Maxfacts

This section provides additional information about some of the bone lesions mentioned previously. For most of these conditions, their aetiology as well as some new treatment ideas are the subject of ongoing research.

Inflammatory and other non-neoplastic bone lesions

Osteomyelitis

The term osteomyelitis covers a bewildering range of acute and chronic inflammatory bone conditions, with a considerable degree of confusion about nomenclature in the literature. We will not try to resolve this issue but instead give descriptions of some of the acute and chronic forms of osteomyelitis without paying too much attention to giving the problem a name.

Acute osteomyelitis usually follows on from some form of odontogenic infection and mostly affects the mandible. The mandible is more prone to this kind of infection than the maxilla because the vascularisation (supply with blood vessels) and blood supply in the maxilla is better than in the mandible.

The typical signs and symptoms are: pain, swelling, erythema (redness) of overlying skin and systemic upset. In suppurative (pus producing) osteomyelitis, sinus tracts (‘tunnelling wounds’) may develop. Paraesthesia (abnormal sensation or numbness) of local nerves may occur, a classic sign being numbness of the lower lip on the affected side of the mandible. Pathological fracture may occur and teeth become loose.

Infection persisting for more than one month is viewed as chronic osteomyelitis. There are a number of different types of the condition described, which can cause confusion. In broad terms these may be viewed as suppurative or non-suppurative. Chronic suppurative osteomyelitis is most commonly the result of inadequately treated acute osteomyelitis.

Garré’s sclerosing osteomyelitis is an unusual condition, most often reported in children and young adults. Typically, there is a non-tender bony swelling of the mandible associated with a carious first molar. Systemic upset is unusual. It is thought that low grade chronic infection stimulates the active periosteum (connective tissue enveloping bone) to lay down bone (Garré’s sclerosing osteomyelitis is also referred to as periostitis ossificans). The subperiosteal bone deposition often has a laminated appearance and needs to be distinguished from malignancies such as osteosarcoma and Ewing’s sarcoma. In the absence of an obvious dental cause, early biopsy is required.

Chronic sclerosing osteomyelitis is a poorly defined term. It may be focal or diffuse. It is thought to be an inflammatory response to low-grade bacterial infection in which there is bone deposition rather than resorption (although the exact mechanism for this is not fully understood). No specific infectious organism has been identified. Intermittent refractory pain is a feature. It is more frequent in the mandible. The symptoms include: pain, swelling, paraesthesia, pressure and trismus. The symptoms may persist for years. Radiographs typically show mixed sclerosis and osteolysis, with the sclerotic component becoming more prominent over time. This is not the same as medication related osteonecrosis of the jaws.

Anecdotally there are an increasing number of atypical, acute or chronic episodes of unusual infections associated with these symptoms. No individual causative organism has been definitely identified but, amongst many, the most commonly mentioned bacterial strain is staphylococcus aureus; pseudomonas, actinomyces meyeri (a strictly anaerobic bacterium, and hence may be difficult to identify) and other actinomyces species (previously often assumed to only infect soft tissue), rhodococcus equi, mycobacteria (tuberculosis) and fungal spores (aspergillus) have all been mentioned. There is no obvious pattern regarding these bacterial infections, the only common pattern seems to be that nearly all implicated microorganisms are part of the normal oral microflora.

Osseointegrated implants have become widely used in restorative dentistry in the recent past and more long-term results become available. Like on any other hard, smooth surface a specific kind of bacterial plaque, a biofilm, can form on implants and / or the attached crowns. Biofilms are difficult to eliminate and can be a source of persistent low-grade bacterial infection and give rise to osteomyelitis-like problems (‘peri-implantitis’) in the absence of meticulous oral hygiene.

There are multiple isolated cases where, despite clinical and radiographic evidence of abnormality such as localised or cyclical pain and sclerosis, there is no bacterial colonisation or active infection (sometimes referred to as non-bacterial or non-infectious osteomyelitis).

Recurrent diffuse, non-bacterial osteomyelitits of the mandible has been postulated as being one of the signs of SAPHO syndrome. SAPHO syndrome is a rare condition of unclear aetiology, thought to be an autoimmune condition possibly triggered by an initial inflammatory process. SAPHO (synovitis (inflammation of the membrane surrounding a joint), acne, pustulosis (recurrent pustules on palms and soles), hyperostosis (calcification of ligaments), osteitis (bone inflammation) syndrome may be diagnosed when some or all of these recurrent signs and symptoms can be identified.

Fibrous dysplasia

The cause(s) of fibrous dysplasia are not fully understood. It is thought that a spontaneous gene mutation (of gene GNAS1) at the early embryonal development stage is likely responsible, with some cells consequently carrying a copy of the defect gene and other cells carrying the normal gene. This explanation is consistent with clinical observation of a strong variability of symptoms of fibrous dysplasia, ranging from asymptomatic to severely disabling. GNAS1 is a gene that is involved, amongst others, in the regulation of endocrine activity (activity of glands that produce hormones). GNAS1 defects can lead to skin lesions and overactivity of endocrine glands, in addition to fibrous dysplasia (McCune-Albright syndrome).

Cherubism on the other hand, thought to be a hereditary variant of fibrous dysplasia, has been associated with a different, hereditary genetic mutation (affecting gene SH3 BP2; the mutation has been observed in the majority of people with cherubism but the mechanism of pathology is not yet understood).

Fibrous dysplasia can affect one (monostotic) or several (polyostotic) bones. When the skull and/or facial bones are affected, the bone deformities can lead to neurological symptoms (vision or hearing impairment) when cranial nerves in the vicinity are compressed. Distortion of facial features and other resulting symptoms vary greatly.

Paget’s disease of the bone

Paget’s disease of the bone (sometimes referred to as osteitis deformans) often only affects one or few bones, with the pelvis, hip, vertebrae in the lower spine and skull / facial bones most commonly affected. A number of different avenues have been explored to find the cause(s) of Paget’s disease of the bone but so far there is no conclusive answer. It is essentially not known what causes the specific imbalance of the bone remodelling process that gives rise to the condition. It is also not yet clarified if only the osteoclasts display abnormally high activity or if the osteoblasts also show abnormalities.

Some 30 to 40 years ago, several viral infections have been described as being associated with the occurrence of Paget’s disease of bone later in life. The suspects were mostly viruses from the paramyxovirus group, including measles, influenza, respiratory and canine distemper infections. All of these studies have been questioned; for example there is no single proven case of a human being infected with canine distemper disease. For the time being, a viral aetiology for Paget’s disease of the bone can be deemed highly unlikely.

An alternative hypothesis about the causes of Paget’s disease of the bone highlights a genetic predisposition: approximately half of people with a family history of Paget’s disease and 10 percent of people with ‘spontaneous’ Paget’s disease carry mutations of a particular gene (SQSTM1); this gene is involved in the upregulation of (not yet fully understood mechanism of) osteoclast activation. Patterns of genetic mutations have also been identified for other, rare bone syndromes. The data does not yet make a definitive conclusion as to the aetiology of Pagets disease.

In part, this is due to yet another hypothesis: environmental factors and the results of epidemiology studies. Epidemiology reveals not only a well-known clustering of cases and geographic distribution (for example, in the UK Lancashire is a hot spot for Paget’s disease of the bone) but also shows that the number of cases has drastically fallen from 1974 (first census) to 1994 (second census). The prevalence in 1994 was roughly half that of 1974, and currently stands at affecting 1 to 2 % of people older than 55 years in the UK; the prevalence increases with age.

A predominantly or exclusively genetic cause of Paget’s disease of the bone would be very difficult to explain with such a drastic reduction in the number of cases over a short period of only 20 years (in the UK and elsewhere). It would also be difficult to explain the reduced observed geographic variations. It makes more sense to see genetic patterns of mutations as an important predisposing factor, in tandem with additional environmental factors as trigger. Such environmental factors may include malnutrition in childhood (vitamin D deficiency and rickets), poor diet, pollutants (pesticides).

Clearly, more research is needed to identify the combined roles of genetics and environment in leading to Paget’s disease; understanding the reasons for the drastic reduction in cases over a short period of only 20 years may well hold key information for future rational treatment planning of the disease.

Malignant neoplastic bone lesions (bone cancers)

With primary bone malignancies being rare and thus only amounting to small numbers of cases (osteosarcoma affecting approximately 1 in 100.000 people), there are nevertheless large numbers of publications dedicated to the condition and ‘big data’ attempts have been made to understand the aetiology of osteosarcoma. Epidemiology and genomics combined have so far not really revealed much new insight. There seems to be a large variety of sub-types and variants of these malignant tumours (as well as strongly varied clinical behaviour and aggressiveness, including some variants related to very rare genetic disorders such as Li-Fraumeni syndrome) – one might be tempted to conclude that every osteosarcoma sufferer have their own and unique genetic tumour sub-type. We may just add to the speculations here, by contributing our own: perhaps the lack of discernible clear patterns will eventually lead to the conclusion that developing osteosarcoma may just be related to the statistics of a higher probability of error at periods of rapid cell proliferation and growth of bone?

The only robust information that can be taken from epidemiologic data concerns the peak of occurrence around puberty (at the time when there is a spurt of body growth, alongside massive hormonal changes), with a second smaller peak found for people older than 60 to 70 years. In older people, in most cases the occurrence of osteosarcoma is related to a history of long-standing bone disease and unbalance, such as in conjunction with Paget’s disease of the bone (see above; possibly this might be a hint that there may be common causes related to malfunctioning of the bone remodelling in Paget’s disease of the bone and osteosarcoma).

The only clearly identified external factor that can be considered as causative for osteosarcoma is previous exposure to high-energy radiation, such as received in radiotherapy. In the past, Paget’s disease of the bone sometimes used to be treated by radiotherapy; this is obviously no longer considered an appropriate treatment. The long-term enhanced risk for developing osteosarcoma (or other secondary malignancies) following radiotherapy is a concern for the treatment options of young oral-cancer sufferers (in addition to an increased risk to develop osteoradionecrosis). Previous radiotherapy to treat Hodgkin lymphoma or brachytherapy for the treatment of ankylosing spondylitis (a chronic inflammatory conditon of the spine and other body parts) have been mentioned in the literature.

This brief summary of the state of insight with regard to the aetiology of osteosarcoma illustrates several other aspects and dilemmas of research into, and treatment of, rare diseases in general. Sometimes it can be attractive from a point of view of gaining general knowledge, beyond a specific condition, to conduct research into rare conditions. These are sometimes related to specific and identifiable genetic aberrations (hereditary as well as spontaneous mutations). But that knowledge does not directly lend itself to improved treatments, for a number of reasons. It would be completely unethical to insists that only large-scale clinical trials should be considered as adequate evidence support for treatment recommendations – it may literally take hundreds of years to collect enough data for rare conditions to have statistically meaningful data for analysis. Also, there is no incentive for private pharmaceutical industry to develop drugs for rare diseases – there is no money to be made from such endeavours. On the other hand, it may not always be beneficial to suffer from a less rare condition and end up being (over)treated in ways that often do not add to quality of life or improved survival rates but have been made available following pressure and lobbying, sometimes ill-informed. This topic has recently received increasing attention, from the professionals and patients.

So, for the time being much of the treatment of rare diseases (of which osteosarcoma and chondrosarcoma are just two examples; another, not yet completely understood aspect being that these solid bone malignancies are resistant to radiotherapy) has to rely on qualitative experience and anecdotal information.