by Josef Vizkelety, Paracelsus Klinik
Bisphosphonates are a class of drugs advertised to prevent the loss of bone mass, such as Fosamax, Boniva, Skelid, Reclast, Zometa, Bonefos, Actonel and Aredia. Under the belief that they might reduce the risk of fractures in post-menopausal women, doctors administer bisphosphonates to treat osteoporosis and similar diseases like Paget’s disease of bone, bone metastasis, multiple myeloma, primary hyperparathyroidism, osteogenesis imperfecta, fibrous dysplasia, and other conditions that exhibit bone fragility, leading to bone pain. However, serious side effects, including increased risk of unusual atypical fractures and serious dental problems, have made this class of drugs highly controversial.
Mechanism of action
Bone is constantly undergoing turnover and is kept in balance (homeostasis) by bone remodeling, performed by osteoblasts creating bone, and osteoclasts breaking down bone.
Bisphosphonates mechanisms of action all stem from their structures similarity to pyrophosphate. A bisphosphonate group mimics pyrophosphate’s structure, thereby inhibiting activation of enzymes that utilize pyrophosphate. Bisphosphonate based drugs specificity comes from the two phosphonate groups that work together to coordinate calcium ions and preferentially “stick” to calcium and bind to it. The largest store of calcium in the human body is in bones, so bisphosphonates accumulate to a high concentration in bones.
There are two types of bisphosphonates: nitrogenous (N-containing) and non-nitrogenous (non-N-containing) and they are designed to destroy osteoclasts in different ways. N-containing bisphosphonates like Clodronate (Bonefos) or Tiludronate (Skelid) when attached to bone tissue are “ingested” by osteoclasts, causing immediate cell apoptosis and blockage of cytokines and angiogenesis. Non-N-containing bisphosphonates like Alendronate (Fosamax) or Ibandronate (Bonviva) act by inhibiting protein formation inside osteoclasts consequently affecting osteoclastogenesis, cell survival, and cytoskeletal dynamics. In particular, the cytoskeleton is vital for contact between a resorbing osteoclast and a bone surface (bone remodeling).
Unfortunately, if bone metabolism is already limited and slowed down, bone quality and quantity will stay weak and fragile with a high fracture liability even after bisphosphonate administration.
Looking back through history, exposure to phosphorus has caused health problems in the past. Found in workers in the match industry in the 19th and early 20th century, “Phossy jaw,” also known as phosphorus necrosis of the jaw, was an occupational disease of those who work with white or yellow phosphorus. Phosphorus based drugs like bisphosphonates elicit similar effects and without proper safeguards, may lead to unusual bone fractures, tooth loosening, gum swelling, and intraoral abscess with foul smelling discharge.
In medicine, bisphosphonates are either administered orally or intravenously for months or years and may cause side effects such as venous thromboembolism, pulmonary embolism and serious cardiovascular disorders, including atrial fibrillation and myocardial infarction. Most commonly they can cause fever, flu-like symptoms bone, joint, or musculoskeletal pain, upset stomach, inflammation leading to the erosions of the esophagus, and even esophageal cancer formation. In large medical studies, women taking bisphosphonates for osteoporosis have had unusual fractures (“bisphosphonate fractures”) as bone turnover is strongly suppressed in an already weakened and fragile state.
Treatment for these unusual fractures, frequently occurring in the femur shaft, requires extensive complex care over months or years for repaired function.
In dentistry, bisphosphonates are associated with osteonecrosis of the jaw (often abbreviated BON,BONJ, or BON of the jaw), with the mandible twice as frequently affected as the maxilla. In many of these cases, the osteonecrosis occurs following a dental surgical procedure involving the bone, and therefore it has been suggested that bisphosphonate treatment should be postponed until after any dental work. However, this is very difficult.
Because bisphosphonates are preferentially deposited in bone with high turnover rates like the jaw, it is possible that the levels of bisphosphonate within the jaw are selectively elevated. Signs and symptoms present themselves by jaw pain and neuropathy, loose teeth, mucosal swelling, erythema, suppuration, soft tissue ulceration, trismus, non healing extraction sockets, paraesthesia or numbness, bad breath and exposed necrotic bone. This is caused by intravenously administered bisphosphonates in over 90 % of cases.
A diagnosis of bisphosphonate-associated osteonecrosis of the jaw relies on three criteria:
- The patient possesses an area of exposed bone in the jaw persisting for more than 8 weeks;
- The patient must present with no history of radiation therapy to the head and neck; and
- The patient must be taking or have taken bisphosphonate medication.
Treatment usually involves antimicrobial mouth washes, oral or intravenous antibiotics for infection management and extensive resection of the necrotic bone lesion with extensive soft tissue management (safe double layer technique).
Many patients with bisphosphonate associated osteonecrosis of the jaw and the consequent application of Dr. Rau´s biological holistic approach have successful outcomes after treatment at the Paracelsus Klinik, with the local osteonecrosis stopped, the infection cleared, and the mucosa healed, once again covering the bone.
If you would like more information or are interested in becoming a patient at the Paracelsus Clinic, please contact: Barbara Christian, Patient Coordinator, firstname.lastname@example.org.
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