Bisphosphonate examples: Osteoporosis Medications (Bisphosphonates) : Johns Hopkins Lupus Center
Osteoporosis Medications (Bisphosphonates) : Johns Hopkins Lupus Center
- Risedronate (Actonel)
- Alendronate (Fosamax)
- Ibandronate (Boniva)
- Zoledronic Acid (Reclast)
- Pamidronate (Aredia)
- Etidronate (Didronel)
What are bisphosphonates and why are they used in lupus treatment?
Bisphosponates such as risedronate (Actonel), alendronate (Fosamax), ibandronate (Boniva), zoledronic acid (Reclast), and pamidronate (Aredia) are used to treat and prevent osteoporosis—or, bone thinning—which occurs when the bones lose calcium and other minerals that help keep them strong and compact. This condition can lead to fractures, bone pain, and shorter stature. Everyone is at risk for osteoporosis as they age, and women experience a greater risk of the condition after menopause. However, studies have shown that people with lupus are at an increased risk for osteoporosis due to the inflammation they experience with the disease. Certain medications taken by lupus patients also increase the risk of osteoporosis, especially corticosteroids such as prednisone.
How do bisphosphonates work?
Your bones are constantly remodeling in a process that removes old bone cells and deposits new ones. In people with osteoporosis, the bones lose minerals faster than they can be regenerated. Bisphosphonates help prevent your bones from losing calcium and other minerals by slowing or stopping the natural processes that dissolve bone tissue. In doing this, they help your bones remain strong and intact. If you have already developed osteoporosis, these medications may slow the thinning of your bones and help prevent bone fractures (broken bones). In fact, studies have shown that alendronate (Fosamax) and risedronate (Actonel) can lower your risk of fractured vertebrae—bone segments that make up your spine—by 50%. Similar studies demonstrate that these medications can lower the chance of breaking other bones by 30-49%.
What are the usual doses of bisphosphonates, and what should I remember while taking these medications?
Most bisphosphonates are taken anywhere from once a week to once a month. All of these medications come in tablet form except for zoledronic acid (Reclast), which is given intravenously (IV) once per year. Both women and men may take bisphosphonates.
You should take these medications in the morning with a full glass of water at least a half-hour before eating, drinking, or taking other medications. Do not lie down for 30 minutes after taking the medication.
What else can I do to maintain strong, healthy bones and lower my risk of developing osteoporosis?
It is important for you to take other steps to help keep your bones healthy and strong. Exercise and movement are important for the health of your bones, joints, and muscles and may lower your risk of osteoporosis. Walking, stretching, yoga, and other activities will help ward off bone thinning and muscle loss. Studies have shown that people who live more sedentary lifestyles are at an increased risk of developing osteoporosis. In addition, your doctor will most likely recommend that you take calcium and vitamin D supplements while taking bisphosphonates, since vitamin D helps your body to absorb calcium. It is important that you also try to eat foods rich in calcium, such as milk, light ice cream/frozen yogurt, cottage cheese, pudding, almonds, broccoli, fortified cereal, oranges, yogurt, hard cheese, soybeans and soymilk, navy beans, oysters, sardines, and spinach.
Your doctor will most likely recommend that you get a bone density scan, or DEXA scan, every two years to evaluate your response to treatment. The test takes only about fifteen minutes to perform and can provide your doctor with valuable information regarding the health of your bones.
What are the side effects of bisphosphonates?
Potential side effects of these medications include:
• Heartburn, stomach pain, and throat irritation
• Muscle and joint pain
• Flatulence (constipation, diarrhea, gassy stomach)
• Dysphagia (difficulty swallowing)
• Pain or burning under the ribs or in the back
• Jaw pain, numbness, and swelling
• Dizziness, weakness
• Allergic reaction
• Reclast may be linked to an irregular heartbeat called atrial fibrillation.
In addition, some people have reported problems with bone healing (specifically, osteonecrosis of the jaw), especially after dental extractions or implants. Talk to your doctor if you plan to have this sort of treatment, since she/he will most likely recommend that you stop taking these medications before the event and begin taking an antibiotic. Also talk to your doctor if any of the side effects you experience are particularly bothersome.
Who should not take bisphosphonates?
The following people should not take bisphosphonates unless your doctor approves the treatment:
• Pregnant women or women planning to become pregnant
• People with severe kidney problems
• People with esophagitis (inflammation of the esophagus, the tube down which food travels from your mouth to your stomach)
• People who are currently taking parathyroid hormone (Forteo), although exceptions may be made.
Talk to your doctor if you have low blood calcium (hypocalcemia), a vitamin D deficiency, kidney disease, or an ulcer in your stomach or esophagus, since you may not be advised to use these medications.
What if I am taking other medications?
Certain medications can affect how your body deals with bisphosphonates. Your lupus treatment may involve several medications, but you should still tell your doctor if you are taking any other medicines—prescription drugs, over-the-counter medications, supplements, and vitamins—especially NSAIDs, such as ibuprofen (Advil, Motrin), celecoxib (Celebrex), naproxen (Aleve, Naprosyn), meloxicam (Mobic), and diclofenac (Voltaren, Cataflam). In addition, antacids and other supplements that contain aluminum, calcium, and magnesium can interfere with how your body absorbs bisphosphonates, so you should not take these medicines for at least 30 minutes after taking your bisphosphonate tablet.
Bisphosphonates – Warnings, Precautions, Side Effects & Interactions
These drugs are used to treat several conditions associated with bone loss.
Bisphosphonates are a group of drugs used to help prevent and treat bone loss.
They’re prescribed for people with osteopenia (softening of the bones), osteoporosis (brittle and easily broken bones), Paget’s disease, and certain bone cancers.
These drugs work by interfering with the process through which the body breaks down bone tissue.
In some cases, bisphosphonates can halt this process altogether.
The following drugs belong to the bisphosphonate family:
Reclast and Zometa (zoledronic acid) are administered by intravenous (IV) injection once a year. The other bisphosphonates come in pills, taken orally.
Warnings and Precautions
Don’t take bisphosphonates if you:
- Are allergic to them
- Have disorders of the food pipe (esophagus), including tears, holes, narrowing, or difficulty swallowing
- Have severe kidney disease
- Can’t sit in an upright position for at least 30 minutes
- Have low levels of calcium in your bloodstream
To avoid irritation to your stomach and food pipe, you must remain in an upright position for at least 30 minutes after taking a bisphosphonate by mouth.
Boniva requires you to remain upright for 1 hour.
Except for Altevia, all pill forms of bisphosphonates should be taken on an empty stomach before eating breakfast — generally 30 minutes beforehand.
Take Boniva on an empty stomach 1 hour before eating; Altevia should be taken after meals.
Bisphosphonates should be taken with a full glass of water only — no juice, coffee, soda, or flavored beverages.
Always take a bisphosphonate by itself. Wait at least 30 minutes (or 1 hour with Boniva) before taking any other medications or supplements.
Common Side Effects
The most common side effects of bisphosphonates are stomach irritation and heartburn, but these problems are often avoided by taking the medication correctly.
Other common side effects include:
- Bone or joint pain, or generalized pain
- Muscle cramps or aches
- Nausea, constipation, diarrhea, or other stomach discomfort
- Headache or dizziness
- Head colds, sinus or throat infections, or the flu
- Bladder infections
- Tiredness or trouble sleeping
Ask your doctor or pharmacist about bisphosphonates if you’re taking:
List of bisphosphonates uses, brands, and safety recommendations
Bisphosphonate treatment reduces the risk of fractures in people with conditions that cause bone loss, such as osteoporosis
Bisphosphonates list | What are bisphosphonates? | How they work | Uses | Who can take bisphosphonates? | Safety | Side effects | Costs
Bisphosphonates are a class of medications that slow down and prevent bone loss. Used to increase bone strength and reduce the risk of bone fractures, bisphosphonate medications help treat osteoporosis, Paget’s disease, and other conditions that may lead to a loss of bone mineral density.
Continue reading to learn more about bisphosphonates, their uses, and their side effects.
- Zometa (zoledronic acid)
- Aclasta (zoledronic acid)
- Actonel with Calcium (risedronate/calcium carbonate)
- Skelid (tiludronate)
- Didronel (etidronate)
- Aredia (pamidronate)
What are bisphosphonates?
Bisphosphonates are medications that strengthen bones by slowing or preventing bone turnover and bone loss. Bone loss is a normal part of the aging process, but women can experience an increased risk of bone disease after menopause. Estrogen levels decrease in postmenopausal women, which can lead to decreased bone mass. A loss of bone mass can lead to an increased risk of hip fractures and vertebral fractures.
Bisphosphonate treatment reduces the risk of fractures in people with conditions that cause bone loss, such as osteoporosis. Bisphosphonates are recommended for the management of osteoporosis because they help slow the bone remodeling process and prevent bones from losing calcium and other minerals.
How do bisphosphonates work?
Your bones are constantly rebuilding themselves in a process known as bone remodeling. During this process of bone turnover, old bone tissue is broken down and replaced with new bone tissue. As old bone tissue is broken down, calcium is released from the bone into the bloodstream.
Osteoclasts are the bone cells that are responsible for removing old bone tissue and osteoblasts are the bone cells that help form the new bone tissue. In conditions like osteoporosis, osteoclasts may be more active causing bone tissue to be broken down faster than it can be rebuilt. Bisphosphonates slow down the process of bone remodeling and help maintain the strength of bones.
Like other antiresorptive agents, bisphosphonates inhibit the action of the osteoclasts and decrease bone resorption. As bisphosphonates bind to sites on the bone’s surface, osteoclasts cannot carry out their function of removing old bone cells. This mechanism of action helps slow the thinning of bones and prevents bone fractures.
What are bisphosphonates used for?
Bisphosphonates are primarily used for the treatment of osteoporosis but may also be used for the following conditions:
- Paget’s disease
- Breast cancer with bone metastases
- Heterotopic ossification from spinal cord injury or hip replacement surgery
- Osteolytic bone lesions
- Osteogenesis imperfecta
Bone density can be measured in a test known as a DEXA scan. This scan is a type of x-ray that assesses bone loss by measuring bone mineral density. A DEXA scan measures how many grams of calcium and other bone minerals a segment of bone contains. The scan typically measures bone mineral density in the spine, hip, or forearm. The higher the mineral content, the denser your bones are. With a high bone mineral density, the bones are less likely to break. If you have a low bone mineral density for your age, you may be a candidate for treatment with a bisphosphonate.
Who can take bisphosphonates?
Adults can take various forms of bisphosphonates. Most bisphosphonates are available in tablet form. For example, Fosamax is supplied as an effervescent tablet. Some formulations of bisphosphonates are given once weekly while others may be taken daily. Reclast is only available as an injection, which is administered yearly. Vitamin D and calcium supplementation are usually recommended in those treated with bisphosphonates for bone loss.
Bisphosphonates are often taken first thing in the morning on an empty stomach. Tablets should be swallowed whole, and the medication should be taken with six to eight ounces of water. You should remain sitting upright for at least 30 minutes after taking a bisphosphonate or until you have consumed food.
Bisphosphonates are generally taken for a period of three to five years of treatment. Bone density tests can determine if bisphosphonates are needed for bone loss and if they have effectively prevented further loss.
Children with osteogenesis imperfecta or other diseases that lead to bone loss may be prescribed bisphosphonates. However, bisphosphonates have not been FDA-approved for use in children. Bisphosphonates like Fosamax, Reclast, or Aredia may sometimes be prescribed off-label in children. The dosage may be based on the child’s weight.
Bisphosphonates should be taken first thing in the morning on an empty stomach. Tablets should be swallowed whole, and medication should be taken with six to eight ounces of water. Children should remain sitting upright for at least 30 minutes after taking a bisphosphonate or until eating. Liquid bisphosphonates should be followed with at least two ounces of water.
Seniors can take bisphosphonates without any dose adjustments required.
Are bisphosphonates safe?
In general, bisphosphonates are deemed safe by the FDA and have few side effects when taken as prescribed. However, there are a few groups of people that should not take bisphosphonates. Individuals with altered kidney function should not take bisphosphonates, including those on peritoneal dialysis or hemodialysis.
There are no current bisphosphonate recalls as of May 2021.
Individuals prescribed bisphosphonates must tolerate sitting upright or standing for at least 30 minutes after taking the medication. If you have active stomach problems, esophageal problems, or esophagitis, bisphosphonates may increase the risk of worsened symptoms from these conditions. For those that cannot tolerate oral bisphosphonates, intravenous bisphosphonates, such as Reclast, may be an option.
Can you take bisphosphonates while pregnant or breastfeeding?
Bisphosphonates may cross the placenta during pregnancy and lead to adverse effects on both the unborn baby and mother. Because of this, the risks and benefits of taking a bisphosphonate during pregnancy should be evaluated by a healthcare provider.
Bisphosphonates may cross into breast milk in small amounts. Although bisphosphonates are likely to be poorly absorbed by a nursing infant, a healthcare provider should be consulted before taking a bisphosphonate while breastfeeding.
Are bisphosphonates controlled substances?
No, bisphosphonates are not controlled substances.
Common bisphosphonate side effects
The most common side effects of bisphosphonates include:
- Muscle pain
- Bone pain
- Joint pain
- Flu-like symptoms
- Irritation of the esophagus
More severe but rare side effects of bisphosphonates include:
- Allergic reactions
- Severe bone pain
- Chest pain
- Muscle spasms
- Muscle twitching
- Tingling or numbness around the mouth, fingers, or toes
- Pain or difficulty with swallowing
- Unusual pain in the groin, thigh, or hip
- Pain, swelling, numbness, or a heavy feeling in the jaw
- Loose teeth or tooth problems
- Blistering, peeling, red skin rash
Bisphosphonates have two side effects that, while rare, are quite serious. The first is a risk for a rare type of fracture in the femur of the thigh bone. This type of femoral fracture has been reported with bisphosphonate use.
Another possible serious side effect of using bisphosphonates is osteonecrosis of the jaw (ONJ). It can develop spontaneously, especially after a dental extraction or other dental procedure. Injury to the bone during dental surgery could lead to loss of bone in the jaw, which can lead to symptoms of pain and swelling in the jaw. The risk of developing osteonecrosis of the jaw may be higher with high doses of bisphosphonates or infusions of bisphosphonates, such as Reclast, rather than other oral bisphosphonates. Other risk factors for developing ONJ include older age, female gender, chemotherapy, and steroid treatment.
This list of side effects is not comprehensive. Speaking with a healthcare professional is the best way to get a complete list of side effects and determine whether bisphosphonate use is suitable for you.
Tell your doctor if you have a history of any of the following before taking a bisphosphonate:
- Any medication allergies
- Problems in the esophagus
- Low calcium levels (hypocalcemia)
- Kidney disease or other kidney problems
- Trouble swallowing food or medications
- Inability to stand or sit upright for 30 minutes
- Pregnancy or plans to become pregnant
- Use of parathyroid hormone (Forteo)
- Vitamin D deficiency
- Stomach ulcers
You should also tell your doctor about any and all medications you may be taking, including over-the-counter medications, prescription medications, and herbal supplements. Some medications may interact with bisphosphonates. For example, supplements that contain aluminum or magnesium can alter the absorption of bisphosphonates and should not be taken within 30 minutes after taking a bisphosphonate.
How much do bisphosphonates cost?
Bisphosphonates are generally affordable medications that are available in brand-name and generic formulas. Almost all Medicare and insurance plans will cover bisphosphonates. Costs will vary depending on your insurance plan. Without insurance, the price can vary widely depending on the medication and quantity of tablets prescribed. However, using a prescription discount card from SingleCare may help reduce the cost of bisphosphonates.
Side-effects, uses, time to work
Bisphosphonates are generally well tolerated. The risk of digestive problems with oral preparations is very much reduced if you carefully follow the instructions that come with your medicine.
Less common side-effects include:
- itchy rashes or photosensitivity (rash on exposure to sunlight)
- a sore mouth
- flu-like symptoms (more common with intravenous treatment)
- bone pain (more common with intravenous treatments)
- muscle pain
You should report any side-effects to your doctor or rheumatology nurse and the drug may be stopped if necessary.
There are three very rare side-effects:
- Osteonecrosis of the jaw is a condition where healing is incomplete following an invasive dental procedure. An area of bone is exposed through the gum and a small amount of bone dies. This condition is more common if you have cancer, are having chemotherapy or you have severe, recurrent dental infections and are having dental treatment.
- It’s been suggested that there’s a possible, though small, increase in the risk of cancer of the oesophagus (gullet) in people taking bisphosphonates by mouth for more than 3–5 years. However, the evidence is mixed and in most situations, the benefits of treatment are greater than any potential risk.
- Some people taking bisphosphonates have developed painful, partial or complete fractures in the upper, outer region of the thigh bone (femur) below the hip. Partial fractures are usually confirmed by a special diagnostic scan. The risk appears to increase the longer you’ve been taking these drugs, and may be greater if you’re also having steroid treatment or have diabetes. However, it’s still extremely rare.
Your doctor will review your treatment from time to time to make sure the benefits of the treatment still outweigh the risks. Most specialists limit treatment with oral bisphosphonates to five years (or three years for intravenous zoledronate) to minimise the risks of rare, long-term side-effects. However, some people will need more lengthy treatment.
Bisphosphonates and cancer | Cancer Research UK
Bisphosphonates are drugs that help prevent or slow down bone thinning (osteoporosis). They can help to treat some types of cancer that cause bone damage.
You might hear bisphosphonates called bone hardening or bone strengthening treatment. They are also a treatment for high levels of calcium in your blood.
Doctors also use a drug called denosumab as a bone targeted treatment. It’s a type of targeted therapy called a monoclonal antibody.
Cancers that can affect bones
Most cancers that affect bones are ones that have started in another part of the body and have spread to the bone (secondary bone cancer). The most common types are breast cancer, prostate cancer and lung cancer.
Myeloma develops from cells in the bone marrow called plasma cells. Bone marrow is the spongy tissue found inside the inner part of some of our large bones.
Some types of cancer treatment can also affect the bones making them weaker, this includes chemotherapy and hormone therapies.
How cancer affects bones
Cancers that spread to the bones damage the bones as they grow. The cancer cells that have spread into the bones also release proteins that interfere with the normal bone shaping process. These proteins are cytokines and growth factors.
The proteins stimulate the cells that break down bone (osteoclasts) and make them overactive. So, bone is destroyed faster than it’s rebuilt.
This means your bones can become thinner and weaker, causing:
- pain in the affected bone
- high calcium levels in the blood
- an increased risk of breaks (fractures)
Calcium is normally stored in the bones and the breakdown of bone cells releases more calcium than usual into the blood.
Doctors call a high level of calcium in the blood hypercalcaemia. Symptoms of hypercalcaemia include:
- feeling thirsty
- feeling sick
- feeling drowsy
- abdominal pain
- bone pain
Bisphosphonate treatment can stop some types of cancer from spreading into the bone for some people. Studies have also shown that bisphosphonates can help some people with breast cancer and myeloma to live longer.
Bisphosphonates might also help to:
- prevent or control bone thinning (osteoporosis)
- reduce the risk of bones breaking
- reduce the level of calcium in your blood
- reduce pain
Types of bisphosphonate
There are several different types of bisphosphonate, including:
- disodium pamidronate (Aredia)
- ibandronic acid or ibandronate (Bondronat)
- sodium clodronate (Bonefos, Clasteon, Loron)
- zoledronic acid or zoledronate (Zometa)
You can have sodium clodronate as tablets or capsules. You have ibandronic acid as a drip into your bloodstream (infusion) or as tablets. And you have zoledronic acid and disodium pamidronate as a drip into your bloodstream.
Most of the research so far has looked at using bisphosphonates in secondary breast cancer, secondary prostate cancer and myeloma. The type of bisphosphonate your doctor prescribes for you will depend on the type of cancer you have. You will have one that works for your type of cancer.
There might sometimes be a choice of bisphosphonates for your type of cancer. Your doctor will give you the bisphosphonate best suited to your medical and practical needs. For example, you might prefer to take a bisphosphonate tablet at home rather than travel to hospital every month for treatment by drip.
You might have bisphosphonate treatment if you have myeloma to:
- slow down or prevent bone disease
- treat the symptoms of myeloma such as bone pain or high levels of calcium
- treat myeloma if you have bone damage
This is usually:
- zoledronic acid
- disodium pamidronate, if you can’t have zoledronic acid for some reason
- sodium clodronate, if you can’t have zoledronic acid or disodium pamidronate for some reason
You might have bisphosphonate treatment if you’re having hormone therapy and have osteoporosis (thinning of the bones). If you can’t have bisphosphonates for any reason you might have denosumab.
Bisphosphonates are not recommended to try and prevent prostate cancer that hasn’t spread, spreading to the bone.
Advanced prostate cancer
You might have bisphosphonate treatment if you have advanced cancer and hormone treatment is no longer controlling your cancer. This aims to prevent or reduce problems with your bones. You are likely to have zoledronic acid.
You might have bisphosphonates as tablets or an injection into the vein for pain relief in one of the following situations:
- you have advanced cancer and hormone treatment is no longer controlling the cancer
- other treatments, including painkillers and radiotherapy, have not helped your pain enough
For some women, bisphosphonate treatment can help reduce the risk of their breast cancer spreading to the bones. And improve some women’s chance of surviving their cancer.
You might have bisphosphonate treatment alongside your cancer treatment if:
- you have early and locally advanced breast cancer, with cancer in the nearby lymph nodes
- and you are postmenopausal
Or you might have this treatment if all of the following apply:
- have locally advanced breast cancer, which isn’t in the nearby lymph nodes
- are postmenopausal
- are at high risk of your cancer coming back after treatment
For these women, the bisphosphonates recommended are:
- zoledronic acid into a vein, usually every 6 months given at the same time as chemotherapy, for 3 years
- sodium clodronate, as a tablet for 3 years – if you can’t have zoledronic acid for some reason
You might also have bisphosphonates if you:
- have breast cancer that has spread to the bones, to try and prevent any bone problems and reduce pain
- have, or are at high risk of, bone thinning (osteoporosis)
You can find a clinical trial looking at bisphosphonates and cancer on our clinical trials database. Click on the ‘recruiting’, ‘closed’ and ‘results’ tabs to make sure you see all the trials.
Bisphosphonates for Osteoporosis: Risks and Side Effects
Bisphosphonates have been used for decades to treat various conditions. But they can have risks and side effects in certain patients.
What are bisphosphonates?
Bisphosphonates, also known as diphosphonates, are a class of drugs that have been used commonly for more than two decades for the treatment and prevention of osteoporosis. Bisphosphonates slow bone resorption by reducing osteoclast function. Many studies have shown that this class of medication can improve bone density and reduce the risk of fracture in patients with a reduced bone density. They are administered in two ways: orally and intravenously.
Bisphosphonates include the following medications:
- alendronate (Fosamax)
- pamidronate (Aredia)
- risedronate (Actonel)
- ibandronate (Boniva)
- zoledronic acid (Reclast)
- etidronate (Didronel)
Alendronate (Fosamax), risedronate (Actonel) and ibandronate (Boniva) are available orally. The former two agents can be taken daily or weekly; the latter two agents can be taken daily or monthly.
Pamidronate (Aredia), ibandronate (Boniva) and zoledronic acid (Boniva) are available intravenously. The former two agents are generally given every three to four months, and the latter agent yearly. Pamidronate was the first available intravenous bisphosphonate. Although it has been used to treat osteoporosis, it along with is FDA-approved for hypercalcemia (too much calcium in the blood) caused by cancer, as well as for and Paget’s disease. Zoledronic acid is also FDA-approved to treat both of these conditions.
These drugs reduce the risk of osteoporosis-related fractures as quickly as six months after institution of the drug. Alendronate has been FDA-approved since 1995 and hundreds of millions of prescriptions have been written. Fewer people have used risedronate and ibandronate, primarily because they have not been available as long as alendronate. Zoledronic acid attained FDA-approval for the treatment of osteoporosis in 2007, but it has also been used since the 1990s for the treatment of other conditions such as Paget’s disease, malignancy metastatic to bone and early on (off-label) for the treatment of osteoporosis.
Do bisphosphonates cause esophageal cancer?
There has been concern about a possible association between esophageal cancer and oral bisphosphonate use, however the FDA has not concluded that patients taking bisphosphonates have an increased risk of esophageal cancer.
Bisphosphonates are known to cause esophageal and gastric irritation in a small percentage of patients. Because of this, patients are instructed to remain upright for 30 to 60 minutes after ingestion. This is felt to improve both absorption and to promote gastric motility and reduce the time available for these agents to irritate the upper gastrointestinal tract. Patients who report gastric side effects may well be non-compliant with dosing instructions, as incidence of side effects is very low if instructions are followed correctly.
Review of large Medicare databases have not shown increased risk of esophageal cancer in patients taking oral bisphosphonates. However, from October 1995 to May 2008, the FDA reviewed reports of 23 patients in the US with a new diagnosis of esophageal cancer in patients taking alendronate. In Europe and Japan, 31 cases of esophageal cancer were identified as possibly related to bisphosphonate use. A few of these patients had a diagnosis of Barrett’s esophagitis, which is known to increase the risk of esophageal cancer.
There have been case reports of finding crystalline material similar to ground alendronate in biopsies of patients who have endoscopy for erosive esophagitis. This raises the question of a possible carcinogenic role of bisphosphonates associated with gastrointestinal irritation.
Obviously, millions of patients have taken oral bisphosphonates since alendronate was FDA-approved in 1995. If there is an increased risk of esophageal cancer associated with use of these drugs, it does seem to be low; the increased risk may be associated with the patients having chronic gastrointestinal irritation, which has been described with this class of drug.
The FDA recommends avoiding oral bisphosphonates in patients with a history of Barrett’s esophagitis. Any patients who describe gastrointestinal symptoms related to bisphosphonate use should be evaluated. These patients may well be candidates for intravenous zoledronic acid, which is FDA-approved for the treatment of osteoporosis and is not associated with gastrointestinal irritation.
Do bisphosphonates cause osteonecrosis of the jaw?
There has been a lot written on a possible relationship between bisphosphonates and a condition called osteonecrosis of the jaw (ONJ), which refers to an area of bone that has lost its blood supply. However, there is lack of rigorous scientific evidence to support a cause-and-effect relationship between bisphosphonates and ONJ.
Patients with ONJ (also known as avascular necrosis of the jaw) develop exposed bone in the jaw. The overlying tooth often falls out and a non-healing, often painful lesion remains. Also, an associated drainage tract may be present, connecting the area of damaged bone to the gum surface. Osteonecrosis of the jaw is more common in the lower than in the upper jaw.
Reports emerged first in oncology patients receiving 12 times the dose of zoledronic acid used to treat osteoporosis. Cases of non-healing maxillofacial bone lesions were recognized primarily in patients on chemotherapy who had poor dental hygiene. Controlled studies in patients with osteoporosis and Paget’s disease have failed to show an increased risk of ONJ, even after years of treatment with alendronate.
In 2011, an American Dental Association (ADA) expert panel estimated the prevalence of ONJ in patients receiving bisphosphonates for osteoporosis to be very low, about 0.10% at most. The ADA recommended that necessary dental work be done, regardless of the use of bisphosphonates.
How is osteonecrosis of the jaw treated?
When avascular necrosis of the jaw develops, it remains unclear how best to treat it. This has led to the great concern that both patients and healthcare providers are experiencing. Treatment protocols are being designed, but they have not been tested.
It is prudent for all patients to have a dental exam and cleaning prior to beginning bisphosphonate therapy, and regular dental cleaning should continue throughout the duration of use. As infection possibly triggers ONJ, the hope is that proper dental care will reduce the incidence of osteonecrosis of the jaw.
Discontinuing bisphosphonate therapy for low turnover state of bone may help prevent this condition (one way to measure turnover state in bone is the urinary N-Telopeptide, and some physicians suggest stopping bisphosphonate therapy if this result is less than 10). However, this remains controversial, and there is little evidence to support this approach.
If ONJ develops in any patient, patients should be treated with conservative debridement of affected bone, antibiotics, antimicrobial mouth washes, and pain control. Bisphosphonate therapy is generally discontinued if this condition occurs, although there is no data to show that this leads to resolution of the problem.
What are other side effects of bisphosphonates?
Uncommon side effects of bisphosphonate therapy include fractures of the femur (such as a hip fracture) and inflammatory eye disease.
Atypical stress fractures of the thighbone
Stresss fracture of the femur (thighbone), is an uncommon side effect believed to occur as a result of slow bone turnover and a lack of remodeling of “old” bone into new bone. The risk of this rare complication increases with duration of treatment. It almost never occurs in patients who have been treated with bisphosphonates for less than five years. The fracture has a classic appearance on X-ray.
If a patient receiving bisphosphonate therapy notes thigh pain, a femur X-ray should be obtained. The radiologist may be able to see signs suggestive of patients at risk for this type of fracture. If a patient is on a bisphosphonate at the time of an atypical femur fracture, the bisphosphonate should be held and the fracture repaired. The patient may be a good candidate for teriparatide.
Inflammatory eye disease
Data suggests that scleritis and uveitis, which are types of eye inflammation, may also be rare side effects of bisphosphonate therapy. Symptoms are often a red, painful eye that is sensitive to light. The condition can usually be treated with eye drops. Patients on bisphosphonates should be instructed to call their provider if these signs are noted.
What are the risks and benefits of bisphosphonates?
As when any medication is prescribed, the risks and benefits of that medication must be considered. For the treatment of osteoporosis, patients must understand that hip fractures can lead to significant disability and death (e.g., from clots in the lung related to leg clots that develop after fracture), and that multiple vertebral fractures can cause very significant pain and disability. This must be weighed against what appears to be a probably very low risk of osteonecrosis of the jaw, atypical stress fractures of the femur, esophageal irritation, and inflammatory eye disease.
Oncologists treating patients with multiple myeloma and metastatic cancer have a different set of concerns, and the use of bisphosphonates in a patient who has cancer requires that a different set of issues be weighed. In patients being treated for osteoporosis, the consequences of untreated disease, with resultant fractures must not be forgotten when striking the proper balance.
Osteoporosis remains a significant problem for society. The number of osteoporotic fractures is expected to rise as the population ages. The risk of an osteoporotic fracture in a patient at risk is much greater than the risk of ONJ in that patient. Most cases of ONJ can be treated conservatively. This area requires additional study so that we can all better understand the risk and appropriate treatment of ONJ.
After balancing the risks and benefits, bisphosphonates will likely remain the best choice for many patients with osteoporosis. However, the decision regarding the optimal drug for managing osteoporosis in each patient is quite individual and should be determined on a case-by-case basis. Patients on bisphosphonate therapy should be reevaluated annually to see if continued use of the medication is indicated.
Katherine Noto Haseltine, MD
Assistant Attending Physician, Hospital for Special Surgery
Assistant Professor of Clinical Medicine, Weill Cornell Medical College
Assistant Attending, NewYork-Presbyterian Hospital
Linda A. Russell, MD
Associate Attending Physician, Hospital for Special Surgery
Director of Perioperative Services, Hospital for Special Surgery
Bisphosphonates | How do bisphosphonates work?
Examples of conditions which bisphosphonates can help treat are:
The rest of this leaflet is only about bisphosphonates that your doctor may prescribe for osteoporosis in order to prevent broken bones (fractures). See the separate leaflet called Osteoporosis to learn about this condition.
The bisphosphonates that are usually prescribed for this are tablets. Those available in the UK are alendronate (the most used one), risedronate and ibandronic acid and they have various different brand names. In some circumstances, bisphosphonates can also be given by injection. The ones available in the UK for injection are ibandronic acid and zolendronic acid.
How do bisphosphonates work?
Bisphosphonates work by slowing down the cells which break down bone (osteoclasts). Therefore they slow down bone loss, allowing the bone building cells (osteoblasts) to work more effectively. They can help to strengthen bone and help to prevent it getting any weaker. People who take a bisphosphonate are less likely to break (fracture) a bone.
Who should have bisphosphonates?
Your doctor may prescribe a bisphosphonate if you:
How quickly do bisphosphonates work?
It takes several months for bisphosphonates to work. Usually there is an increase in bone density 6-12 months after you start taking one. This then helps to prevent breaks (fractures) of the spine, the hip, and other bones such as the wrist. But you can still have a fracture while you are taking a bisphosphonate – they do not totally reduce your risk. They usually need to be taken for some years to see the full effect.
What is the usual length of treatment?
Not everyone agrees on how long bisphosphonates should be taken for. Most doctors recommend that a bisphosphonate be taken for at least three to five years. After this they will review you to see if you still need to take it. You may not need to continue taking a bisphosphonate. However, some people need to take a bisphosphonate for longer. Your doctor will advise. There is some evidence from studies that bisphosphonates keep working on the bone for a few years after the medicine has been stopped. It may also be that taking them for longer than five years does more harm than good. More studies are being done to find out exactly what should be recommended in terms of how long bisphosphonates should be taken.
Which bisphosphonates might I be prescribed?
In the UK, bisphosphonates are usually prescribed in the form of tablets:
- Alendronic acid – taken usually once a week, although they are also available as a daily tablet. This is also available as a liquid for people who have difficulty swallowing the tablets, although it is much more expensive for the NHS.
- Risedronate – taken usually once a week, although also available as a daily tablet.
- Ibandronic acid – taken once a month (also available as an injection – see below).
In some cases – for example, if the tablets give you too many side-effects, or if you are at greater risk of fractures – bisphosphonate injections might be used:
- Ibandronic acid – an injection into your vein every three months. Each injection takes less than a minute
- Zoledronic acid – an infusion once a year. This is slowly given into the vein over at least 15 minutes. You will need a blood test before each infusion, to check on your calcium, vitamin D, magnesium levels and kidney function. Injections are usually given by a specialist nurse.
How to take bisphosphonate tablets
Bisphosphonates are taken either once a day, once a week (on the same day of the week), or once a month (on the same day of the month), depending on the one prescribed. Most people take their bisphosphonate first thing in the morning before they eat or drink anything. If you take a bisphosphonate with food, or drinks other than water, only a small amount of the medicine is absorbed.
You need to wait between 30 minutes and 2 hours before eating or drinking anything (other than water). The information leaflet that comes with your tablets will tell you exactly how long you should wait.
You need to swallow the tablet with a full glass of water and sit upright for 30 minutes afterwards. This is because bisphosphonates can irritate the upper part of your gullet (oesophagus – the tube that takes food and drink from your mouth to your stomach).
When taking bisphosphonates
Some important considerations are:
- What to do if you forget to take your tablets.
- Have regular dental check-ups.
- What to do if you have heartburn or difficulty swallowing.
- Take calcium and vitamin D tablets.
- Do not take certain other medicines.
What to do if you forget to take your tablets
- If you are taking a once-a-day bisphosphonate: skip the missed tablet for that day and continue taking them as usual the next day.
- If you are taking a once-a-week bisphosphonate: take the missed tablet when you remember and take the next tablet when it is normally taken. Do not take more than two tablets on the same day.
- If you are taking a once-a-month bisphosphonate and you are due to take your tablet within the next seven days then do not take another tablet. Take another tablet on the day you are next due to take one.
- If you are taking a once-a-month bisphosphonate and you are due to take your next tablet in more than seven days then take the tablet when you remember (in the morning). Do not take two tablets within the same week.
Regular dental check-ups
You must tell your dentist if you are taking a bisphosphonate. You will need to have regular dental check-ups. Also it is advisable to have a dental check-up before starting a bisphosphonate. This is because there is a very small chance that you will get a condition called osteonecrosis of the jaw. In this rare condition the jawbone does not receive enough blood and the bone starts to weaken and die. It is usually painful, but not always. In most people, this goes away after they have stopped taking their medicine.
Heartburn or difficulty swallowing
Bisphosphonates can sometimes cause difficulty swallowing, pain when you swallow, chest pain, or new/worsened heartburn. You must stop taking the bisphosphonate and speak with your doctor if you have any of these problems. Your doctor may consider prescribing a different bisphosphonate or a different type of medicine to help prevent broken bones (fractures).
Calcium and vitamin D
You need calcium and vitamin D to make bone. Many doctors will usually also prescribe calcium and vitamin D if you take a bisphosphonate. This is in order to make sure there is enough calcium and vitamin D in your body. There are quite a few calcium and vitamin D preparations. They include: a chewable tablet, an effervescent tablet, or a sachet. They can be prescribed as a combination of the two, just calcium, or just vitamin D. Your doctor will advise which one is right for you. Your doctor will ask about your diet. If you are already having enough calcium in your diet, you should not take calcium supplements as well. This is because too much calcium may be harmful for you. Calcium and vitamin D are normally taken every day (at a different time to the bisphosphonate).
Taking other medicines
Bisphosphonates sometimes react with other medicines that you may take. So, make sure your doctor knows of any other medicines that you are taking, including ones that you have bought rather than been prescribed. Always check with your pharmacist before you buy any painkillers from the pharmacy or supermarket. Some painkillers – for example, ibuprofen and aspirin – can irritate your gullet (oesophagus) if you take them with a bisphosphonate.
What are the possible side-effects?
The most common side-effects of bisphosphonates are feeling sick (nausea), indigestion and heartburn (dyspepsia), tummy (abdominal) pain, diarrhoea or constipation. These side-effects usually happen in the first month of treatment but usually go away after this.
Other common side-effects are joint, and/or muscle pain (usually not severe). This pain can happen a few days or a few months after you first start treatment. This pain normally goes away after you stop taking a bisphosphonate. A full list of possible side-effects (each of which will only happen to a few people) is included in the leaflet which comes with the medicine.
Less commonly some people experience more serious side-effects to their gullet (oesophagus). The oesophagus is the upper part of the digestive system, the food pipe that carries food and drink from your mouth to your stomach. Sometimes bisphosphonates can cause inflammation or ulcers of the oesophagus, or a narrowing of the oesophagus. Taking the medicine carefully according to the instructions makes these side-effects less likely. As mentioned above, if you develop any symptoms such as difficulty or pain swallowing, worsening heartburn, or chest pain, you should stop the tablets and see your doctor. There have been very rare reports of bisphosphonates possibly causing cancer of the oesophagus but there is no definite evidence for this currently.
A rare side-effect is osteonecrosis of the jaw. This occurs when the jawbone does not receive enough blood, and the bone starts to weaken and die. You must stop taking bisphosphonates if this happens.
These medicines sometimes react with other medicines that you may take. So, make sure your doctor knows of any other medicines that you are taking, including ones that you have bought rather than been prescribed.
Can I buy bisphosphonates?
You cannot buy bisphosphonates. They are only available from your chemist, with a doctor’s prescription.
Who cannot take bisphosphonates?
You cannot take a bisphosphonate if:
- You have low calcium levels in your blood (hypocalcaemia).
- You have uncorrected vitamin D deficiency.
- You are pregnant or breastfeeding.
- Your kidneys do not work very well.
- You cannot sit upright or stand for 30 minutes after you have taken the tablet.
- You have structural problems with your gullet (oesophagus) which slows down the length of time it takes for the bisphosphonate to reach your stomach. Examples of these include: a narrowing of the oesophagus, or Barrett’s oesophagus.
In addition, you may not be able to take a bisphosphonate if you have a recent history of tummy problems such as stomach ulcers, duodenal ulcers or inflammation of the upper gut.
How to use the Yellow Card Scheme
If you think you have had a side-effect to one of your medicines you can report this on the Yellow Card Scheme. You can do this online at www.mhra.gov.uk/yellowcard.
The Yellow Card Scheme is used to make pharmacists, doctors and nurses aware of any new side-effects that medicines or any other healthcare products may have caused. If you wish to report a side-effect, you will need to provide basic information about:
- The side-effect.
- The name of the medicine which you think caused it.
- The person who had the side-effect.
- Your contact details as the reporter of the side-effect.
It is helpful if you have your medication – and/or the leaflet that came with it – with you while you fill out the report.
Bisphosphonates for the treatment of steroid-induced osteoporosis
Steroids (glucocorticosteroids) are widely used to treat inflammation. Bone loss (osteoporosis) and spinal fractures are serious side effects of this therapy. Bisphosphonates, which have been used since the 1990s, are considered the first line of treatment for osteoporosis.
We reviewed studies published up to April 2016 and found a total of 27 eligible trials involving 3,075 adults with inflammatory conditions who required steroid treatment for at least 1 year.Individuals were randomly assigned to receive either bisphosphonates (alone or in combination with calcium and / or vitamin D) or “no treatment” (received calcium or vitamin D or placebo). Our goal was to determine the benefits and harms of bisphosphonates in adult patients on long-term steroid therapy.
New spinal fractures (12 to 24 months)
For this analysis, there were 12 trials involving 1343 people.We found that 77 out of 1,000 untreated patients suffered new spinal fractures, compared with 44 out of 1,000 (27 to 70) treated with bisphosphonates. The absolute benefit was that 2% fewer patients (5% decrease to 1% increase) experienced spinal fractures while taking bisphosphonates.
Approximately 31 people (20 to 145) will need bisphosphonate treatment to prevent spinal fractures in one person.
New fractures other than the spine (12-24 months)
For this analysis, there were 9 trials involving 1245 people.We found that 55 out of 1000 untreated people experienced new fractures other than the spine, compared with 42 out of 1000 (25 to 69) who received bisphosphonates. The absolute benefit was that 1% fewer people (from a 4% decrease to a 1% increase) experienced fractures other than the spine while taking bisphosphonates.
Bone mineral density of the lumbar spine (BMD) after 12 months
For this outcome, there were 23 trials involving 2042 people.We found that lumbar spine BMD in people treated with bisphosphonates was 3.5% higher (2.9% to 4.1%) than in untreated people.
Approximately 3 people (2 to 3) will need bisphosphonate treatment for 12 months in order to see minimal significant changes in lumbar BMD in one person.
BMD of the femoral neck (upper part of the femur) after 12 months
For this outcome, there were 18 trials involving 1665 people.We found that femoral neck BMD in people in the bisphosphonate group was 2.06% higher (range 1.45% to 2.68%) than in people in the “untreated” group.
Approximately 5 people (4 to 7) will need bisphosphonate treatment for 12 months in order to see minimal significant changes in BMD of the femoral neck in one person.
Serious adverse events (requiring hospitalization, life-threatening or fatal)
For this outcome, there were 15 trials involving 1703 people.We found that 162 out of 1000 untreated people had serious adverse events, compared with 147 out of 1000 (120 to 181) who received bisphosphonates. The absolute increase in harm was 0% (from a 2% increase in serious adverse events to a 2% decrease) with bisphosphonates.
Dropout from research due to adverse events
For this outcome, there were 15 trials involving 1790 people. We found that 73 out of 1000 untreated patients dropped out of the trial, compared with 77 out of 1000 (56 to 107) who received bisphosphonates.The absolute increase in harm was 1% (from a 1% decrease in the number of dropouts due to adverse events to an increase of 3%) with bisphosphonates.
Based on moderate to high certainty evidence, we have found that bisphosphonates are useful in the prevention of new spinal fractures and in the prevention and treatment of steroid-induced bone loss in the lumbar spine and femoral neck.For the prevention of non-vertebral fractures, we found little or no difference between patients receiving or not receiving bisphosphonates, although the evidence was low in confidence due to the risk of bias in the methods used to assess fractures at other sites ( not the spine).
When comparing bisphosphonates with no treatment, we found little or no difference in the number of serious adverse events or dropouts due to adverse events.Confidence in the evidence for these outcomes was low, and we are cautious in drawing any conclusions about the dangers of bisphosphonates based on this data alone.
Overall, our review supports the use of bisphosphonates to reduce the risk of spinal fractures and to prevent and treat steroid-induced osteoporosis.
Bisphosphonates: Issues of Long-Term Therapy and Evidence of Efficacy in Real Clinical Practice
Article published on p.29-36
The importance of the problem of osteoporosis is primarily determined by its consequences – fractures of the vertebrae and bones of the peripheral skeleton, causing a significant increase in morbidity, disability and mortality in such patients. Treatment of osteoporosis is a difficult task: on the one hand, this is due to the multifactorial and multifaceted nature of its pathogenesis and progressive course, on the other, by the latent onset and development of a complete clinical picture only when complications appear: fractures, skeletal deformities, persistent pain syndrome.Bisphosphonates (BP) were among the first drugs for the treatment of osteoporosis worldwide. The structural similarity to bone hydroxyapatite makes them resistant to chemical and enzymatic hydrolysis in the human body. Due to this property of BP, it was possible to increase the intervals between repeated administrations of drugs of this group from a single daily oral intake to a single annual intravenous administration and thus to increase the efficiency and adherence of patients to treatment .To date, there is incontrovertible evidence of the high efficacy of BP in long-term continuous therapy for 3 to 10 years, regardless of the method of administration of the drug.
The molecular mechanism of action of nitrogen-containing bisphosphonates is based on the suppression of the key enzyme of the intracellular mevalonate pathway of cholesterol synthesis – farnesyl diphosphate synthase (PDS). Metabolic products of mevalonate include cholesterol and specific low molecular weight G proteins of the Rab, Ras, Rap and Rho families.They are involved in the processes of intracellular signaling, proliferation, differentiation, apoptosis, cell migration, regulation of gene transcription, maintenance of the cytoskeleton, and the implementation of protective reactions of bone cells. When bisphosphonate suppresses the enzyme PDS, these proteins do not undergo post-translational modification with the help of farnesyl pyrophosphate and geranyl pyrophosphate, which leads to disruption of the vital functions of osteoclasts and causes a powerful and long-term anti-resorption effect of BP [16, 20, 21].The mechanism of action of bisphosphonates is shown in Fig. 1. Each BP has a unique profile of binding affinity for hydroxyapatite and antiresorptive power, which probably leads to clinically significant differences in the rate of onset and retention of the effect, the degree of decrease in bone metabolism, absorption by spongy tissue and the severity of the anti-fracture effect (reducing the risk of vertebral and non-vertebral fractures).
Thus, the main pharmacological effect of BP is a decrease in the rate of bone remodeling with inhibition of the resorption phase .Among the anabolic effects of BP, the ability to increase the survival of osteocytes and osteoblasts by blocking their apoptosis, to increase the synthesis of type 1 collagen by osteoblasts, is distinguished. This is accompanied by positive changes in bone microarchitectonics and an increase in the mineral component. As a result, bone trabeculae thicken and bone loss is prevented [1, 11].
To date, the duration of pharmacological therapy for osteoporosis has not been determined. Treatment of osteoporosis requires a comprehensive risk assessment (no later than 2 years from the start of therapy) and an individual determination of the duration of treatment .It is assumed that the doctor should be guided by the assessment of the risk of fractures in the patient, indicators of the effectiveness and safety of the drug with long-term use . The efficacy with long-term use of BP was evaluated in various studies: with 10-year use of alendronate , 7-year use of risedronate  and 9-year intravenous administration of zoledronate , 5-year use of ibandronate [22, 31].
Since BP accumulates in the bones, they create a kind of “healing reservoir” leading to their continued release from the bone for several months or years after the therapy is stopped .It is this property of BF that justified the possibility of holding the so-called drug holidays without reducing the effect and increasing the risk of fractures after 5-10 years of continuous use. Therapy with any drugs that do not belong to the BP group gives an effect that disappears after the end of treatment (the presence of a clinical effect only during therapy). In contrast, BP (including ibandronic acid) continues to act even after stopping treatment. Therefore, it is possible to stop taking BP and preserve the residual effect of their effect, which protects against fractures, for several years.
For the first time, the establishment of the duration of BP therapy and a possible interruption in treatment were discussed after the description of cases of serious side effects, primarily atypical bone fractures and osteonecrosis of the jaw [2, 5]. And although subsequent studies indicated a multiple excess of the benefits of BF therapy over the potential risk of these rare unwanted effects, the question of the need for interruptions in treatment, including to reduce the risks of adverse reactions, has become an important and most studied topic.The latest recommendations for the rational use of BP indicate the possibility of 5-year BP administration without the risk of developing atypical hip fractures; in the future, an assessment of the risk of fractures and a break in treatment is necessary , but this does not apply to patients with a high risk of fractures, who are recommended to continue taking BP under the control of markers of bone resorption . Thus, the duration of treatment and drug vacation is based on the assessment of the risk of fractures and the pharmacokinetics of the BPs used [7, 14].
The estimated duration of the use of bisphosphonates and drug vacations is presented in table. 1.
Patients at moderate risk of fracture may discontinue treatment after 5 years of BP and not resume treatment as long as BMD remains stable and fractures do not occur. Patients with a higher risk should take BP for a long time – up to 10 years, and the duration of the drug vacation is shortened, respectively, up to 1–2 years. For this period, it is recommended to prescribe drugs with a different mechanism of action .
Numerous studies have shown that there is a residual effect of BP after discontinuation. Therefore, it has been suggested that doctors might consider taking a drug vacation, a kind of vacation after prolonged use of BP, in some patients. The main questions are related to the need for a clear definition of the duration of BF therapy, the identification of groups of patients in whom interruptions in treatment can be applied, and also with the establishment of the boundary period for stopping BF treatment .It has been proposed  to stratify patients according to their known or potential fracture risk. The high-risk group included patients with a previous history of fractures, a low T-score, as well as with secondary osteoporosis and using glucocorticoid therapy. In such patients, it was recommended to continue BF therapy for up to 10 years and only then consider the possibility of a drug vacation. During this time, the use of other agents such as teriparatide or raloxifene may be warranted.In the middle-risk group, a break in BF treatment is possible after 5–10 years, and at a low risk – after 3-5 years of BF therapy. BP therapy should be resumed if BMD, as measured by two-photon X-ray absorptiometry (DXA) every 1–2 years, decreases, or new fractures occur. The exact duration of the drug vacation is unknown, it should be determined individually for each patient, however, researchers suggest a period of 1–2 years in high-risk patients and 3–5 years in moderate-risk patients .The algorithm for long-term treatment of osteoporosis using bisphosphonates and the principles of monitoring the effectiveness are shown in Fig. 2.
Therefore, physicians treating patients with osteoporosis should clearly discuss with them the duration of treatment and possible interruptions in therapy before starting treatment, explaining the benefits and possible risks. The decision on the duration of therapy should be individual for each patient, with an annual assessment of risk factors, response to therapy, increase in BMD and, potentially, determination of markers of bone metabolism.This is how serious adverse events can be prevented while maximizing the benefits of effective osteoporosis therapies.
One of the well-known and widely used BP is ibandronic acid (ibandronate, Bonviva), which is successfully used for the treatment and prevention of osteoporosis in more than 60 countries of the world, including the European Union and the United States. The most famous form of the drug is 150 mg tablets, used once a month.Ibandronate is so far the only BP that, when taken monthly, leads to the restoration of adequate bone metabolism, an increase in bone mineral density and bone strength, and reduces the risk of vertebral and extravertebral fractures in the high-risk group . More recently, an injectable form of ibandronate has appeared in Ukraine – for intravenous administration at a dose of 3 mg for use once every 3 months. Thus, the advantages of intravenous administration of ibandronate in the form of an increase in the interval between injections up to 3 months., independence of food intake and body position after taking the drug, the possibility of safe use in patients with pathology of the gastrointestinal tract allowed to significantly expand the therapeutic potential of osteoporosis treatment. The form for intravenous administration is especially preferred in patients with low adherence to treatment and in those who cannot comply with the requirements for taking tablet forms, including due to the development of side effects . The drug is administered as a short (15–30 s) bolus injection.Intravenous ibandronate has a greater bioavailability than the oral form (100 versus 0.6%) and may be prescribed less frequently to provide the same or greater total annual cumulative dose .
Several pivotal studies have been conducted on ibandronate, most notably the MOBILE study, an international phase III study comparing the efficacy and safety of monthly and daily ibandronate supplementation, and the DIVA study, a 2-year trial showing that intravenous ibandronate is effective, well is tolerated and represents an alternative to the oral form [13, 15].
Thus, as a result of recent studies, including long-term studies of MOBILE and DIVA, the efficacy of two dosage forms of ibandronic acid (1 tablet monthly and 1 intravenous injection quarterly) has been confirmed in the form of a continuing increase in BMD and a continuing low level of markers of bone resorption. The main advantage of ibandronate is the possibility of intermittent oral administration and parenteral administration, which is rational both from a medical and pharmacoeconomic point of view.
Clinical experience shows that the use of Bonviva in the complex therapy of postmenopausal osteoporosis contributes not only to a progressive increase in BMD in the lumbar spine and proximal femur, but also to a decrease in the risk of vertebral fractures. We present the most striking clinical examples of the use of Bonviva in the treatment and prevention of osteoporosis.
Case 1. Patient D., 50 years old, at the next visit to the gynecologist noted the appearance of pain in the bones, joints, lumbar region, not associated with physical activity, as well as limited mobility in the morning, which lasts 20-30 minutes.From the anamnesis it is known that menopause came at the age of 47. Vegetative disorders are not significantly expressed. She did not receive hormone replacement therapy.
On physical examination: height 170 cm, weight 67 kg. When calculating the risk of fractures using the FRAX system, the following risk factors were identified: smoking, the presence of a fracture of the radius in a typical place (3 years ago, falling from a height during icy conditions on the street), the presence of a fracture of the femur in the mother. When calculating the risk of fractures, the following indicators were identified: the risk of osteoporotic fractures within the next 10 years – 10%, fractures of the femoral neck – 1.4%.To determine BMD, the patient was referred for bone densitometry. According to its results, a significant decrease in BMD in the lumbar region was recorded – 0.924 g / cm2, T-index – –1.1 SD. However, more significant changes were found in the femoral neck: BMD – 0.607 g / cm2, T-index – –2.2 SD. The data obtained served as the basis for recalculating the risk of fractures according to the FRAX system. Taking into account the BMD data of the femoral neck, it was found that the risk of osteoporotic fractures was 15%, femoral neck fractures – 3.8%.Thus, low values of the mineral density of the femoral neck significantly increased the risk of fractures, which became the basis for the appointment of anti-osteoporotic therapy. The patient was prescribed Bonviva 150 mg once a month in the morning on an empty stomach. A conversation was held regarding the need for careful adherence to the rules for taking the drug. Additionally, calcium supplements were prescribed at a dose of 1200 mg per day (in terms of elemental calcium) and recommendations were given for dietary nutrition with an emphasis on calcium-containing foods.
After 10 months. therapy, a significant significant increase in bone mass was noted, which was objectively reflected by the BMD of the lumbar region and the femoral neck (Fig. 3, 4).
Thus, the increase in bone mass in the lumbar spine was 6.9%, the BMD increased from 0.924 to 0.988 g / cm2, the T-index decreased to –0.5 SD. In the femoral neck, the changes in BMD were just as dynamic: the mineral density increased by 2.8% – from 0.607 to 0.639 g / cm2. But most importantly, this therapy helped to reduce the risk of fractures according to the FRAX system.After 10 months. the risk of major osteoporotic fractures decreased to 13%, and of fractures of the femoral neck – to 2.5%. The data obtained indicate the effectiveness of Bonviva in the prevention of postmenopausal osteoporosis and in reducing the risk of osteoporotic fractures.
Case 2. Patient M., 51 years old. Natural menopause from 45 years old. Complaints about a decrease in height by 3 cm over the past 3-4 years, constant pain in the lumbar spine and its stiffness, pain in the peripheral joints without swelling.No other risk factors for osteoporosis were identified in the patient. Height 160 cm, weight 52 kg. When tested according to the FRAX system, the risk of osteoporotic fractures is 6.4% over the next 10 years, the risk of developing femoral neck fractures is 1.1%. The densitometric study established the following results: the total BMD in the lumbar spine is 0.768 g / cm2, the T-index is –2.5 SD. In different vertebrae, the T-index ranged from –2.3 to –2.8 SD (Fig. 5). In the femoral neck, the T-index on the right was –1.5 SD, on the left –1.6 SD.
The patient was prescribed therapy with Bonviva at a dose of 150 mg once a month with calcium (1200 mg / day) and vitamin D (800 IU / day). Evaluation of the effectiveness of treatment was carried out after 12 months. In the lumbar spine, the increase in bone mass was + 5.6%; in the area of the femoral neck – + 6.8%. The T-index of the lumbar spine was –2.1 SD, in the region of the neck of the left femur –1.2 SD. After 27 months. therapy, the increase in BMD in the lumbar spine was + 6.9% (Fig. 6), in the area of the left femur neck – +7.3% (Fig. 6).7). The risk of fractures decreased to 5.5%, femoral neck fractures – to 0.6%.
This case demonstrates a persistent positive effect of Bonviva during 27 months of continuous therapy, which led to an increase in BMD and a decrease in the risk of fractures. It should be noted that during the entire follow-up period, the patient had no new fractures or significant side effects.
Thus, the use of ibandronic acid (Bonviva) leads to a decrease in the risk of osteoporotic fractures, a persistent increase in the BMD of the lumbar spine and femur.Therefore, the drug can be successfully used in the prevention and treatment of patients with postmenopausal osteoporosis.
BPs have been used for the treatment of osteoporosis since 1995, and during this time their high efficacy, combined with safety and good tolerance, has been demonstrated both in randomized clinical trials (RCTs) and in real clinical practice. BP remains the most studied drugs for the treatment of osteoporosis with a huge evidence base for anti-fracture efficacy.The summarized data of RCTs of ibandronate, meta-analyzes, studies with surrogate endpoints and studies on the quality of bone tissue using both the latest technologies and traditional histological examination, as well as the results of observational studies in routine clinical practice, indicate comparable therapeutic efficacy of ibandronate and all others. BP in relation to the prevention of vertebral fractures and all extravertebral fractures [1, 6]. Ibandronate is advantageous due to its more convenient dosing regimen and different routes of administration.In addition, ibandronate is well tolerated and has a fairly high safety, possibly even surpassing other nitrate-containing BP in some respects.
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10. Bone H.G., Hosking D., Devogelaer J.-P. et al. Alendronate Phase III Osteoporosis Treatment Study Group Ten years ’experience with alendronate for osteoporosis in postmenopausal women // N.Engl. J. Med. 2004; 350: 1189-1199.
11. Burr D.B., Diab T., Koivunemi A. et al. Effects of 1 to 3 years ’treatment with alendronate on mechanical properties of the femoral shaft in a canine model: implications for subtrochanteric femoral fracture risk // J. Orthop. Res. 2009; 27 (10): 1288-1292. doi: 10.1002 / jor.20895.
12. Cosman F., de Beur S.L., LeBoff M.S. Clinician’s Guide to Prevention and Treatment of Osteoporosis // Osteoporos. Int. 2014; 25 (10): 2359-2381.doi: 10.1007 / s00198-014-2794-2.
13. Delmas P.D., Adami S., Strugala C. et al. Intravenous ibandronate injections in postmenopausal women with osteoporosis: one-year results from the dosing intravenous administration study // Arthr. Rheum. 2006; 54: 1838-1846.
14. Diab D.L., Watts N.B. Bisphosphonate drug holiday: who, when and how long // Ther. Adv. Musculoskelet. Dis. 2013; 5 (3): 107-111. doi: 10.1177 / 1759720X13477714.
15. Eisman J.A., Civitelli R., Adami S. et al. Efficacy and tolerability of intravenous ibandronate injections in postmenopausal osteoporosis: 2-year results from the DIVA study // J. Rheum. 2008; 35 (3): 488-497.
16. Matthew E.L., Robert A.P., Robert E.F. Farnesyl Diphosphate Synthase: a novel genotype association with bone mineral density in elderly women // NIH Public Access. 2007; 57 (3): 247-252. doi: 10.1016 / j.maturitas.2007.01.005.
17. Mellstrom D. D., Sorensen O. H., Goemaere S. et al. Seven years of treatment with risedronate in women with postmenopausal osteoporosis // Calcif.Tissue Int. 2004; 75: 462-468.
18. Ott S.M. What is the optimal duration of bisphosphonate therapy? // Cleveland Clin. J. Med. 2011; 78 (9): 619-630. doi: 10.3949 / ccjm.78a.11022.
19. Ro C., Cooper O. Bisphosphonate drug holiday: choosing appropriate candidates // Curr. Osteoporos. Rep. 2013; 11 (1): 45-51. doi: 10.1007 / s11914-012-0129-9.
20. Rogers M.J., Crockett J.C., Coxon F.P., Mönkkönen J. Biochemical and molecular mechanisms of action of bisphosphonates // Bone.2011; 49 (1): 34-41. doi: 10.1016 / j.bone.2010.11.008.
21. Rogers M.J. New insights into the molecular mechanisms of action of bisphosphonates // Curr. Pharm. Des. 2003; 9 (32): 2643-2658.
22. Stakkestad J. A., Lakatos P., Lorenc R. et al. Monthly oral ibandronate is effective and well tolerated after 3 years: the MOBILE long-term extension // Clin. Rheum. 2008; 27 (8): 955-960.
23. Watts N.B., Diab D.L. Long-term use of bisphosphonates in osteoporosis // J.Clin. Endocrinol. Metab. 2010; 95 (4): 1555-1565. doi: 10.1210 / jc.2009-1947.
Treatment of hypercalcemia with bisphosphonates in breast cancer
Paraneoplastic hypercalcemia is not such a rare occurrence, its frequency in some diseases reaches 10-15%. Usually it is detected at a late stage of the tumor, but sometimes it is the first symptom of the disease. This applies, as a rule, to humoral hypercalcemia – one of the tumor variants that develops as a result of the secretion of a tumor of substances – PTH-like peptides that stimulate bone resorption.An example is humoral hypercalcemia in squamous cell lung cancer or hypernephroma, when the presence of bone metastases is not necessary for the development of a pathological condition. Substances secreted by the tumor change the metabolism of bone tissue, enhancing the activity of osteblasts and osteoclasts. The second variant of paraneoplastic hypercalcemia is osteolytic, resulting from the destruction of bone tissue by the tumor. In breast cancer, hypercalcemia has signs of both.The prevailing variant is osteolytic hypercalcemia, when tumor cells not only destroy the bone themselves, but also secrete cytokines, group E prostaglandins, which activate osteoclasts and stimulate bone resorption near metastases. Breast cancer cells also secrete parathyroid hormone-like peptides, which is a sign of humoral hypercalcemia.
A special form of hypercalcemia, the so-called “tumor flare hypercalcemia”, occurs in 5-6% of breast cancer patients in the first 6 weeks of taking tamoxifen or progestins.This drug-induced hypercalcemia is very successfully treated with bisphosphonates without discontinuation of endocrine drugs .
Hypercalcemia may be associated with an overdose of vitamin D preparations. Vitamin D deficiency occurs when its absorption is impaired in a number of non-neoplastic diseases, insufficient insolation from October to March. It is no secret that many breast cancer patients are taking vitamin D supplements under the influence of advertising for no reason. Such hypercalcemia is treated with drug withdrawal, bisphosphonates are inappropriate here.
Symptoms of hypercalcemia appear when calcium is higher than 3 mmol / l, but this is not at all necessary – there is no clear relationship between the degree of hypercalcemia and clinical manifestations. Sometimes high blood calcium is an accidental finding. Paraneoplastic hypercalcemia can manifest as fatigue, depression, confusion, lack of appetite, nausea, vomiting, reversible renal tubular dysfunction, and arrhythmia. Therefore, if you suspect hypercalcemia, you should immediately do a blood calcium test.By postponing this study and sending the patient home for 1-2 days, you risk losing her. Severe hypercalcemia with calcium levels above 3.7 mmol / L is dangerous for the development of coma and cardiac arrest. Under the guise of a satisfactory state of health with symptoms of minimal severity, a far from easy hypecalcemia can be hidden.
Unfortunately, knowing about the clinical manifestations of hypercalcemia and the gradation of severity according to the blood calcium content, we forget that in pathological conditions, the level of total blood calcium, consisting of three fractions, should not be taken as a basis: 40% of it is associated with proteins, 10 % – over-ionized ions and half – ionized.The body of a healthy person contains 1-2 kg of calcium, of which 98% is in the bone tissue. Only 0.5% of total bone calcium is freely exchanged with calcium in the extracellular fluid. The constant change in calcium is associated with the pH of the plasma and the state of the intestines and kidneys, controlled by at least three hormones. Only ionized calcium is constant and changes in diseases of the bone tissue .
The norm of serum (total) calcium 8.5-10.3 mg% or 4.2-5.2 meq / l or 2.2-2.6 mmol / l; ionized – 4.2-5.2 mg% or 2.1-2.6 meq / l or an average of 1.2 mmol / l; in SI: total 2.1-2.2 mmol / l, ionized 1.05-1.3 mmol / l .If direct measurement is impossible, the ratio of ionized and bound calcium can be estimated by the formula :
Protein-bound calcium (%) = 0.8 × Albumin (g / L) + 0.2 × Globulin (g / L) + 3
In his already classic, constantly updated work “Bisphosphonates in Bone Disease” Herbert Fleisch, having analyzed a huge amount of literature, concludes that for the treatment of acute hypercalcemia it is difficult to give preference to any drug – clodronate, pamidronate or ibandronate, and in chronic hypercalcemia – for calcemia, oral clodronate and intravenous pamidronate are equally effective .
Everyone knows the table of the antiresorption activity of bisphosphonates, showing an increase in the latter from etidronate (-1x) to zoledronate (> 10000x), where the differences between clodronate, pamidronate and ibandronate are -10x, -100x,> 1000- <10000x. But this study was carried out on rats . Unlike rats, the power of inhibition of bone resorption by bisphosphonates in humans is ten times lower, which is not surprising, if only because the life cycle of a rat is 2-2.5 years, so the processes in its body go much faster, with a different potency and differently than in humans.
Back in 1994, Green J.R. et al showed that the activity slightly differed between clodronate and pamindronate, significantly increased in vitro in mouse cells, in vivo in rats, these differences were exacerbated . A prospective study involving 8905 healthy women with different bone mineral density showed that the likelihood of developing bone metastases is higher than bone mineral density is higher, while this indicator is lower in osteoporosis .It would seem that bone lysis in osteoporosis should be more favorable for the occurrence of metastases against this background, but it turns out just the opposite. And if in one biological type, with the apparent similarity of the mechanism of pathological resorption and bone formation, such differences are noted, then when comparing the therapeutic effect of a drug in different biological types, these differences increase manifold. That is why it cannot be assumed that ibandronate in women will be 10-100 times more effective than pamidronate and 100-1000 times more effective than clodronate.In contrast to rats, the power of inhibition of bone resorption by bisphosphonates in humans is ten times lower.
A randomized study of the comparative efficacy of recommended doses ibandronate and pamidronate for hypercalcemia, conducted in 19 centers on 72 patients, stratified by baseline calcium and daily monitoring, gave the following results. The mean decrease in calcium from baseline after 4 days was greater for the ibandronate group than for the entire pamidronate cohort.The frequency of the effect, the duration and the time of the onset of the calcium decline were the same for both groups. However, in 11 patients with a baseline calcium level of 3.4–4.0 mmol / L, the mean decrease in the ibandronate group was more than two-fold higher than in the pamidronate group. Thus, the advantage of ibandronate in tumor-associated hypercalcemia is detected when the initial calcium level is not lower than 3.5 mmol / L. It should be attributed to the advantages and the possibility of faster administration of ibandronate (30-minute infusion per 250 ml of saline), which does not increase the percentage of negative reactions compared to 2-hour .
Hoffmann-La Roche archival data confirm that ibandronate is more effective in osteolytic hypercalcemia than humoral hypercalcemia. At a dose of 2 mg, the effect was recorded in 63% and 57%, respectively. Ibandronate 4 mg was effective in 84% versus 68% in the humoral variant. In breast cancer, both variants can be present, but more often it is osteolytic .
The role of clodronate in the treatment of tumor-associated hypercalcemia has been extensively studied for 20 years.Most studies have shown high efficiency – up to 90% . It is possible to use both 5-day infusions and a single administration of 1500 mg of the drug , but not in those situations when an ambulance is really needed, that is, in severe hypercalcemia. There are very few doctors who risked injecting a five-day dose of 1500 mg at once – not because of fear of toxic reactions, but because of the prospect of subsequent proceedings with the administration of the institution adhering to traditional approaches.Therefore, it is better to use clodronate for mild or moderate hypercalcemia, “gently” reducing calcium for 5 days.
Zoledronate, in comparison with pamidronate, more effectively normalized serum calcium concentration: 32% of the day versus 18% . The effect of zoledronate is twice as long. The undoubted ease of infusion of zometa is also impressive. But this does not bode well for savings, since the cost of a zometa is much higher than aredia.
I think one should agree with Dr. Fleisch and in practice use any of the 4 drugs to treat hypercalcemia.Restrictions on treatment are imposed only by the spectrum of toxic reactions, which will be discussed below.
In outpatient practice, severe hypercalcemia is rarely recorded, such patients need to be hospitalized due to the possibility of coma. After all, the treatment of hypercalcemia cannot be limited only to the introduction of bisphosphonates, it is necessary to restore the BCC, force diuresis and at the same time make up for sodium losses. Mild hypercalcemia can be easily stopped on an outpatient basis, you just need to be sure that this is really a mild degree.
90,000 JC, program for 11/19/2019 – Institute of Chemistry, St. Petersburg State University
19.11.2019 within the framework of JC the following reports will be presented:
“ Platinum complexes of bisphosphonate derivatives as potential anticancer agents ”
Complex compounds of platinum (II), in particular cisplatin, are widely used in the therapy of a number of tumors localized in various areas of the body due to their high cytotoxic effect.Despite its widespread use, there are a number of problems associated with severe side effects due to their high toxicity, which makes it impossible to increase the therapeutic dose for more effective treatment. A promising approach is the use of bisphosphonate derivatives with a high affinity for the main component of bone tissue, hydroxyapatite, for the targeted delivery of platinum (II) complex compounds.
The report will consider a number of platinum complexes of bisphosphonate derivatives, evaluate the efficiency of their binding to hydroxyapatite, and evaluate and compare the cytotoxicity of potential anticancer agents.
“ Reactions of substituted 3-indolylmethanols under conditions of acid catalysis ”
Compounds containing an indole fragment are found in many natural objects, as a result of which indole is a unique pharmacophore exhibiting a wide spectrum of biological activity. Synthetic indole derivatives are used as medicines.
In view of the above, the study of the properties and methods of synthesis of structures, including indole, is a modern problem in organic chemistry.In recent years, the interest of the scientific community has been attracted by the chemistry of 3-indolylmethanols – indole derivatives exhibiting electrophilic activity in the presence of Lewis and Brønsted acids. The structures under consideration are synthetically available, and based on the analysis of the literature data, we can say that 3-idolylmethanols make it possible to successfully approximate the synthesis of many natural mediators.
Basic information on the reactivity of 3-indolylmethanols in the presence of acidic agents will be considered in the report.Also, the ways of using 3-indolylmethanol in organic synthesis studied to date will be presented.
“ Molecular magnets based on clusters and complexes of lanthanides ”
The history of molecular magnets dates back to 1993, when it was discovered that some transition metal compounds are capable of retaining magnetization in the absence of an external field. Molecular magnets can be called microscopic analogs of conventional ferromagnets, and therefore they can also be used to store information.However, their unique properties make it possible to store information at a much higher density, as well as to process it at unprecedented speeds. In addition, the phenomenon of molecular magnetism can be used in such a scientific field as spintronics.
The report will consider the essence of the phenomenon of molecular magnetism, demonstrate some approaches to the creation of effective magnets, and also outline the current problems of this scientific direction.
“ Firefly Luciferin Luciferase System: Bioluminescent Imaging Method ”
The firefly luciferin luciferase system is the most widely used non-invasive bioluminescence imaging in rodents in preclinical studies in vivo .The technology is based on an enzyme (luciferase) that catalyzes the oxidation of a low molecular weight substrate (luciferin) with the formation of electronically excited oxyluciferin, which emits a quantum of light during relaxation into the ground state, which can be registered by a sensitive detector. Limitations in in vivo bioluminescence experiments are the absorption and scattering of light by the tissue, as well as the poor permeability of the substrate into the cells of the body. To overcome the above obstacles, two ways can be used: either changing the structure of luciferase through mutagenesis, or engineering of luciferin, examples of the application of which will be considered in this work.
We would also like to draw your attention to the changes in the schedule of performances.
Bisphosphonates for the treatment of osteoporosis
Conditions leading to osteoporosis
Osteoporosis is not a rare disease and occurs in older people who are sedentary and do not use hormone replacement therapy. The disease is associated with a violation of calcium-phosphorus metabolism, when the processes of destruction in bone cells begin to prevail over recovery.The construction of new bone tissue is facilitated by osteoblasts, when the excess production of osteoclasts is able to release calcium into the blood from the bones.
Bisphosphonates – Application
The process that regulates calcium-phosphorus metabolism occurs continuously. If the patient does not receive calcium from food or this element is poorly absorbed, then in order to maintain its normal level in the blood, reserves from the bone tissue are released, which always maintain the same amount of the element in the plasma.If the calcium deficiency is prolonged, which is often the case with malnutrition and low physical activity, then over time osteopenia occurs – reduced bone mineral density, but not yet osteoporosis. Unlike mild osteopenia, osteoporosis is characterized by significant bone loss.
In what cases osteoporosis develops:
- Functional hypothalamic amenorrhea in women of reproductive age.
- Nutritional deficiencies.
- Low body weight.
- The presence of bad habits.
- Bone cancer.
- Rheumatoid arthritis long treated with corticosteroids.
Significant risk factor – pregnancy, long period of breastfeeding, childhood and adolescence in puberty.
Signs of osteoporosis
At the initial stages of the development of the disease, it is difficult to suspect osteoporosis. Osteoporosis is manifested by sudden falls and fractures, usually of the hip neck.If such a situation has occurred and the patient is at risk for the development of this disease (for example, a postmenopausal woman who does not take hormone replacement therapy or a person who uses corticosteroids for a long time), then densitometry is performed – the only accurate diagnostic method that allows you to determine bone mineral density for any stages. Less commonly, the disease is determined by the level of parathyroid hormone in the blood, but the laboratory type of diagnosis is less accurate.
Other signs may also indicate osteoporosis, including:
- Caries, erasure of tooth enamel.
- Muscle cramps in the calf muscles, occurring mainly at night.
- Pain in the bones and spine that is not relieved by the use of nonsteroidal anti-inflammatory drugs and other analgesics.
- Decrease in the height of the spine due to compression fractures, which appear mainly for no reason, which is also characterized by the development of an acute pain process.
If such symptoms appear, taking into account the entry into the risk group, you should consult a doctor – a rheumatologist or endocrinologist.
What are bisphosphonates, the mechanism of action of medicines
Bisphosphonates are medicines that directly affect bone metabolism. In terms of chemical structure, these substances are similar to phosphates of inorganic origin. Bisphosphonates also show a high affinity for calcium ions, which makes it easy to penetrate into bone tissue.
The mechanism of action of these drugs is associated with the inhibition of the vital activity of osteoclasts (cells that destroy bone tissue), which is embodied in several ways, including:
- Suppress the activity of osteoclasts, due to which these cells stop destroying bones and even die.
- Influence osteoclast progenitor cells, which slows down their growth and inhibits the process of reproduction.
- Bisphosphonates also have a positive effect on the activity and vital functions of osteoclasts (cells that form bone tissue), which triggers the regeneration of connective tissue.
Considering the points listed above, it can be understood that bisphosphonates have a complex effect, suppressing catabolic processes in bones and stimulating bone cell anabolism.A large sample of clinical studies have confirmed the indisputable efficacy that therapeutic bisphosphonate therapy for osteoporosis is also safe.
Also, these medicines are suitable for the prevention and treatment of bone metastases. The use of bisphosphonates in oncological practice is justified if a tumor formation is found in the bones, and not in other parts of the body. In such a situation, bisphosphonate drugs will slow down the formation of malignant cells through the effects of bone repair.
Types of bisphosphonates
According to the modern classification, 8 drugs are prescribed in medical practice, which are divided into 3 groups, depending on the pharmacological properties:
- Nitrogen-free bisphosphonates. This group includes medicines of the first generation. This list includes clodronate, tiludronate, and etidronate.
- Nitrogen-containing bisphosphonates. This group includes second generation medicines. List of medicines – pamidronate, risedronate, alendronate.
- Amino bisphosphonates are the last, third generation. This list includes ibandronate and zoledron.
Depending on the individual characteristics of the patient’s condition, the doctor chooses which medication should be prescribed. The price of the product depends on the generation. There is a clear gradation between bisphosphonates in terms of drug novelty and cost. The 3rd generation products are the most expensive, as they are the most effective and at the same time the safest.
Bisphosphonates for the treatment of osteoporosis – drug names
Depending on which drug was prescribed, it has its own individual pharmacological properties.To find out these nuances, you need to carefully study the classification. According to the conclusions of evidence-based medicine, the therapy of bone demineralization requires long-term use of drugs. The optimal period is several years before the bone tissue begins to fully recover.
This drug belongs to the second generation of bisphosphonates. Contains an additional nitrogen atom in the formula. Due to this property, Pamidronate inhibits the rearrangement of proteins in osteoclasts, which leads to their death due to the processes of apoptosis.This medication is also effective in suppressing osteolytic metastases that occur with the development of multiple myeloma and breast cancer.
Most Effective Bisphosphonates
Minus medication – high doses of medication are needed to suppress hyperparathyroidism and induced hypercalcemia. If you take higher doses of the medication, it often leads to damage to the gastrointestinal tract. Also, some patients have reduced blood concentrations of the drug if there is a genetic mutation associated with osteoilisis.The method of using the drug is intravenous infusion in a single dosage of 60 – 90 mg. The medicine is used 3 times a week, and the duration of the infusion is 4 hours. This is another drawback of the drug, because you have to spend a lot of time on its administration.
This is a first generation bisphosphonate. Available as a solution for intravenous infusion and oral tablets. The minus of the tablet form of release is poor absorption from the stomach. Clodronate is named, as one of the earliest members of the bisphosphonate group, intended for systematic use for osteoporosis.
This is a bisphosphonate belonging to the latest generation of this pharmacological group. It contains 2 nitrogen molecules. This allows the genetic trait to be bypassed in some patients. The medicine is good because it does not show nephrotoxic properties and is well tolerated. The medication is taken once a month as a 15-minute intravenous infusion, which is much more convenient than with other medications.
Zolendronic acid belongs to the third generation medicines.The composition of the drug contains 2 nitrogen atoms, which are located in opposite positions. With the help of these properties, the drug not only effectively fights against the destruction of bone tissue, but also exhibits an antitumor effect on malignant formation, which makes it possible to prescribe this drug for bone tissue oncology.
Another valuable property of zoledronic acid in the fight against the oncological process is its antiangiogenic effect. With the help of this effect, there is an active obstacle to the growth of endothelial cells, which leads to a violation of the blood supply to the neoplasm.This method also slows down the growth of cancer in the bone tissue. Zoledronic acid is administered intravenously. A single dose is 4 mg. The infusion is given every 3-4 weeks. The duration of the procedure is 15 minutes. In parallel, the patient should definitely drink calcium and vitamin D in order to reduce the risks of transient hypocalcemia.
The active ingredient is alendronic acid. This is the second generation substance most often prescribed for the long-term therapy of osteoporosis.Alendronate is good for being easy to use and suitable for home use. The drug is administered orally once a week and is inexpensive when compared with other analogues. Alendronate is drunk on an empty stomach, being strictly upright for half an hour from the moment the tablet is consumed (if you lie down, there is a risk of burning the esophagus).
Possible side effects
Despite a high safety profile when used correctly, bisphosphonates are not harmless drugs.They should be used only strictly as directed and under the supervision of the attending physician.
Most often, therapy is accompanied by the following possible side effects:
- Dyspeptic symptoms – nausea, stomach pain and bloating.
- Possible increase in body temperature to subfebrile values, the appearance of myalgia or arthralgia.
- Occurrence of transient hypocalcemia – a temporary decrease in the level of calcium in the blood.
- Headache, itching of the skin, urticaria, hematuria.
In rare cases, aseptic necrosis of the jaw joint may occur. To prevent this complication, all dental procedures must be completed before starting treatment with bisphosphonates.
Use of medications for bone metastases
If metastases have gone to the bones, then bisphosphonates are the gold standard for the relief of complications associated with the course of oncology. The drugs can be used for several years, then they switch to Denosumab (monoclonal antibodies).The beginning of treatment begins after instrumental confirmation of the presence of bone metastases on an X-ray. The research method using scintigraphy is not informative enough.
Hyperparathyroidism is a significant problem as a complication of bone oncology. It is a life-threatening condition that occurs if antiresorptive therapy is not used. Hypercalcemia is fraught with kidney damage, dehydration, decreased blood pressure, and arrhythmias. The gastrointestinal tract also suffers, which is manifested by constipation, constant thirst and abdominal pain.Over time, there are signs of clouding of consciousness, which are accompanied by lethargy. Without treatment, the patient falls into a coma and dies. Bisphosphonates solve this problem effectively.
Use of antiresorptive therapy for osteopenia of bone
In osteopenia, there is a persistent decrease in bone mass. The disease is chronic and always progresses without treatment, leading to serious complications, including falls and fractures. At an older age, a hip fracture is fraught with death, since you need to lie for a long time to heal the bones.In older patients, this often leads to blood clots, which are the cause of heart attacks. Bisphosphonates are effective in counteracting bone loss. Treatment requires an integrated approach that includes medication, diet and exercise from the arsenal of physiotherapy exercises.
Bisphosphonates are modern and effective drugs for the prevention and treatment of osteopenia.Also, these funds help in the fight against the spread of bone metastases, which are a complication of a malignant tumor process in the body. Medicines can be used only under the supervision of a doctor and according to strict indications.
90,000 Assigned Zometa or Bonviva? Important information for dental patients
Zometa and Bonviva (bisphosphonates) are often prescribed for the treatment of osteoporosis and the fight against metastases in oncology. As with all drugs, they have some side effects that patients with dental problems or planning future dental treatment should be aware of.Several recommendations for such patients are given by the chief physician of Dial-Dent Sergey Vladimirovich Tsukor. In this article, he will talk about the tactics of the behavior of patients planning an appointment, taking or taking drugs Zometa and Bonviva.
What are bisphosphonates?
Bisphosphonates are a large group of drugs that stop bone loss. This group includes many different drugs with different names from different manufacturers, including Zometa and Bonviva.
In a healthy bone, from birth to death of a person, two processes go in parallel: the construction of a new bone by osteoblasts (special cells that build bone tissue) and bone loss by osteoclasts (bone killer cells). These two processes are related to each other, like day and night. The processes of building new bone and thinning the old must be in complete balance. Any bias, dominance or disconnection of one of the processes speaks of a disease. In a healthy person, due to the renewal of bone tissue, the entire skeleton is replaced in six months! Bone is a tissue that regenerates 100% precisely due to metabolic processes.
Bisphosphonates interfere with the balance of the normal processes of renewal (dilution of old and building of new) bone. Bisphosphonates kill bone destroyer cells (osteoclasts). The bone loss process stops. But along with it, the ability of the bone to regenerate is turned off! The bone seems to be there, and it seems to be stronger, because osteoclasts do not work. But in any situation where the restoration potential of the bone is needed, for example, a fracture or tooth extraction, bone restoration does not occur, since bisphosphonates “turned off” the renewal.A number of very unpleasant complications can occur, including bone suppuration – osteomyelitis.
You need to understand that bisphosphonates are a great find in medicine that saved many people’s lives! Bisphosphonates are very effective in killing the growth of bone metastases, for example, in breast cancer. Therefore, in case of oncological diseases that are not amenable to surgical treatment, the use of bisphosphonates is justified. But the problem is that bisphosphonates are not always prescribed as a last resort! Taking bisphosphonates for osteoporosis seems questionable, since in this case they do more harm than good.With osteoporosis, there is no question of life and death; there are many ways to prevent this condition. And taking bisphosphonates will make it impossible in the future any surgical dental treatment involving the bone, since the bone simply will not heal!
Even a single dose of bisphosphonates is a lifelong contraindication to dental implantation! There may be problems with bone healing after banal tooth extractions. If, nevertheless, the benefits of taking bisphosphonates are more important than harm, then you need to carefully prepare for their intake.
Advice for patients planning to take Zometa or Bonviva:
- Make sure to visit your dentist before taking any medication.
- It is necessary to carry out a thorough debridement of the oral cavity! Cure everything that is possible! Anything that cannot be cured must be removed BEFORE taking bisphosphonates.
- Allow the bone to heal for a while if surgical procedures have been performed.
Advice for patients taking Zometa or Bonviva:
- If a patient comes to the dentist, already having a history of taking bisphosphonates, then it is imperative to notify the doctor about the fact of taking them (drugs of the group: “Zometa”, “Bonviva”, “Zolendronate”, “Bondronat”, “Boniva”, etc.).NS.). These drugs DO NOT have a prescription period. Even if you only took bisphosphonates once five years ago, you need to tell your dentist.
- A dentist notified by you of taking bisphosphonates should try to avoid any dental surgical treatment that requires bone healing (tooth extraction, dental implants, etc.). If, nevertheless, treatment is necessary, for example, tooth extraction, then you must be prepared for complications in order to cope with them more easily.
For all questions of dental treatment when taking bisphosphonates, please contact specialized state medical institutions.
Effect of zoledronic acid on the incidence of bone complications in patients with bone metastases
TIMES IN 3 MONTHS – NEW ADMINISTRATION REGIME
ZOLEDRIC ACID IN PATIENTS WITH BONE METASTASIS?
01/03/2017 – Within 2 years, the introduction of Zoledronic acid every 3 months is equally effective
(=) monthly introduction [Andrew L.Himelstein et al. – JAMA, 2017].
01/26/2017 – The maintenance regimen of Zoledronic acid 1 time in 3 months is equally effective (=)
monthly, in patients receiving bisphosphonate therapy for a year or more [Gabriel N. Hortobagyi
et al. – JAMA, 2017].
ZOLEDRIC ACID ADMINISTRATION EVERY 3 MONTHS EQUALLY EFFECTIVE TO MONTHLY
Effect of zoledronic acid on the incidence of bone complications in patients with bone metastases
with the standard regimen and appointment every 12 weeks ( Andrew L.Himelstein
et al. – JAMA , 2017 ).
The randomized study included 1822 patients with metastatic breast cancer, metastatic cancer
prostate gland and multiple myeloma, of which 795 patients received Zoledronic acid in
within 2 years and completed the study.
Among 29.5% of patients receiving zoledronic acid (ZA) every 4 weeks, and 28.6% of patients,
treated with ZK every 12 weeks, identified at least one bone complication that
proves the lack of advantage of more frequent ZK administration.
Relevance: Zoledronic acid belongs to the 3rd generation
aminobisphosphonates and is intended to reduce the incidence of bone complications, including,
pain syndrome. However, the optimal long-term use interval has not been unequivocally defined.
The aim of the study was to identify the benefits of prescribing
zoledronic acid (ZA) when administered once every 12 weeks and once every 4 weeks.
Material and Methods:
- The study was conducted at 269 US clinical centers between May 2009 and April
2012; the observation was carried out until April 2014.
- Included 1822 patients with bone metastases of breast cancer, prostate cancer and
- Patients were randomized into 2 groups: the first group was injected intravenously with ZK every 4 weeks
(n = 911), in the second – once every 12 weeks (n = 911).
- The duration of ZK therapy was 2 years.
- The primary endpoint was the proportion of patients with at least one bone
complication during treatment.
- Intergroup difference of 7% was defined as an indicator of advantage.
- Secondary endpoints – proportion of patients with pain syndrome, ECOG functional status
(range 0-4), incidence of osteonecrosis of the jaw, impaired renal function, bone complications
(average number of bone complications per year), suppression of bone metabolism.
- Among 1822 patients randomized (mean age 65 years) – 980 (53.8%) women.
- After 2 years, out of 1822 patients (855 patients with breast cancer, 689 patients with prostate cancer and 278 patients with
multiple myeloma) – 795 patients completed the study.
- At least one bone complication within 2 years was observed in 29.5% (260
patients) in the 12-week ZK prescription group and in 28.6% (253 patients) in the
4-week ZK prescription, (p <0.001)
- Frequency of pain, deterioration in functional status, incidence of osteonecrosis of the jaw, impairment
renal function did not differ significantly between groups.Bone progression also
did not differ numerically, however, bone metabolism was higher in patients who received
ZK every 12 weeks.
In patients with bone metastases of breast cancer, prostate cancer and
multiple myeloma, using zoledronic acid every 12 weeks versus
the standard interval of 4 weeks for 2 years did not lead to an increase in the risk of bone
complications.According to the authors, the duration of the interval of administration of zoledronic acid in 12
weeks may be an acceptable treatment option.
MAINTAINING MODE OF ZOLEDRIC ACID 1 TIME IN 3 MONTHS EQUALLY EFFECTIVE FOR MONTHLY
PATIENTS RECEIVING BISPHOSPHONATE THERAPY FOR A YEAR AND MORE THAN 90 074
Randomized clinical trial OPTIMIZE-2:
“Comparison of the effectiveness of administration of zoledronic acid every 12 weeks or every 4
weeks in patients with breast cancer bone metastases receiving bisphosphonate therapy for
years or more “(Gabriel N.Hortobagyi et al. – JAMA ,
- In this randomized clinical trial of 416 patients with
bone metastases of breast cancer receiving bisphosphonate therapy for a year or more,
further administration of zoledronic acid every 12 weeks was not inferior in effectiveness
Relevance: Zoledronic acid is indicated for patients with bone
metastases to reduce the risk of complications from the skeletal system. However, recently
there are concerns about its long-term use due to the likelihood of complications
bisphosphonate therapy, including osteonecrosis of the jaw.
The aim of the study was to compare the effectiveness of zoledron
acid when administered 1 time in 12 weeks and 1 time in 4 weeks in patients with metastatic breast cancer with
bone metastases receiving long-term bisphosphonate therapy.
Materials and methods:
- OPTIMIZE-2 – prospective, randomized, double-blind, multicenter study 3
- 1: 1 randomization – group 1 received zoledronic acid 4.0 mg IV every 4
weeks, the second group – every 12 weeks with placebo every 4 weeks; lasting 1 year.
- The study was conducted at 102 US clinical centers from March 3, 2006 to July 25, 2013
- Data analysis was carried out from October 7, 2013 to March 24, 2014
- The study included 416 women (≥18 years old) with bone metastases of breast cancer who
previously received 9 or more doses of zoledronic acid and / or pamidronate during the first 10 –
15 months of therapy.
- The primary endpoint was the proportion of patients with one or more bone complications.
- Secondary endpoints – time to first bone complication or progression into
- A total of 416 women randomized: 200 patients received zoledronic acid
every 4 weeks (mean age 59.2 years; 173 [86.5%] – European), 203 patients –
every 12 weeks (average age 58.6 years; 178 [87.7%] – European race), and 13 patients
received placebo (mean age 60.8 years; 13 [100%] Caucasian). The original
the characteristics of both groups were comparable.
- After a year of follow-up, bone complications occurred in 44 patients (22.0%) in the first group and
in 47 patients (23.2%) in the second.
- The time to the first adverse event associated with bone metastases is not statistically significant
differed between both groups (hazard ratio [RR] 1.06; 95% CI 0.70-1.60; p = 0.79).
- The mean bone progression was 0.46 (1.06) in the first group and 0.50
(1.50) cases per year in the second (p = 0.85).
- The toxicity profile was also comparable, in 189 patients (95.5%) in the first group there was
this or that toxicity, and in 189 (93.5%) patients – in the second.
According to the authors, the maintenance of zoledronic acid once every 12
weeks is not inferior in efficiency and safety compared to the introduction of 1 time in 4
weeks in patients with metastatic breast cancer who received long-term bisphosphonate therapy.
L. Himelstein et al. Effect of Longer-Interval vs Standard Dosing of Zoledronic
Acid on Skeletal Events in Patients With Bone Metastases. JAMA. 2017; 317 (1): 48-58.
- https: // jamanetwork.com / journals / jama / article-abstract / 2595526
N. Hortobagyi et al. Continued Treatment Effect of Zoledronic Acid Dosing
Every 12 vs 4 Weeks in Women With Breast Cancer Metastatic to Bone. JAMA Oncol. Published
online January 26, 2017.
- https: // jamanetwork.com / journals / jamaoncology / article-abstract / 2598744
Prepared by: Latipova
Dilorom Khamidovna, oncologist, candidate of medical sciences, researcher Scientific department of innovative methods
therapeutic oncology and rehabilitation.