Cardamonin inhibits osteogenic differentiation by downregulating Wnt/beta-catenin signaling and alleviates subchondral osteosclerosis in osteoarthritic mice.

Osteoarthritis (OA) is a common degenerative joint disease, and subchondral osteosclerosis is an important pathological change that occurs in its late stages. Cardamonin (CD) is a natural flavonoid isolated from Alpinia katsumadai that has anti-inflammatory activity. The objectives of this study were to investigate the therapeutic effects and potential mechanism of CD in regulating OA subchondral osteosclerosis at in vivo and in vitro settings. Eight-week-old male C57BL/6J mice were randomly divided into four groups: sham operation, anterior cruciate ligament transection (ACLT)-induced OA model, low-dose and high-dose CD treated ACLT-OA model groups. Histological assessment and immunohistochemical examinations for chondrocyte metabolism-related markers metalloproteinase-13, ADAMTS-4, Col II, and Sox-9 were performed. Microcomputed tomography was used to assess the sclerosis indicators in subchondral bone. Further, MC3T3-E1 (a mouse calvarial preosteoblast cell line) cells were treated with various concentrations of CD to reveal the influence and potential molecular pathways of CD in osteogenic differentiations. Animal studies suggested that CD alleviated the pathological changes in OA mice such as maintaining integrity and increasing the thickness of hyaline cartilage, decreasing the thickness of calcified cartilage, decreasing the Osteoarthritis Research Society International score, regulating articular cartilage metabolism, and inhibiting subchondral osteosclerosis. In vitro investigation indicated that CD inhibited alkaline phosphatase expression and production of calcium nodules during osteogenic differentiation of MC3T3-E1 cells. In addition, CD inhibited the expression of osteogenic differentiation-related indicators and Wnt/ß-catenin pathway-related proteins. In conclusion, CD inhibits osteogenic differentiation by downregulating Wnt/ß-catenin signaling and alleviating subchondral osteosclerosis in a mouse model of OA.

Association between lung function and bone mineral density in children and adolescents: Insights from the NHANES.

Bone development and lung function are integral to child and adolescent health. Both influence an individual's overall well-being and potentially affect long-term health. Utilizing a comprehensive dataset from the National Health and Nutrition Examination Survey, this study aims to elucidate the relationship between lung function and bone mineral density (BMD) in a representative sample of children and adolescents. The analysis covered 3410 participants aged 8 to 19 years. We employed weighted multivariate linear regression and restricted cubic spline curve visualizations to explore the intricate association between lung function metrics, particularly first-second expiratory volume 1 second/forced vital capacity ratio, and lumbar BMD. Our data indicated a positive association between lung function and lumbar BMD in children and adolescents. Specifically, higher lung function metrics were linked with increased lumbar BMD. This association was more pronounced in younger participants or those with a lower body mass index. A significant positive relationship exists between lung function and BMD in the pediatric population. Recognizing this association is crucial for holistic health strategies for children and adolescents. This study underscores the need for integrated health monitoring during formative years, which can influence health trajectories as these individuals transition to adulthood.

Non-endemic skeletal fluorosis: Causes and associated secondary hyperparathyroidism (case report and literature review).

Skeletal fluorosis (SF) is endemic primarily in regions with fluoride (F)-contaminated well water, but can reflect other types of chronic F exposure. Calcium (Ca) and vitamin D (D) deficiency can exacerbate SF. A 51-year-old man with years of musculoskeletal pain and opiate use was hypocalcemic with secondary hyperparathyroidism upon manifesting recurrent long bone fractures. He smoked cigarettes, drank large amounts of cola beverage, and consumed little dietary Ca. Then, after 5 months of Ca and D3 supplementation, serum 25(OH)D was 21 ng/mL (Nl, 30-100), corrected serum Ca had normalized from 7.8 to 9.4 mg/dL (Nl, 8.5-10.1), alkaline phosphatase (ALP) had decreased from 1080 to 539 U/L (Nl, 46-116), yet parathyroid hormone (PTH) had increased from 133 to 327 pg/mL (Nl, 8.7-77.1). Radiographs revealed generalized osteosclerosis and a cystic lesion in a proximal femur. DXA BMD Z-scores were +7.4 and +0.4 at the lumbar spine and "1/3" radius, respectively. Bone scintigraphy showed increased uptake in two ribs, periarticular areas, and proximal left femur at the site of a subsequent atraumatic fracture. Elevated serum collagen type I C-telopeptide 2513 pg/mL (Nl, 87-345) and osteocalcin >300 ng/mL (Nl, 9-38) indicated rapid bone turnover. Negative studies included hepatitis C Ab, prostate-specific antigen, serum and urine electrophoresis, and Ion Torrent mutation analysis for dense or high-turnover skeletal diseases. After discovering markedly elevated F concentrations in his plasma [4.84 mg/L (Nl, 0.02-0.08)] and spot urine [42.6 mg/L (Nl, 0.2-3.2)], a two-year history emerged of "huffing" computer cleaner containing difluoroethane. Non-decalcified histology of a subsequent right femur fracture showed increased osteoblasts and osteoclasts and excessive osteoid. A 24-hour urine collection contained 27 mg/L F (Nl, 0.2-3.2) and <2 mg/dL Ca. Then, 19 months after "huffing" cessation and improved Ca and D3 intake, yet with persisting bone pain, serum PTH was normal (52 pg/mL) and serum ALP and urine F had decreased to 248 U/L and 3.3 mg/L, respectively. Our experience combined with 15 publications in PubMed concerning unusual causes of non-endemic SF where the F source became known (19 cases in all) revealed: 11 instances from high consumption of black tea and/or F-containing toothpaste, 1 due to geophagia of F-rich soil, and 7 due to "recreational" inhalation of F-containing vapors. Circulating PTH measured in 14 was substantially elevated in 2 (including ours) and mildly increased in 2. The severity of SF in the cases reviewed seemed to reflect cumulative F exposure, renal function, and Ca and D status. Several factors appeared to influence our patient's skeletal disease: i) direct anabolic effects of toxic amounts of F on his skeleton, ii) secondary hyperparathyroidism from degradation-resistant fluorapatite bone crystals and low dietary Ca, and iii) impaired mineralization of excessive osteoid due to hypocalcemia.

A Rare Cause of Hypophosphatemia: Raine Syndrome Changing Clinical Features with Age.

Raine Syndrome (RS) is caused by biallelic loss-of-function mutations in FAM20C gene and characterized by hypophosphatemia, typical facial and skeletal features. Subperiosteal bone formation and generalized osteosclerosis are the most common radiological findings. Here we present a new case with RS. A 9-month-old male patient on a home-type ventilator was referred for hypophosphatemia. He was born with a weight of 3800 g to non-consanguineous parents. Prenatal ultrasound had demonstrated nasal bone agenesis. A large anterior fontanel, frontal bossing, exophthalmos, hypoplastic nose, high arched palate, low set ears, triangular mouth, and corneal opacification were detected on physical examination. Serial skeletal X-rays revealed diffuse osteosclerosis at birth which was gradually decreased by the age of 5 months with subperiosteal undermineralized bone formation and medullary space of long bone could be distinguishable with bone-within-a-bone appearance. At 9 months of age, hand X-ray revealed cupping of the ulna with loose radial bone margin with minimal fraying and osteopenia. Cranial computed tomography scan showed bilateral periventricular calcification and hydrocephalus in progress. The clinical, laboratory, and radiological examinations were consistent with RS. Molecular analyses revealed a compound heterozygous mutation in FAM20C gene (a known pathogenic mutation, c.1645C > T, p.Arg549Trp; and a novel c.863 + 5 G > C variant). The patient died due to respiratory failure at 17 months of age. This case allowed us to demonstrate natural progression of skeletal features in RS. Furthermore, we have described a novel FAM20C variant causing RS. Previous literature on RS is also reviewed.

Human Genetics of Sclerosing Bone Disorders.

PURPOSE OF REVIEW: The group of sclerosing bone disorders encompasses a variety of disorders all marked by increased bone mass. In this review, we give an overview of the genetic causes of this heterogeneous group of disorders and briefly touch upon the value of these findings for the development of novel therapeutic agents. RECENT FINDINGS: Advances in the next-generation sequencing technologies are accelerating the molecular dissection of the pathogenic mechanisms underlying skeletal dysplasias. Throughout the years, the genetic cause of these disorders has been extensively studied which resulted in the identification of a variety of disease-causing genes and pathways that are involved in bone formation by osteoblasts, bone resorption by osteoclasts, or both processes. Due to this rapidly increasing knowledge, the insights into the regulatory mechanisms of bone metabolism are continuously improving resulting in the identification of novel therapeutic targets for disorders with reduced bone mass and increased bone fragility.

Characterization of nano-structural and nano-mechanical properties of osteoarthritic subchondral bone.

BACKGROUND: Although articular cartilage is the primary tissues affected by osteoarthritis (OA), the underlying subchondral bone also undergoes noticeable changes. Despite the growing body of research into the biophysical and mechanical properties of OA bone there are few studies that have analysed the structure of the subchondral sclerosis at the nanoscale. In this study, the composition and nano-structural changes of human osteoarthritis (OA) subchondral bone were investigated to better understand the site-specific changes. METHODS: OA bone samples were collected from patients undergoing total knee replacement surgery and graded according to disease severity (grade I: mild OA; grade IV: severe OA). Transmission electron microscopy (TEM), Electron Diffraction, and Elemental Analysis techniques were used to explore the cross-banding pattern, nature of mineral phase and orientation of the crystal lattice. Subchondral bone nano-hydroxyapatite powders were prepared and characterised using high resolution transmission electron microscopy (HR-TEM) and fourier transform infrared spectroscopy (FTIR). Subchondal bone mechanical properties were investigated using a nano-indentation method. RESULTS: In grade I subchondral bone samples, a regular periodic fibril banding pattern was observed and the c-axis orientation of the apatite crystals was parallel to the long axis of the fibrils. By contrast, in grade IV OA bone samples, the bulk of fibrils formed a random and undulated arrangement accompanied by a circular oriented pattern of apatite crystals. Fibrils in grade IV bone showed non-hierarchical intra-fibrillar mineralization and higher calcium (Ca) to phosphorous (P) (Ca/P) ratios. Grade IV OA bone showed higher crystallinity of the mineral content, increased modulus and hardness compared with grade I OA bone. CONCLUSIONS: The findings from this study suggest that OA subchondral sclerotic bone has an altered mineralization process which results in nano-structural changes of apatite crystals that is likely to account for the compromised mechanical properties of OA subchondral bones.

Osteosclerosis and inhibition of human hematopoiesis in NOG mice expressing human Delta-like 1 in osteoblasts.

NOD/Shi-scid IL2rγnull (NOG) mice with severe immunodeficiency are excellent recipients to generate "humanized" mice by the transplantation of human CD34(+) hematopoietic stem cells (HSCs). In this study, we developed NOG mice carrying a human Delta-like1 (DLL1) gene, which is a ligand of the Notch receptor and is known to be important in HSC maintenance and self-renewal. We also analyzed the effect of DLL1 signaling on human hematopoiesis and HSC maintenance using humanized DLL1 transgenic NOG mice. To develop DLL1 transgenic NOG (NOG-D1-Tg) mice, a transgenic vector consisting of a human DLL1 complementary DNA fragment placed downstream of the α1(I) collagen (Col1a1) promoter for expression specifically in osteoblasts was constructed. Human CD34(+) HSCs were transplanted into NOG-D1-Tg mice, and differentiation of lymphoid or myeloid lineage cells from human HSCs and maintenance of HSCs in bone marrow were analyzed. Severe osteosclerosis accompanied by increased bone mass and a decreased number of bone marrow cells were observed in NOG-D1-Tg mice. After human HSC transplantation, development of human B lymphocytes, but not T lymphocytes, was significantly suppressed in both bone marrow and the periphery of NOG-D1-Tg mice. Contrary to the initial expectation, retention of human CD34(+) HSCs was inhibited in the bone marrow of NOG-D1-Tg mice. In conclusion, our data suggest that the development of human B lymphocytes and HSC maintenance in osteosclerotic bone may be suppressed by introducing DLL1. These unique humanized mice with sclerotic bone reconstituted by human HSCs are useful models of hematopoiesis in patients with osteosclerosis, such as osteopetrosis, and for investigation of osteogenesis via Notch signaling.

[Osteopathia striata with cranial sclerosis]. / Osteopatía estriada con esclerosis craneal.

Osteopathia striata with cranial sclerosis is a rare disease: fewer than 100 cases have been reported. The radiologic findings of osteopathia striata are characteristic, and once they are identified, they lead to the correct diagnosis. Longitudinal sclerotic striation in long bones and osteosclerosis in facial bones should raise suspicion of osteopathia striata with cranial sclerosis. This is not a serious disease, although it is often associated with other kinds of disorders and extraskeletal malformations that can affect the prognosis. Involvement of cranial and facial bones can lead to facial deformity and marked functional incapacity when the cranial nerves are affected. We present a case of osteopathia striata with cranial sclerosis discovered incidentally in a young woman studied for clinical manifestations unrelated to this disease.

Skeletal fluorosis from brewed tea.

BACKGROUND: High fluoride ion (F(-)) levels are found in many surface and well waters. Drinking F(-)-contaminated water typically explains endemic skeletal fluorosis (SF). In some regions of Asia, however, poor quality "brick tea" also causes this disorder. The plant source of brick, black, green, orange pekoe, and oolong tea, Camellia sinensis, can contain substantial amounts of F(-). Exposure to 20 mg F(-) per day for 20 yr of adult life is expected to cause symptomatic SF. High F(-) levels stimulate osteoblasts and enhance bone apposition but substitute for OH(-) groups in hydroxyapatite crystals and thereby result in skeletal fragility and perhaps lead to secondary hyperparathyroidism. Beginning in 2005, we showed that daily consumption of 1-2 gallons of instant tea made from this plant can lead to SF. AIM: We describe a 48-yr-old American woman who developed SF from brewed tea. PATIENT AND METHODS: Our patient had elevated bone mineral density revealed by dual-energy x-ray absorptiometry (spine Z-score, +9.9), severe chronic bone and joint pain, and kyphosis after consuming 1-2 gallons of brewed orange pekoe tea daily for more than three decades. F(-) levels were high in her serum, urine, and clippings of fingernails and toenails, as well as in our reproduction of her beverage. Renal function was normal. She had vitamin D deficiency. Elevated serum PTH levels were unresponsive to adequate vitamin D supplementation. Pain resolved over several months when she stopped drinking tea and continued ergocalciferol. CONCLUSION: Our patient shows that SF can result from chronic consumption of large volumes of brewed tea.

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.

[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.

[Osteopathia striata with cranial sclerosis]. / Osteopatia estriada com esclerose craniana.

We report on a female patient who presented failure to thrive, laryngotracheomalacia, conductive deafness and facial dysmorphisms. A skeletal survey revealed thickening of the cranial vault, linear striations in the diametaphyses of all long bones and fan-like striations of the iliac bones. CT scan of the temporal bone showed thickening of the cranial base, sclerotic mastoids, abnormal ossicular fixation and stenosis of the otic foramina. The radiological findings led to the diagnosis of Osteopathia Striata with Cranial Sclerosis. A mutation in WTX gene confirmed the clinical and radiological diagnosis of Osteopathia Striata with Cranial Sclerosis in this patient and allowed proper genetic counseling and providing prenatal diagnosis.

X-ray analysis on 114 patients with moderate endemic skeletal fluorosis by treatment of Guo's Chinese herbal / 中国骨伤

<p><b>OBJECTIVE</b>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.</p><p><b>METHODS</b>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).</p><p><b>RESULTS</b>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).</p><p><b>CONCLUSION</b>There is no obvious improvement in radiology of patients with skeletal fluorosis treated by Guo's therapy.</p>

Bone resorption increases tumour growth in a mouse model of osteosclerotic breast cancer metastasis.

Osteosclerotic metastases account for 20% of breast cancer metastases with the remainder osteolytic or mixed. In mouse models, osteolytic metastases are dependent on bone resorption for their growth. However, whether the growth of osteosclerotic bone metastases depends on osteoclast or osteoblast actions is uncertain. In this study, we investigate the effects of high and low bone resorption on tumour growth in a mouse model of osteosclerotic metastasis. We implanted human breast cancer, MCF-7, cells into the tibiae of mice. Low and high levels of bone resorption were induced by osteoprotegerin (OPG) treatment or calcium deficient diet respectively. We demonstrate that OPG treatment significantly reduces tumour area compared to vehicle (0.42 +/- 0.06 vs. 1.27 +/- 0.16 mm2, P < 0.01) in association with complete inhibition of osteoclast differentiation. In contrast, low calcium diet increases tumour area compared to normal diet (0.90 +/- 0.30 vs. 0.58 +/- 0.20 mm2, P < 0.05) in association with increased osteoclast numbers (84.44 +/- 5.18 vs. 71.11 +/- 3.56 per mm2 bone lesion area, P < 0.05). Osteoblast surfaces and new woven bone formation were similarly increased within the tumour boundaries in all treatment groups. Tumour growth in this model of osteosclerotic metastasis is dependent on ongoing bone resorption, as has been observed in osteolytic models. Bone resorption, rather than bone formation, apparently mediates this effect as osteoblast surfaces in the tumour mass were unchanged by treatments. Treatment of breast cancer patients through correction of calcium deficiency and/or with anti-resorptive agents such as OPG, may improve patient outcomes in the adjuvant as well as palliative settings.

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.

Defining a noncarcinogenic dose of recombinant human parathyroid hormone 1-84 in a 2-year study in Fischer 344 rats.

The carcinogenic potential of human parathyroid hormone 1-84 (PTH) was assessed by daily subcutaneous injection (0, 10, 50, 150 microg/kg/day) for 2 years in Fischer 344 rats. Histopathological analyses were conducted on the standard set of soft tissues, tissues with macroscopic abnormalities, selected bones, and bones with abnormalities identified radiographically. All PTH doses caused widespread osteosclerosis and significant, dose-dependent increases in femoral and vertebral bone mineral content and density. In the mid-and high-dose groups, proliferative changes in bone increased with dose. Osteosarcoma was the most common change, followed by focal osteoblast hyperplasia, osteoblastoma, osteoma and skeletal fibrosarcoma. The incidence of bone neoplasms was comparable in control and low-dose groups providing a noncarcinogenic dose for PTH of 10 microg/kg/day at a systemic exposure to PTH that is 4.6-fold higher than for a 100 microg dose in humans. The ability of PTH to interact with and balance the effects of both the PTH-1 receptor and the putative C-terminal PTH receptor, may lead to the lower carcinogenic potential observed with PTH than reported previously for teriparatide.

A case of hepatitis C-associated osteosclerosis in an elderly Japanese man.

Hepatitis C-Associated Osteosclerosis (HCAO) is characterized by a marked increase in bone mass with deep bone pain. Since 1992, eleven cases of HCAO have been reported. This report describes an elderly Japanese man with HCAO, whose clinical course we followed for 3 years. A 68-year-old man developed pain in both pretibial regions in June 2000, and he had frequent episodic loss of muscular strength in his hands. He had recieved blood transfusion for a bleeding ulcer 43 years before and was seropositive for hepatitis C virus. His serum alkaline phosphatase (ALP) level was markedly increased, while his serum calcium was slightly decreased and serum phosphate was normal. Skeletal radiographs of the lower extremities showed a progressive increase in skeletal density, but did not show any apparent deformity. Administration of nonsteroidal anti-inflammatory drugs led to a reduction in bone pain. Treatment with vitamin D3 and calcium decreased the number of episodes of sudden muscular weakness and maintained serum calcium within the normal range. Three years after the onset of the disease, bone mineral density of his lumbar vertebrae and left hip rose from 0.963 g/cm2 to 1.096 g/cm2, and from 0.938 g/cm2 to 1.383 g/cm2, respectively. His serum ALP level decreased from 2889 to 277 IU/L (normal range: 104-338) and serum calcium normalized. These findings were accompanied by a decrease in bone pain. This case and previous reports suggest that the skeletal tissue of this disease appears to be of good quality.