Manufacturer
Bisphosphonates are now sold by almost all well-known manufacturers. The first substance that was brought to market was Fosamax®. Most information exists about this substance.
The active ingredient alendronic acid or alendronate is still the so-called lead substance in osteoporosis requiring therapy. The efficacy of novel substances is being tested against this drug. Further manufacturer names of bisphosphonates are for example
- Actonel ®
- Fosamax®
- Fosavance®
- Bonviva®
- … …
Bisphosphonate is the chemical name of the active ingredient in various drugs used for the treatment of tumors, especially in the head area, but also in other localizations and especially for the treatment of osteoporosis.
Bisphosphonates are also used in gynaecology – in addition to orthopaedics and dentistry – for the treatment of breast cancer. They are taken as tablets or administered as an infusion. However, their absorption, i.e. their uptake into the body, is very low, ranging from 1 to 10%.
Most of it becomes active on the bone, the rest is excreted. The bone is subject to constant build-up and breakdown. In osteoporosis, the breakdown by the bone-destroying cells outweighs the osteoclasts.
Calcium loss occurs and the bone becomes porous. There is a risk of fracture and pain occurs. The treatment of osteoporosis with bisphosphonates is based on the inhibition of osteoclast activity.
Bisphosphonates accumulate in the bone and inhibit degradation processes there, resulting in stabilisation of the bone substance. Bone contains cells which, like small macrophages, always eat a small part of the bone and thus degrade it. In addition, there are cells that constantly produce bone substance again and again, thereby renewing the bone and strengthening it.
In women after the menopause, in old age in general or in the case of bone diseases such as tumours, the build-up processes decrease. This is the reason why bone resorption is predominant. As a result, the bone loses stability and becomes brittle.
In addition, increased bone resorption can lead to pain. One reason for this pain is that in tumour diseases tumour cells and their harmful ingredients and signalling substances accumulate in the bone, which are released during bone resorption. After taking bisphosphonates, these are stored in the bone and released during remodelling processes.
Their effect is mainly to inhibit the cells that break down the bone. Consequently, the balance is shifted in favour of bone formation. As the breakdown of all substances in the bone is reduced by bisphosphonates, they lead to a reduced release of harmful substances, especially in the case of tumour diseases of the bone marrow.
As a result, fewer signalling substances that could activate and attract other tumour cells are released and the pain associated with tumour diseases is reduced. The active ingredients of bisphosphonates can be differentiated according to whether they contain nitrogen or not. The substances containing nitrogen, such as alendronic acid (Fosamax®) and ibandronic acid (Bonviva®), usually have a stronger effect.
Although both groups of active substances attack at a different site, they all cause a loss of function of the cells that break down bone, which ultimately leads to the death of these cells. The nitrogen-free bisphosphonates include etidronic acid (Didronel®) and clodronic acid (Bonefos®). In all groups there are drugs that are taken in tablet form and drugs that are administered through an access into the vein of the patient.
Particularly in the case of tablet form, all active ingredients must be taken with a glass of water at least half an hour after meals, as they combine with substances such as calcium and can therefore no longer be sufficiently absorbed. Similar problems arise when the active ingredients are taken at the same time as iron, magnesium or zinc. Ibandronic acid can be given as a tablet or as an infusion, the other drugs mentioned are taken in tablet form.
Via a venous access, the active ingredient reaches the blood directly and is thus completely available, independent of its absorption in the intestine. Here, however, attention must be paid to an exact dosage, as both the effect and the undesired side effects can be stronger. Bisphosphonates are used in diseases that are associated with increased bone resorption.
These include, for example:
- Paget’s disease (osteodystrophia deformans)
- Tumor-associated hypercalcemia
- Bone resorption (osteolysis) in the context of tumour diseases (among other things due to tumour metastases) and
- Post-menopausal osteoporosis, a condition commonly known as “bone loss” in post-menopausal women. A further indication for bisphosphonates is also used for diagnostic purposes in nuclear medical skeletal scintigraphy. Due to their anti-osteolytic properties, bisphosphonates have an inhibitory effect on bone resorption.
This effect is mainly mediated by the inhibition of so-called osteoclasts (bone-eating cells). As they are stored directly in the bone after resorption, they can quickly develop their effect at the target site. For this reason, bisphosphonates are used in diseases that lead to excessive osteoclast activity and thus to severe bone resorption.
Currently, they are even the most frequently prescribed drugs for the treatment of osteoporosis. As with all highly effective drugs, unfortunately bisphosphonates also have side effects. We call them side-effects, but in reality they are also effects, but we do not want to have them.
In addition to stomach intolerances, bisphosphonate can also cause bone necrosis in the jaw. However, this undesirable side effect is very rare. It is not a destruction of bone tissue caused by bacteria, but a spontaneous, aseptic process.
The term necrosis means that cells are hit so hard by damage of any kind that they die and decay. This damage can be, for example, radioactive radiation, poisons or drugs. Thus, jaw necrosis can also occur during therapy with bisphosphonates, which strongly influence the remodelling process of the jaw bone.
The bone becomes more unstable and tends to break. In addition, jaw necrosis is manifested by the fact that more and more bone is released under the oral mucosa. This leads to pus-filled areas in the mouth area.
Without any other cause, the teeth become loose and partially fall out. This damage to the jawbone can even lead to severe inability to chew. In order to definitely speak of necrosis of the jaw, the open areas reaching the bone must remain at the same point for at least eight weeks.
In addition, it must be determined with certainty that the cause of the necrosis is really bisphosphonate therapy. For this purpose, it must be ensured that no therapy with radioactive substances in the head and neck area has taken place. Other therapies, such as certain chemotherapies for cancer or the use of drugs that affect bone structure, must not have been carried out.
The symptoms are for the most part painless. Soft tissue swelling, tooth loosening, exposed jaw bone or even protracted inflammation of the periodontium can be signs of this bone necrosis caused by bisphosphonates. It is not yet known why such clinical pictures occur in rare cases.
It is doubtful whether tooth removal or the treatment of the periodontium are possible causes. In any case, doctor and dentist should treat the patient together. Prophylaxis is not yet known.
Individual prerequisites of the patient may pose a risk. For this reason, the dentition should always be rehabilitated before therapy with bisphosphonate. This includes the treatment of carious teeth as well as the elimination of inflammatory processes in the oral cavity.
A regular presentation at the dentist is recommended. The treatment of bisphosphate-associated bone necrosis is difficult and lengthy. It involves the removal of the lost, dead bone and the covering of the resulting defect.
In patients who receive bisphosphonates in tablet form, jaw necrosis with a new occurrence of 0.0007% per year is very rare. This undesirable side effect occurs most frequently in patients with tumor diseases who receive a very high dose of bisphosphonates via an access directly into the vein. In this case, jaw necrosis occurs in 0.8-12% of patients per year.
In multiple myeloma, a disease in which white blood cells develop into malignant cells, migrate especially into the bone marrow and spread there, the incidence of pine necrosis with bisphosphonate therapy is 1-10%. The risk of developing pine necrosis through treatment with bisphosphonates is strongly dependent on other factors which themselves increase the risk of pine necrosis. For example, drugs such as hormone preparations used for prostate or breast tumours can lead to bone loss.
Bisphosphonates are used to prevent this. If jaw necrosis occurs during therapy with both drugs, it is difficult to say which drug is the main trigger of the complications. Other known risk factors are old age, smoking or diabetes mellitus.
In addition, dentures, which always press on the jaw in the same places, can lead to bone loss. Also longer lasting inflammations and infections in the tooth and jaw area damage the tissue permanently and can promote jaw necrosis if insufficient therapy is given. For this reason, the dentist should be checked before starting the therapy and good oral hygiene should be ensured.
Furthermore, the risk increases with the frequency of use and the dose of bisphosphonates. Especially areas of the jaw that are only covered with a very thin layer of the oral mucosa are often affected. The lower jaw has the highest risk of suffering from necrosis.
We have devoted a completely separate topic to this topic: Bisphosphonate-associated jaw necrosisThe most important approach to therapy for jaw necrosis caused by bisphosphonates is to prevent the worsening and spread of the necroses and the development of new necroses in particular. First of all, the pain that has occurred should be treated. In addition, infections can be prevented by means of an antibacterial mouth rinse, even before taking the bisphosphonates.
If an infection already exists, it is treated with antibiotics. However, if the affected areas of the jaw are no longer able to repair themselves, the damaged part of the bone must be removed by a surgeon. Special attention should be paid to necroses that have not yet reached the surface of the jaw.
The remaining, not yet affected part is covered again with the normal oral mucosa. Afterwards, the pain is still treated. Furthermore, the tissue in the wound area can heal better by the administration of oxygen.
If there are renewed outbreaks after the removal of the diseased bone parts, it is possible that further, very large sections of the jaw will have to be separated. First of all, various plates are screwed on as a replacement. However, if there are signs that the disease has stopped, these can be permanently replaced by bone parts that are taken from another part of the body.