What is Bisphosphonate Toxicity?
Bisphosphonates are crucial in treating metabolic and cancer-related bone diseases. They are particularly helpful for patients with multiple myeloma, a type of bone marrow cancer, and metastatic bone diseases, where cancer has spread to the bones, decreasing the chances of unexpected fractures. Bisphosphonates are effective due to their abilities to slow down or prevent bone loss, making them a top-choice treatment in cases of osteoporosis. Research shows that using these reduces the risk of spinal and hip fractures by 30% to 70% among women with osteoporosis.
Originated in the industrial field in the 19th century, bisphosphonates were initially used to ‘soften water’ to avoid pipe scaling and corrosion. They weren’t utilized in the medical field until the late 1960s when they started being used for the treatment of diseases that affect bone health. The initial bisphosphonates used were Etidronate acid and Clodronic acid. Over time, more powerful versions have been developed that can act over an extended period. A well-known bisphosphonate, Zoledronic acid, can be administered once a year through an intravenous infusion.
It’s essential to note that although bisphosphonates have numerous benefits, they also have short-term and long-term side effects. Having a strong understanding of these potential side effects is vital when a doctor prescribes these types of medications.
What Causes Bisphosphonate Toxicity?
In healthy bones, there’s a continuous cycle happening where old bone is being broken down (resorption) by cells called osteoclasts while new bone is being formed (production) by cells called osteoblasts. It’s crucial to keep these two processes balanced to keep our bones healthy.
Several factors help maintain this balance. For example, during the bone breakdown phase, growth factors like insulin-like growth factor-1 (IGF) and transforming growth factor-beta (TGFB) are released to kickstart the formation of new bone. Additionally, other factors like parathyroid hormone (PTH) and prostaglandin E can turn on both bone break down and formation at the same time.
Bisphosphonates, medications commonly used to treat bone diseases, and calcium pyrophosphates, which normally bind to calcium in the bone to strengthen it, have a similar structure. Cells called osteoclasts, which are overly active in some types of cancer, can eat away at the bone, making it weak. Because bisphosphonates look structurally like calcium pyrophosphates, these overactive osteoclasts can consume them too. This interferes with the cells’ normal function, eventually leading to their death. So, in a way, bisphosphonates help protect the bone by decreasing the activity of these hungry osteoclasts.
But there’s a flip side too. Using bisphosphonates for a long time could result in too much decrease in bone turnover, meaning, our body could be slowing down both its bone absorbing and forming processes too much, which can lead to fragile bones and unusual bone fractures, particularly in the thigh bone. It is believed that these unusual fractures happen because bisphosphonates interfere with the natural repair process of the outer layer of the bone.
Lastly, bisphosphonates can have adverse effects, regardless of whether they’re used at the recommended dose or in an overdose, and irrespective of the patient’s kidney or liver function. However, to minimize some of the side effects (especially a condition called hypocalcemia, which is low levels of calcium in the blood), it’s recommended that patients ensure they get adequate calcium and vitamin D before, during, and after taking bisphosphonates.
Risk Factors and Frequency for Bisphosphonate Toxicity
A recent study that reviewed 47 research projects with over 20,000 breast cancer patients receiving bisphosphonates through an IV found that the most common side effect was flu-like symptoms. This side effect occurred equally in both men and women. Other side effects included fatigue, fever, stomach discomfort, and loss of appetite.
In addition, the study revealed that about 2% of these patients developed a condition called osteonecrosis of the jaw. This rate is much higher than patients who take oral bisphosphonates for osteoporosis, where the rate is between 1 in 10,000 to 1 in 100,000 patient-years.
The study also found that patients who use bisphosphonates for a long term (around 7 years on average) may experience unusual fractures. The risk varies, with 3.2 to 50 cases per 100,000 patient-years.
Signs and Symptoms of Bisphosphonate Toxicity
Bisphosphonate toxicity can lead to a variety of complications, all depending on the individual’s personal medical history and exposure to the drug. To determine the course of treatment, doctors look at a detailed history of the patient’s exposure to bisphosphonates along with a physical examination.
Some patients may experience systemic adverse effects, especially if injected via an IV. Symptoms like fever, fatigue, joint and muscle pain, nausea, and increased bone pain can appear within 24 to 72 hours of administration. These symptoms are thought to be caused by the release of certain proteins that trigger an inflammatory response. The good news, however, is that these effects often decrease with subsequent infusions.
Oral usage of bisphosphonates may result in a series of upper gastrointestinal complications. Erosive esophagitis, a condition that results in the inflammation of the esophagus, can occur especially when the medication isn’t taken properly. Taking the medication with a full glass of water and remaining upright for 30-60 minutes can help to prevent this. Nausea, indigestion, and abdominal pain are less common, but if they do occur, further evaluation is needed to rule out other underlying gastrointestinal conditions.
Risks of hypocalcemia, or low calcium levels in the blood, can increase during bisphosphonate use due to conditions such as Vitamin D deficiency, hypoparathyroidism, and hypomagnesemia. Symptoms can range from lethargy and weakness to severe muscle contractions and seizures. These symptoms can appear within days of the first infusion but can also take months of repeated infusions.
- Eye complications such as scleritis, uveitis, and conjunctivitis, as well as eye pain and redness, can occur even with recommended dosing.
- Osteonecrosis of the Jaw (ONJ), a condition where damage occurs to the jaw bone due to lack of blood supply and infection, has been reported.
- Subtrochanteric femoral fractures can occur either spontaneously or from low-impact trauma, particularly in those on long-term bisphosphonate treatment. Vague femoral pain or weakness are common symptoms.
Each of these conditions requires specialized diagnosis and targeted treatment options.
Testing for Bisphosphonate Toxicity
If your doctor believes you may be having complications from using bisphosphonates, a type of medicine often used for conditions like osteoporosis, they will want to run some tests. These tests can include checking your blood for low levels of hemoglobin, as this can suggest a problem like erosive esophagitis (an inflammation of the lower part of the esophagus). They might also look at your calcium and vitamin D levels to check for low levels (hypocalcemia), and check your creatinine (a waste product in your blood) to see if your kidneys are working well.
Sometimes, plain X-rays can show if you’ve suffered an unusual type of break or fracture in your thigh bone (femur). These fractures can look different from normal ones, appearing sideways or slanted, and with a ‘beak’ shape on the outer layer of bone. A special type of scan that uses a safe, radioactive substance called technetium (Tc)-99m can show if the part of your bone affected by the break is taking in more of the substance than it should.
If your X-ray doesn’t show a fracture but your doctor still thinks you might have one, they might ask for a magnetic resonance imaging (MRI) scan. This can show up a fracture line that wouldn’t appear on an X-ray. Plus, it can show if the innermost part of your bone, the marrow, is behaving unusually. This marrow could have a low signal in T1 and a high signal in T2 and STIR pictures, which are different types of images that an MRI scanner can take.
Treatment Options for Bisphosphonate Toxicity
If you experience systemic reactions, such as fever, headaches, or fatigue, these symptoms typically resolve on their own. If needed, the main treatment includes the use of over-the-counter medications like acetaminophen (Tylenol) and possibly a group of medications known as nonsteroidal anti-inflammatory drugs (NSAIDs). It’s essential to ensure these symptoms aren’t caused by an infection.
Upper gastrointestinal (GI) side effects can be prevented by correctly administering the medication. In simple terms, taking the medicine exactly as prescribed can prevent issues like heartburn or indigestion. However, patients suffering from long-standing esophageal conditions like Barrett’s esophagus should avoid using a certain group of drugs known as bisphosphonates.
If hypocalcemia (low calcium level in the blood) is discovered while using bisphosphonates, it’s important to pinpoint the causes, which could include previous radiotherapy to the head and neck, a past surgery to remove the thyroid gland, or low magnesium levels (hypomagnesemia). When detected, the low calcium level should be corrected and consistently monitored. It’s strongly recommended to correct any pre-existing low calcium or vitamin-D deficiency before starting bisphosphonates.
Ocular complications, which concern the eyes, are rare and usually not threatening to vision. However, if these issues occur, it is advised to see an eye specialist (an ophthalmologist) for the appropriate treatment.
Osteonecrosis of the jaw (ONJ), a condition where the jawbone starts to weaken and die, can be a side effect of using bisphosphonates. The keys to managing ONJ are prevention and early detection. Before starting therapy with bisphosphonates, high-risk patients are strongly advised to have a dental check-up and get necessary treatments. It’s vital to keep up with regular dental care. A temporary break from the medication before any planned dental procedure has also been suggested as a preventive measure to reduce the risk of ONJ.
When ONJ does occur, the management could be challenging. The treatment could range from regular dental visits, mouth rinses with special solutions like chlorhexidine, antibiotics for infections to more aggressive surgical treatments in severe cases. Some other treatments have been tried, such as oxygen therapy and using mesenchymal cells for creating of new bone tissue.
In the case of a specific type of leg fracture (subtrochanteric femoral fracture), discontinuation of bisphosphonates is advised. Also, using supplements like calcium and vitamin D might be considered. Depending upon the severity of the fracture, a referral to an orthopedic specialist, a doctor who specializes in bones and muscles, might be required.
What else can Bisphosphonate Toxicity be?
Keep in mind that there are other conditions that may look the same as osteonecrosis of the jaw when looking at X-ray or other imaging studies. These include osteonecrosis caused by radiation therapy and various infections.
Also, there are other conditions that could be mistaken for atypical femoral fractures, such as:
- Injuries caused by trauma
- Osteoarthritis, a common form of arthritis that damages the cushioning cartilage at the end of the bones
- Inflammatory arthritis, a group of conditions where the body’s immune system starts attacking the joints, causing inflammation.
What to expect with Bisphosphonate Toxicity
The outlook depends on the specific complications a patient experiences. Although flu-like symptoms are harmless and usually go away on their own, some serious complications like erosive esophagitis (a condition where the lining of the esophagus gets damaged), osteonecrosis of the jaw (which is the death of bone tissue in the jaw), and nephrotoxicity (which is kidney damage) can lead to significant health problems and may even be life-threatening.
Possible Complications When Diagnosed with Bisphosphonate Toxicity
Bisphosphonates, drugs used for strengthening bones, can sometimes adversely affect the kidneys, particularly in patients with pre-existing kidney issues or cancer patients undergoing chemotherapy. This is often due to the drugs causing damage to the kidney tubules. When kidneys begin to be affected by bisphosphonates, a gradual rise in creatinine levels, a measure of kidney function, can be detected over a few months. However, discontinuing the drug usually leads to kidney function returning to normal within several months.
Of the various bisphosphonates, zoledronic acid has the greatest tendency to cause kidney failure, especially when taken in higher doses. This drug can cause damage to kidney tubular cells, which can, however, be recovered from but this takes time.
Another bisphosphonate, pamidronate, can make kidney problems manifest as nephrotic syndrome, a condition that causes your body to excrete too much protein in your urine. However, the kinds of kidney damage it causes are usually irreversible and often occur in patients who are taking the maximum recommended dose of the drug. The damage can eventually require patients to undergo a kidney replacement therapy.
For people taking bisphosphonates, monitoring of kidney function, adequate hydration, and avoiding medications that are also hard on the kidneys can help prevent kidney damage. Also, zoledronic acid and pamidronate should not be prescribed if a patient’s kidneys aren’t filtering blood properly, or if their creatinine level doubles from what it was at baseline.
If a patient experiences kidney toxicity related to the use of bisphosphonates, the first step in treating it is to stop taking the drug. The management from this point is generally supportive, as there isn’t a specific treatment. Whether the medication is reinstated depends on the benefits and risks and requires a detailed discussion with the patient.
There may also be a possible link between bisphosphonate use and the occurrence of atrial fibrillation – irregular and often rapid heart beat. Large clinical trials have reported increased occurrence of atrial fibrillation in groups taking bisphosphonates, specifically zoledronic acid. However, other observational studies didn’t find such a link, thus the evidence is not entirely positive or entirely negative. Given that bisphosphonates are often prescribed to elderly people with pre-existing health conditions, including atrial fibrillation, further research is needed to confirm this potential link.
Preventing Bisphosphonate Toxicity
Before beginning a treatment that involves a type of medication called bisphosphonate, it’s important to talk about the possible side effects and harmful effects with your doctor. Assessing your risk levels is crucial when considering bisphosphonate as a treatment option. It’s beneficial to involve your other healthcare professionals and dental team in the discussion. By doing this, they can help identify if you are a suitable candidate for bisphosphonates. In other words, they can help decide whether the benefits of taking bisphosphonates would outweigh any potential risks.
