E-Book, Englisch, 104 Seiten
Marx Drug-Induced Osteonecrosis of the Jaws
1. Auflage 2021
ISBN: 978-1-64724-130-8
Verlag: Quintessence Publishing Co, Inc
Format: EPUB
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)
How to Diagnose, Prevent, and Treat It
E-Book, Englisch, 104 Seiten
ISBN: 978-1-64724-130-8
Verlag: Quintessence Publishing Co, Inc
Format: EPUB
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)
Robert E. Marx, DDS, professor of surgery and chief of the Division of Oral and Maxillofacial Surgery at the University of Miami Miller School of Medicine, is well known as an educator, researcher, and innovative surgeon. He has pioneered new concepts and treatments for pathologies of the oral and maxillofacial area as well as new techniques in reconstructive surgery. As a researcher, he has made valuable contributions in the use of hyperbaric oxygen following radiation therapy, in the development of platelet-rich plasma, and in elucidating the relationships between smoking and carcinogenesis. He also pioneered the clinical applications of recombinant human bone morphogenetic protein and stem cell use and was the first to identify what is now known worldwide as bisphosphonate-induced osteonecrosis of the jaws. For the past 34 years, he has overseen the training of scores of residents and fellows, many of whom have themselves established distinguished careers. His many prestigious awards, including the Harry S. Archer Award, the William J. Gies Award, the Paul Bert Award, and the Donald B. Osbon Award, attest to his dedication and commitment to the field of oral and maxillofacial surgery.
Autoren/Hrsg.
Weitere Infos & Material
Chapter 1
Understanding Drug-Induced Osteonecrosis of the Jaws
What is now most accurately termed 1 came upon the dental scene in 2003.2,3 Since then, there have been over 2,500 refereed articles published on it. Every specialty of dentistry has produced a position paper on it. Every drug company manufacturing one of the offending drugs has a warning in its advertising referring to “dental problems” or “jaw problems.” And most every practicing dentist has seen one or more cases.
Although numerous other terms for DIONJ have been advanced, such as ,4 ,5 and ,6 among others, DIONJ is the most correct due to its identification of a cause-and-effect relationship, its acknowledgment that drugs other than bisphosphonates cause it, and because it is consistent with the term adopted by the World Health Organization and published by the American Medical Association ICD-10 code (M87.10).1 Nevertheless, by any term, the dental profession has come to recognize the necrotic bone in either jaw as osteonecrosis caused by certain drugs.
How Do These Drugs Kill Jaw Bone?
The basic mechanism of the most common drugs known to cause DIONJ is that they are cellular poisons that affect bone remodeling and renewal. A few others cause DIONJ by affecting the blood supply to bone.
Bone is derived from osteoblasts, which secrete osteoid. These cells become entrapped in their mineralized matrix to become osteocytes, which have a life span of about 180 days. During this time, they secrete a protein called , which competes and inhibits RANK ligand (reactive activator of nuclear ?B ligand).7 Because RANK ligand is a natural activator of osteoclasts, this process resists bone resorption and maintains the bone during the 180-day life span of the osteocyte.
The basic mechanism of the most common drugs known to cause DIONJ is that they are cellular poisons that affect bone remodeling and renewal.
When the osteocyte ages or dies off at the end of its life span or from injury, its production of osteoprotegerin ceases, allowing RANK ligand to stimulate osteoclasts to resorb old dysfunctional bone, injured bone, or dead bone. This process is an evolutionary homeostatic process that maintains our skeletons in a healthy state, with bone capable of withstanding loads with proper elasticity and integrity.
Therefore, the clinician should understand that the mandible and the maxilla are not static and are turning over daily. In fact, the alveolar bone of the jaws turns over at a rate that is 10 times faster than that of long bones,8 which is why DIONJ always begins in the alveolar bone. As such, the most vulnerable areas of the jaws are those areas where bone turnover is the greatest—ie, extraction sockets, the posterior lingual areas around mandibular molars, the maxillary alveolus and floor of the sinus above the maxillary molars, areas of alveolar bone surgery, areas of chronic occlusal overloading, and the surface of tori.9
The alveolar bone of the jaws turns over at a rate that is 10 times faster than that of long bones,8 which is why DIONJ always begins in the alveolar bone.
This understanding of bone turnover and bone remodeling also predicted the midshaft femur fractures resulting from osteoporosis drugs first reported in 2008 and now recognized frequently by orthopedic surgeons.10,11 This complication of DIONJ-causing drugs is now warned about by the drug companies.
The femur is the longest bone in the human skeleton. As we walk or run, we plant our feet so that the tibia/fibula and joints absorb the compressive forces. However, the femur flexes somewhat at its midshaft during this process as the knee bends. This creates an increased demand for bone remodeling and renewal in the midshaft areas, which after long-term use from many of the DIONJ-causing drugs results in a unique midshaft fracture due to the brittleness of the old unrenewed bone in that location (Fig 1-1).
Risk Factors for DIONJ
Unfortunately, drug companies and most position papers have published related “risk factors” that are not really risk factors for DIONJ at all. Publications have claimed that obesity or smoking,12 anemia,13 diabetes,14 and many other common human habits and maladies cause DIONJ; however, these things do not actually cause osteonecrosis unless the individual has also been taking one of the drugs known to cause osteonecrosis. These are not risk factors by themselves. Therefore, the clinician examining or treating patients taking drugs that have been known to cause DIONJ should keep in mind the seven critical aspects of risk described in the next section.
FIG 1-1 Atypical fracture of the femur caused by extended use of alendronate (Fosamax).
FIG 1-2 DIONJ from alendronate in a patient treated for osteopenia. DIONJ from denosumab in a patient treated for osteoporosis.
The only risk factor for DIONJ is the drug itself. The degree of the risk is related to the potency of the drug, the dose of the drug, the frequency that it is taken, the length of time the individual has taken the drug, its mechanism of action, and when the last dose was taken.
The only risk factor for DIONJ is the drug itself.
1. Potency
The potency of oral bisphosphonates taken for osteoporosis is well known and is determined relative to the first bisphosphonate introduced: etidronate. Relating the potency of etidronate as 1, tiludronate is 50 times as potent, risedronate and ibandronate 1,000 times as potent, and alendronate 5,000 times as potent. The potency for subcutaneous denosumab, a RANK ligand inhibitor for osteoporosis, is not known as compared to bisphosphonates. However, from its mechanism of action and its track record of DIONJ, it is at least as potent as alendronate when prescribed for osteoporosis and even more potent than zoledronate when administered for cancer patients. In fact, alendronate and denosumab are responsible for over 97% of DIONJ cases in the noncancer patient treated for osteopenia/osteoporosis (Fig 1-2 and Table 1-1).
Table 1-1 Percentage of DIONJ cases in noncancer patients caused by various osteoporosis drugs (N = 211)
| Drug | Dosage | N | % |
| Alendronate | 70 mg per week | 129 | 61% |
| Denosumab | 60 mg every 6 months | 76 | 36% |
| Risedronate | 35 mg per week | 4 | 2% |
| Ibandronate | 150 mg per month | 2 | 1% |
| Raloxifene | NA | 0 | 0% |
| rhPTH 1-34 | NA | 0 | 0% |
| rhPTH 1-80 | NA | 0 | 0% |
| Vitamin D + calcium | NA | 0 | 0% |
This twofold higher dose underscores the danger of alendronate as a major risk factor for DIONJ.
2. Dose and frequency
While the dose of oral risedronate is 35 mg/week and the dose of oral ibandronate is 150 mg/month, which averages out to be 35 mg/week, the dose of oral alendronate is 70 mg/week. This twofold higher dose underscores the danger of alendronate as a major risk factor for DIONJ. Denosumab for the osteopenia/osteoporosis patient is a fixed dose of 60 mg administered subcutaneously every 6 months (see Table 1-1).
3. Half-life
One of the major distinctions between bisphosphonates and denosumab is their half-life in bone. All bisphosphonates become irreversibly bound to the mineral matrix in bone with a half-life of 11.2 years.15 The affinity of bisphosphonates for bone is so great that when an osteoclast dies from ingesting a bisphosphonate and bursts, it releases the bisphosphonate. The bisphosphonate molecules are then rapidly reincorporated into adjacent bone. It is this cumulative buildup of bisphosphonate molecules in the more actively turning over alveolar bone that causes DIONJ from these drugs and targets the jaws.9
Denosumab does not become bound to bone and has a half-life of only 26 days.16 However, its high potency and therefore its equal risk of causing DIONJ compared to alendronate is due to its mechanism of action affecting the very development of osteoclasts in the bone marrow.17
FIG 1-3 Osteoclast resorbing bisphosphonate-loaded bone showing disruption of nuclei as a sign of early toxicity. Pale and ballooned osteoclasts after ingesting a bisphosphonate during bone resorption...
