Public Citizen’s Health Research Group designates bisphosphonates as Limited Use for reducing fracture risk related to postmenopausal osteoporosis, after diet and exercise approaches have first been tried to address such bone disease. We also recommend that these drugs only be used in those with high fracture risk and that they should not be used continuously for more than five years.[4]
Patients taking bisphosphonates need to be aware that these drugs are associated with a wide range of potentially serious adverse effects.
Warnings and precautions[5],[6],[7]
The FDA-approved product labeling for bisphosphonates warns that these drugs can cause upper gastrointestinal (GI) inflammation or injury; worsening hypocalcemia (low calcium level in the blood); osteonecrosis (death of bone) of the jaw; severe bone, joint and muscle pain; and atypical femur (thigh-bone) fracture.
Upper-GI adverse effects
Because inflammation or damage to the inner lining of the esophagus, stomach or duodenum (first part of the small intestine) may be caused by bisphosphonates, which may lead to heartburn, ulcers and bleeding, people with active upper-GI problems (for example, Barrett’s esophagus, gastroesophageal reflux disease or gastritis) should be especially cautious when using bisphosphonates. Accordingly, users should alert their physicians immediately if they develop difficulty or pain with swallowing, chest pain, or new or worsening heartburn. The risk of upper-GI adverse effects can be reduced by taking bisphosphonates with six to eight ounces of water and remaining upright (not laying down) for 30 minutes (for alendronate and risedronate) or 60 minutes (for ibandronate) after swallowing the medication. These drugs should not be used by patients who have disorders that cause delayed emptying of the esophagus (such as a stricture) or are unable to remain upright for the specified 30 or 60 minutes.
Hypocalcemia exacerbation
Because hypocalcemia may be exacerbated by bisphosphonate use, disorders of calcium metabolism (such as vitamin D deficiency) should be corrected before bisphosphonate treatment is begun. These drugs should not be taken by patients with pre-existing hypocalcemia.
Musculoskeletal pain
Following FDA approval of the bisphosphonates, there have been reports of severe and occasionally incapacitating bone, joint or muscle pain in patients taking these drugs. Onset of the pain varied from one day to several months after starting the drugs. Stopping the medication usually relieved the symptoms.
Osteonecrosis of the jaw
Although osteonecrosis of the jaw can occur spontaneously in patients using bisphosphonates, it generally is associated with tooth extraction or local infection with delayed healing. The risk of jaw osteonecrosis may increase with longer bisphosphonate use. For patients requiring invasive dental procedures — including tooth extraction, dental implants and surgery involving the jaw bone — discontinuation of bisphosphonate therapy may reduce the risk of osteonecrosis. An oral surgeon should be consulted if jaw osteonecrosis occurs. Avoiding or discontinuing bisphosphonates should be considered if there are such dental concerns.
Atypical femur fractures
Fractures of the femoral shaft (from just below the hip to above the knee) involving minimal to no trauma — called atypical fractures — have been observed rarely in patients using bisphosphonates, although patients not using bisphosphonates also experience such fractures. Any patient with a history of bisphosphonate exposure who experiences new and otherwise unexplained thigh or groin pain should seek a medical evaluation to rule out an atypical femur fracture. Any patient diagnosed with such a fracture in one leg should be assessed for atypical fractures in the other leg.
Hypersensitivity reactions[8],[9],[10]
Various types of hypersensitivity and potentially life-threatening adverse skin reactions, including angioedema, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported rarely with use of bisphosphonates.
What You Can Do
If you are a woman age 65 or older, ask your doctor to assess your fracture risk, looking at all your risk factors and not just your bone density. You can calculate your fracture risk score using the online calculator at https://www.sheffield.ac.uk/FRAX/tool.aspx?country=9. If you are at high risk of fracture (meaning your risk of hip fracture is 3% or more over the next 10 years) or you already have experienced a hip or vertebral fracture, talk to your doctor about your calcium and vitamin D intake, your exercise regimen and whether you should be prescribed an oral bisphosphonate.
Before beginning oral bisphosphonate therapy, consult with your dentist or oral surgeon regarding any tooth or jaw issues that should be addressed prior to initiation of treatment. Also consult with your physician about any concerns you have regarding your calcium or other mineral metabolism before you begin bisphosphonate treatment.
Take your bisphosphonate tablets with six to eight ounces of water and avoid lying down for at least 30 minutes (or one hour for ibandronate) after taking your dose.
Use bisphosphonates for no more than five consecutive years to minimize the risk of atypical femur fractures. After this time period, you should talk with your doctor about either taking a break from treatment for several years or stopping treatment permanently, depending on your individual risk at that time.
Consult with your doctor right away if you experience any of the following symptoms while on bisphosphonates:
- Muscle, joint or bone pain
- Thigh or groin pain
- Heartburn or other GI disturbances
- Skin rash or other allergic reactions, including swelling
References
[1] Anthamatten A, Parish A. Clinical update on osteoporosis. J Midwifery Womens Health. 2019;64(3):265-275.
[2] National Institute of Health Osteoporosis and Related Bone Diseases National Resource Center. Osteoporosis overview. October 2019. https://www.bones.nih.gov/health-info/bone/osteoporosis/overview. Accessed August 10, 2021.
[3] Barbosa JS, Almeida Paz FA, Braga SS. Bisphosphonates, old friends of bones and new trends in clinics. J Med Chem. 2021;64(3):1260-1282.
[4] New research shows bisphosphonates prevent osteoporosis-related hip fractures. Worst Pills, Best Pills News. April 2021. https://www.worstpills.org/newsletters/view/1391. Accessed August 10, 2021.
[5] Ascend Therapeutics. Label: alendronate (BINOSTO). March 2021. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=b278a11a-b8d7-49f3-9b38-29b67c4c417e&type=display. Accessed August 10, 2021.
[6] Allergan USA, Inc. Label: risedronate (ACTONEL). November 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=24ed00e0-25e2-49a8-97fc-66c1b417dc0b&type=display. Accessed August 10, 2021.
[7] Genentech USA, Inc. Label: ibandronate (BONIVA). October 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=841bf769-0148-42a8-a4d0-ff062b4734e8&type=display. Accessed August 10, 2021.
[8] Ascend Therapeutics. Label: alendronate (BINOSTO). March 2021. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=b278a11a-b8d7-49f3-9b38-29b67c4c417e&type=display. Accessed August 10, 2021.
[9] Allergan USA, Inc. Label: risedronate (ACTONEL). November 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=24ed00e0-25e2-49a8-97fc-66c1b417dc0b&type=display. Accessed August 10, 2021.
[10] Genentech USA, Inc. Label: ibandronate (BONIVA). October 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=841bf769-0148-42a8-a4d0-ff062b4734e8&type=display. Accessed August 10, 2021.
