HIF-1α-mediated autophagy and canonical Wnt/ß-catenin signalling activation are involved in fluoride-induced osteosclerosis in rats.

Fluoride (F) exposure can cause osteosclerosis, which is characterised by a high bone mass, but its mechanism is not fully illustrated. Here, we aimed to evaluate the effects of excessive F exposure on the bone lesion by treating female Sprague-Dawley rats with different concentrations of sodium fluoride (NaF) (0, 55, 110 and 221 mg/L) for 90 days and the corresponding concentrations of fluorine ion (0, 25, 50 and 100 mg/L, respectively). Histopathological results showed that excessive F exposure caused the enlargement of trabeculae and their integration into one large piece, growth plate thickening, articular cartilage impairment and bone collagen abnormality. Meanwhile, F promoted calcium deposition and bone mineralisation, and induced abnormal osteogenesis increased. The results of micro-computed tomography also confirmed that excessive F destroyed the bone microstructure and induced a high-bone-mass phenotype, consistent with the results of pathomorphology. Mechanistically, excessive amounts of F led to angiogenesis inhibition and HIF-1α signalling enhancement. Subsequently, F induced autophagy and canonical Wnt/ß-catenin signalling pathway activation. Collectively, these results manifested that F enhanced the hypoxia inducible factor-1α signalling, which in turn triggered autophagy and canonical Wnt/ß-catenin signalling activation, ultimately leading to osteosclerosis in the rats.

Periarticular calcifications containing giant pseudo-crystals of francolite in skeletal fluorosis from 1,1-difluoroethane "huffing".

Inhalant use disorder is a psychiatric condition characterized by repeated deliberate inhalation from among a broad range of household and industrial chemical products with the intention of producing psychoactive effects. In addition to acute intoxication, prolonged inhalation of fluorinated compounds can cause skeletal fluorosis (SF). We report a young woman referred for hypophosphatasemia and carrying a heterozygous ALPL gene variant (c.457T>C, p.Trp153Arg) associated with hypophosphatasia, the heritable metabolic bone disease featuring impaired skeletal mineralization, who instead suffered from SF. Manifestations of her SF included recurrent articular pain, axial osteosclerosis, elevated bone mineral density, maxillary exostoses, and multifocal periarticular calcifications. SF was suspected when a long history was discovered of 'huffing' a computer cleaner containing 1,1-difluoroethane. Investigation revealed markedly elevated serum and urine levels of F-. Histopathology and imaging techniques including backscattered electron mode scanning electron microscopy, X-ray microtomography, energy dispersive and wavelength dispersive X-ray emission microanalysis, and polarized light microscopy revealed that her periarticular calcifications were dystrophic deposition of giant pseudo-crystals of francolite, a carbonate-rich fluorapatite. Identifying unusual circumstances of F- exposure is key for diagnosing non-endemic SF. Increased awareness of the disorder can be lifesaving.

Case 298: Skeletal Fluorosis Secondary to Huffing.

History A 37-year-old man from the United States presented with a 1-year history of neck pain and stiffness that had been unsuccessfully treated with manipulative therapy by a chiropractor at another institution. Past medical history was remarkable only for marijuana and air duster abuse. He denied use of any prescription medications. Physical examination was notable for markedly reduced range of motion of the cervical spine. Laboratory work-up revealed an elevated alkaline phosphatase level (302 U/L [5.0 µkat/L]; normal range, 40-100 U/L [0.7-1.67 µkat/L]), but all other laboratory findings, including complete blood count, renal function, liver function, vitamin A level, serum protein electrophoresis, and hepatitis C antibodies were within normal limits. Cervical spine radiography was performed, followed by MRI. Subsequently, a full skeletal survey was ordered. Included are representative radiographs of the pelvis, left forearm, and distal right leg with ankle.

Excision of Prominent Bony Mass due to Skeletal Fluorosis: A Case Report.

CASE: A 72-year-old man presented for evaluation of bony prominences over extremities. Radiographic imaging demonstrated masses of varying sizes extending from the cortical surfaces without medullary continuity. The patient had a history of Freon inhalation abuse and was diagnosed with skeletal fluorosis due to elevated serum fluoride levels. He underwent an uncomplicated excision of a left fibular mass that was threatening skin breakdown. CONCLUSIONS: This is the first reported surgical case of skeletal fluorosis demonstrating continued enlargement of bony prominences throughout the body. Skeletal fluorosis not only causes diffuse mineralization but may also lead to protruding lesions throughout the body.

Skeletal fluorosis: don't miss the diagnosis!

Skeletal fluorosis is a rare toxic osteopathy characterized by massive bone fixation of fluoride. The disease occurs as an endemic problem in some parts of the world and is the result of prolonged ingestion or rarely by inhalation of high amounts of fluoride. Radiographic presentation is mainly characterized by bone changes with osteocondensation and later ossification of many ligaments and interosseous membranes. Skeletal fluorosis is not clinically obvious and can be confused with other rheumatologic disorders. Its severity lies in the development of skeletal deformities and neurological complications. Management of fluorosis generally focuses on symptom treatment.

Skeletal Fluorosis Due to Fluorocarbon Inhalation from an Air Dust Cleaner.

Skeletal fluorosis (SF) is an osteosclerotic metabolic bone disorder caused by excessive ingestion or inhalation of fluoride. SF is extremely rare in developed countries. We report a case of SF due to inhalational abuse from a fluoride-containing air dust cleaner. A 33-year-old man with no past medical history presented with progressively worsening low back pain for 2 years. Physical examination was notable for loss of lumbar lordosis and tenderness over the lumbar spine. Radiographs were notable for uniform generalized osteosclerosis in the long bones, entire spine, rib cage, and pelvic bones, and loss of the normal lumbar curvature. DXA scan showed Z-scores of +10.7 at the lumbar spine, +6.5 at the total hip, and +1.0 at the 1/3 radius. Laboratory studies were notable for elevated serum alkaline phosphatase (334 U/L, ref: 40-129 U/L) compared to a normal value 3 years prior, suggesting acquired osteosclerosis. Serum fluoride concentration returned elevated (2.8 mg/L, ref: 0.0-0.2 mg/L). Initially, the source of fluoride excess could not be identified. At a follow-up visit, he was found inhaling from a can of an air duster hidden in an inner pocket. He admitted "huffing" 2-7 cans weekly from a fluorocarbon-containing air dust cleaner for the past 3 years to achieve a euphoric feeling, explaining the source of his SF. Fluoride inhalation can be a potential source for SF, and should be suspected in patients with acquired osteosclerosis, as inhalant abuse is increasingly practiced in many countries.

Tumor-free osteosclerotic lesions in patients treated for metastatic melanoma using BRAF inhibitors.

BRAF inhibitors (vemurafenib and dabrafenib) are commonly prescribed in BRAF-mutant metastatic melanoma and allow improvement of the overall survival and progression-free survival. They are, however, accompanied by many adverse effects which mainly affect the skin. We observed on computed tomographic scans in three different patients after 3 months of treatment, the onset of osteosclerotic lesions. In parallel, the computed tomographic scans showed a significant reduction in all of the previously identified metastases in all patients. The occurrence of such bone modifications under treatment was reported previously in others cancers, such as inoperable non-small-cell lung cancers under epidermal growth factor receptor inhibitors, as the 'osteoblastic bone flare phenomenon'. However, it had never been reported in melanoma patients treated with targeted therapies, and the results of two performed bone biopsies are reported here. This phenomenon is generally believed to indicate a better response under treatment, whereas in our study, the patients experienced, after a short partial response, a severe cerebral relapse leading to death. Finally, although its physiopathological mechanisms are poorly understood, the occurrence of tumor-free osteosclerotic lesions in patients under BRAF inhibitors should not be misinterpreted as a progression of the disease.

Osteosclerotic lesions in patients treated with gefitinib for lung adenocarcinomas: a sign of favorable therapeutic response.

OBJECTIVE: To assess the frequency of osteosclerotic changes on CT that appeared after treatment with gefitinib in patients with lung adenocarcinoma and the relationship between the osteosclerotic changes and the response to the therapy. MATERIALS AND METHODS: Our study included 41 patients with lung adenocarcinoma who underwent chest CT both before (CTpre) and after (CTpost) starting treatment with gefitinib. The presence or absence of bone metastases was assessed on the CTpre, and the interval bony change after the therapy was classified as lytic, sclerotic, or no changes on the CTpost. The relationship between treatment results of primary lung cancer and interval bony changes was evaluated. RESULTS: Osteosclerotic lesions were identified in 11 patients (27%) on CTpost; in 6 of 11 patients osteosclerotic lesions newly appeared where the CTpre showed no bone metastasis before the gefitinib therapy. There were significant differences in the therapeutic response of the primary cancers (P < 0.001) and in the survival rate (P < 0.01) in patients with osteosclerotic changes versus those without osteosclerotic changes. CONCLUSION: Osteosclerotic changes on CT, observed after gefitinib treatment in patients with lung adenocarcinomas, may be an indicator of a good therapeutic response.

[Optimizing orthodontic treatment in patients taking bisphosphonates]. / Optimisation des traitements orthodontiques chez les patients sous biphosphonates.

Bisphosphonates have unique pharmacological characteristics unlike those of any other drug group. Millions of adults take oral bisphosphonates for long-term treatment of osteoporosis and osteopenia; some of these people will most likely also seek orthodontic treatment. Adverse dental effects from bisphosphonates have been reported, including decreased tooth movement, impaired bone healing, and osteonecrosis in the mandible and the maxilla. Osteonecrosis has been rarely observed after bisphosphonate use for osteoporosis. However, adverse drug effects might occur more frequently in orthodontic patients, and they would probably be noted before the end-stage pathology of osteonecrosis. Adverse effects during orthodontic treatment, including decreased tooth movement, could last for years after the drug therapy is stopped. Successful orthodontic treatment requires optimal bone healing to prevent excessive tooth mobility. Bisphosphonates appear to have two bone elimination rates - a fast elimination of weeks from the bone surface and a slow elimination of years after incorporation into the bone structure. This article presents methods to clinically and radiographically monitor orthodontic patients who are taking oral bisphosphonates. Efforts to minimize adverse effects and optimize orthodontic procedures with physician-approved drug holidays are discussed. The orthodontic treatment results of three patients who received bisphosphonate therapy are reported.

[Effect of subchronic fluoride exposure on pathologic change and beta-catenin expression in rat bone tissue].

OBJECTIVE: To explore the effect of subchronic fluoride exposure on the expression of beta-catenin in the bone of rats and the role of beta-catenin in skeletal damage. METHODS: Wistar rats were randomly divided into four groups. The rats were treated at the doses of 50, 100 and 150 mg/L F- in drinking water, and control rats were drunk tap water. The contents of fluoride in bone and serum were determined after three month. The expressions of beta-catenin were analyzed by real-time RT-PCR and immunohistochemistry. RESULTS: HE staining indicated that the compact bone was thicker and the trabecular bone increased in fluoride-treated group in comparison with control group. The hypertrophic chondrocytes accumulated and arranged disordered in fluoride-treated rats. The expressions of p-catenin mRNA and protein expressions in bones of fluoride-treated rats were higher than those of control group. Immunohistochemistry indicated that beta-catenins were mainly expressed by osteoblast and osteoclast. There was also positive staining in hypertrophic chondrocyte. CONCLUSION: It was suggested that beta-catenin could play important role in bone sclerosis of subchronic fluoride exposure.

Fluoride's effects on the formation of teeth and bones, and the influence of genetics.

Fluorides are present in the environment. Excessive systemic exposure to fluorides can lead to disturbances of bone homeostasis (skeletal fluorosis) and enamel development (dental/enamel fluorosis). The severity of dental fluorosis is also dependent upon fluoride dose and the timing and duration of fluoride exposure. Fluoride's actions on bone cells predominate as anabolic effects both in vitro and in vivo. More recently, fluoride has been shown to induce osteoclastogenesis in mice. Fluorides appear to mediate their actions through the MAPK signaling pathway and can lead to changes in gene expression, cell stress, and cell death. Different strains of inbred mice demonstrate differential physiological responses to ingested fluoride. Genetic studies in mice are capable of identifying and characterizing fluoride-responsive genetic variations. Ultimately, this can lead to the identification of at-risk human populations who are susceptible to the unwanted or potentially adverse effects of fluoride action and to the elucidation of fundamental mechanisms by which fluoride affects biomineralization.

Calcitonin-induced osteoplastic reaction in the mandible.

We describe a case of florid osteoplastic response in the mandible to the use of calcitonin. Calcitonin has been used in the treatment of central giant cell granuloma for many years and is widely accepted. We know of no reported cases of calcitonin-related exuberant bony deposition in the jaws or the axial skeleton.

[Osteoporosis and osteosclerosis as parity components of occupational fluorosis].

Assessment of bone tissue density in aluminium plant workers revealed obligatory osteoporosis in them. When primary endocrine disorders ruled out, conclusion can be made of osteoporosis along with osteosclerosis as parity components in occupational fluorosis, so contemporary methods of osteologic studies are necessary for assessment of bone tissue.

Management of osteonecrosis of the jaws in patients with history of bisphosphonates therapy.

Bisphosphonates are compounds used in the treatment of various metabolic and malignant bone diseases. The relation between the use of bisphosphonates and ostenonecrosis of the jaws as an adverse effect of the drug has been intensely discussed during the last few years, and up to this moment, there is no consensus concerning an ideal treatment modality for this condition. Nevertheless, there is an agreement among researchers that the standard goal for controlling jaw osteonecrosis is to prevent it. Otherwise, the rationale for a randomized controlled trial is that current treatment has proven to be suboptimal, and no consensus has been reached yet on the best strategies to repair the exposed bone once bone necrosis is developed. This article is focused on reporting a case of moderate osteonecrosis of the upper jaw induced by bisphosphonates and discusses a possible role for surgical debridement associated to platelet-rich plasma, hyperbaric oxygen therapy, and the cessation of the bisphosphonate use in managing this type of lesion. Moreover, the dentist, the oral surgeon, and the oncologist need to work together to reach better outcomes.

Radiographic findings in bisphosphonate-treated patients with stage 0 disease in the absence of bone exposure.

PURPOSE: Radiographic features in patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ) are well described, but less is known in bisphosphonate-exposed individuals with stage 0 disease (clinical symptoms without exposed necrotic bone) considered at risk for BRONJ. We sought to characterize radiographic findings in a subgroup of patients with concerning clinical symptoms and bisphosphonate exposure to identify imaging features that may presage development of BRONJ. MATERIALS AND METHODS: A dental symptom survey was returned by 8,572 Kaiser Permanente Health Plan members receiving chronic oral bisphosphonate therapy, and 1,005 patients reporting pertinent dental symptoms or complications after dental procedures were examined. Those without BRONJ but with concerning symptoms were referred for clinical evaluation, including imaging. Among the subset who received maxillofacial imaging, we identified those with stage 0 disease and abnormal radiographic features. RESULTS: There were a total of 30 patients without exposed bone but with concerning symptoms who received maxillofacial imaging (panoramic radiography or computed tomography) in the context of clinical care. Among these 30 patients, 10 had stage 0 disease with similar radiographic features of regional or diffuse osteosclerosis in clinically symptomatic areas, most with extension beyond the involved site. Other findings in these 10 patients included density confluence of cortical and cancellous bone, prominence of the inferior alveolar nerve canal, markedly thickened and sclerotic lamina dura, uniform periradicular radiolucencies, cortical disruption, lack of bone fill after extraction, and a persisting alveolar socket. None had exposed bone develop during 1-year follow-up. The remaining 20 patients had normal or localized radiographic findings consistent with odontogenic pathology. CONCLUSION: In 10 of 30 symptomatic patients referred for clinical evaluation and imaging, a consistent finding was conspicuous osteosclerosis in clinically symptomatic areas characteristic of stage 0 disease. These data support the need to better understand radiographic features associated with bisphosphonate exposure and to determine whether osteosclerosis is a specific finding indicative of the risk for progression to BRONJ.

[X-ray analysis on 114 patients with moderate endemic skeletal fluorosis by treatment of Guo's Chinese herbal].

OBJECTIVE: To observe the X-ray features of bone damage in patients with moderate endemic skeletal fluorosis and the changes of X-ray after treatment with herbal therapy. METHODS: From 2007.12 to 2009.8,114 patients with moderate endemic skeletal fluorosis were randomly divided into treatment group and control group by central randomization system. There were 60 patients in treatment group including 26 males and 34 females,aged from 39 to 60 years with an average of (51.68 +/- 4.98) years; There were 54 patients in control group included 30 males and 24 females, aged from 39 to 60 years with an average of (52.15 +/- 4.86) years. Both treatment and control groups were treated with basic treatment including calcium supplementation and preparation stage with herb decoction. Patients were orally given 600 mg Caltrate everyday for calcium suptrointestinal function and promoting the digestion and absorption of herb decoction for 3 days. Patients in treatment group were rally given Guo's Maqian decoction(200 ml,twice daily) for 8 weeks. Eight weeks later,Guo 's Maqian decoction was replaced y Guokangning capsule (0.44 g per cansule,2 capsules,three times daily) for 4 weeks. The treatment course lasted 12 weeks. The time for followed-up after treatment was 24 weeks. When the treatment finished, 7 experts on orthopaedics and radiology evaluated and statistically analyzed the X-ray features pre and post treatment,using expert evaluation scale (including the appearance and changes of osteosclerosis,osteoporosis softening,joint changes close to the bone and mixed changes) designed referring endemic skeletal fluorosis X-ray findings and sub-degree standard(WS192-2008). RESULTS: All X-ray features of endemic skeletal fluorosis appeared in the X-ray of the 114 patients with moderate endemic skeletal fluorosis. Osteosclerosis: 4 cases in forearm, 7 in calf,4 in pelvis,4 in lumbar vertebrae ;Osteoporosis and bone softening: 23 cases in forearm patients, 23 in calf, 5 in pelvis, 8 in lumbar vertebrae; Mixed changes: 6 cases in forearm, 9 in calf, 10 in pelvis, 1 in lumbar vertebrae patients; oint changes: 107 cases in forearm, 47 in calf, 28 in pelvis, 19 in lumbar vertebrae. There were X-ray no changes before and after the treatment in all of parts in control group. In treatment group, there were only 2 patients showed extraperiostealin and joint changes after the treatment, in which one showed better ossification of interosseous membrane of leg and another one showed disappearance of the lateral hyperplasia of the left pelvic acetabulum. There were no changes between before and after treatment in X-ray of all parts in the rest patiens of the treatment group. There was no significant difference between before and after treatment in both groups (P > 0.05). CONCLUSION: There is no obvious improvement in radiology of patients with skeletal fluorosis treated by Guo's therapy.

Resolution of oral bisphosphonate and steroid-related osteonecrosis of the jaw--a serial case analysis.

PURPOSE: To offer recommendations of risk factors, prevention, and treatment of oral bisphosphonate and steroid-related osteonecrosis of the jaw (BSRONJ) in Taiwan. MATERIALS AND METHODS: Twelve patients were clinicopathologically proved to have bisphosphonate-related osteonecrosis of the jaw (BRONJ). All of the patients were taking oral bisphosphonates and were concurrently administered long-term steroids. Of the 12 patients, 3 patients were assigned to the first stage of BRONJ; 5 patients were assigned to the second stage, and 4 patients were assigned to the third stage. The patients' symptoms, localization of necrosis, presence of a fistula, and association with possible triggering factors for onset of the lesion were recorded. RESULTS: The radiologic investigations revealed osteolytic areas and scintigraphy demonstrated increased bone metabolism. Microbiologic analysis showed pathogenic actinomycosis organisms in a majority of patients (91.6%). Antibiotic therapy, minor debridement surgery, and combined hyperbaric oxygen therapy were useful in obtaining short-term symptomatic relief. CONCLUSIONS: Comorbidities of steroid use along with bisphosphonates may cause osteonecrosis of the jaw to occur sooner, be more severe, and respond more slowly to a drug discontinuation. The clinical disease of BSRONJ is more severe and more unpredictable to treat than BRONJ. From the data gained from other published studies of BRONJ and our clinical experience with the series of cases of BSRONJ, we offer recommendations of risk factors, prevention, and treatment of BSRONJ in southern Taiwan.