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.

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.

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.

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.

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.

[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.

[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.

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.

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.

Inhibition of necrotic actions of nitrogen-containing bisphosphonates (NBPs) and their elimination from bone by etidronate (a non-NBP): a proposal for possible utilization of etidronate as a substitution drug for NBPs.

PURPOSE: Nitrogen-containing bisphosphonates (NBPs) have powerful anti-bone-resorptive effects (ABREs). However, recent clinical applications have disclosed an unexpected side effect, osteonecrosis of the jaw. We previously found in mice that etidronate (a non-NBP), when coadministered with alendronate (an NBP), inhibited the latter's inflammatory effects. However, etidronate also reduced the ABRE of alendronate. The present study examined in mice the modulating effects of etidronate on the inflammatory and necrotic actions of zoledronate (the NBP with the strongest anti-bone-resorptive activity and the highest incidence of osteonecrosis of the jaw) and on ABREs of various NBPs including zoledronate. MATERIALS AND METHODS: NBPs were subcutaneously injected into ear pinnas of mice and ensuing inflammation and necrosis at the site of the injection were evaluated. ABREs of NBPs were evaluated by analyzing sclerotic bands induced in mouse tibias. RESULTS: Coinjection of etidronate reduced inflammatory and necrotic reactions induced by zoledronate, and also reduced the amount of zoledronate retained within the ear tissue. When both agents were intraperitoneally injected, etidronate reduced the ABRE of zoledronate and those of other NBPs. Notably, etidronate reduced the ABRE of zoledronate even when this non-NBP was injected 16 hours after the injection of zoledronate. Bone scintigram indicated that etidronate reduced the amount of zoledronate that had already bound to bone. CONCLUSIONS: These results suggest that etidronate may 1) inhibit the entry of NBPs into cells related to inflammation and/or necrosis, 2) inhibit the binding of NBPs to bone hydroxyapatite, 3) at least partly eliminate (or substitute for) NBPs that have already accumulated within bones, and thus 4) if used as a substitution drug for NBPs, be effective at treating or preventing NBP-associated osteonecrosis of the jaw.

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.

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.

Optimizing orthodontic treatment in patients taking bisphosphonates for osteoporosis.

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 2 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 3 patients who received bisphosphonate therapy are reported.

Fluoride-related bone disease associated with habitual tea consumption.

Acquired osteosclerosis is a rare disorder of bone formation but an important consideration in adults with sclerotic bones or elevated bone density results. In such patients, malignancy, hepatitis C, and fluorosis should all be considered when making a diagnosis. We describe 4 patients evaluated at our Metabolic Bone Disease Clinic from May 1, 1997, to July 1, 2006, whose bone disorders resulted from chronic fluoride exposure due to excessive tea intake. Three of these patients had toxic serum fluoride levels (> 15 micromol/L). Although the clinical presentation of the patients varied, all 4 had an unexpectedly elevated spine bone mineral density that was proportionately higher than the bone mineral density at the hip. Other clinical features included gastrointestinal symptoms such as nausea, vomiting, and weight loss; lower extremity pain sometimes associated with stress fractures of the lower extremities; renal insufficiency; and elevated alkaline phosphatase levels. Readily available, tea often contains high levels of fluoride. Obsessive-compulsive drinking behaviors and renal insufficiency may predispose to excessive fluoride consumption and accumulation. The current cases show that fluoride-related bone disease is an important clinical consideration in patients with dense bones or gastrointestinal symptoms and a history of excessive tea consumption. Furthermore, fluoride excess should be considered in all patients with a history of excessive tea consumption, especially due to its insidious nature and nonspecific clinical presentation.

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.

Health effects of indoor fluoride pollution from coal burning in China.

The combustion of high fluoride-content coal as an energy resource for heating, cooking, and food drying is a major exhaust emission source of suspended particulate matter and fluoride. High concentrations of these pollutants have been observed in indoor air of coal-burning families in some rural areas in China. Because airborne fluoride has serious toxicological properties, fluoride pollution in indoor air and the prevalence of fluorosis have been analyzed in a fluorosis area and a healthy nonfluorosis area in China and in a rural area in Japan. For human health, fluoride in indoor air has not only been directly inhaled by residents but also has been absorbed in stored food such as corn, chilies, and potatoes. In the fluorosis area in China, concentrations of urinary fluoride in the residents have been much higher than in the nonfluorosis area in China and in the rural area in Japan. In the fluorosis area, almost all elementary and junior high school students 10-15 years of age had dental fluorosis. Osteosclerosis in the skeletal fluorosis patients was very serious. Urinary deoxypyridinoline in rural residents in China was much higher than in rural residents in Japan. Data suggest that bone resorption was extremely stimulated in the residents in China and that fluoride may stimulate both bone resorption and bone formation. Because indoor fluoride from combustion of coal is easily absorbed in stored food and because food consumption is a main source of fluoride exposure, it is necessary to reduce airborne fluoride and food contamination to prevent serious fluorosis in China.